Tumor necrosis factor

385: 362: 2948:. TNFR2 is only fully activated by tmTNF, while activation by sTNF is partially inhibited. Unlike TNFR1, TNFR2 does not possess a death domain, so it is incapable of directly inducing cell death. Thus, TNFR2 activation most often leads to cell survival. Cell survival can either lead to an inflammatory response, via canonical NF-κB activation, or cell proliferation, via non-canonical NF-κB activation, depending on intracellular conditions and the signaling process of TNFR1. TNFR2 can also indirectly cause cell death by disrupting the cell death checkpoints of TNFR1. 2431: 284: 259: 6289: 2699:. The upper β-sheet consists of three long β-strands supplemented with a loop of two additional β-strands, while the bottom β-sheet consists of five β-strands of steadily decreasing length. The middle β-strand of the bottom β-sheet contains the last 9 residues of the C-terminal, locking it into position. The complete C-terminal has been shown to be vital for bioactivity, whereas up to eight residues can be deleted from the N-terminal without losing bioactivity. A disulphide bridge connects the two longest intersheet loops. 2158:(LPL), an enzyme responsible for breaking down fat in the bloodstream. They injected the serum of endotoxin-treated mice into other mice, and discovered that the serum lowered LPL activity in the recipient mice, even if the recipient mice were resistant to endotoxin itself. This led the authors to deduce that the hypertriglyceridemia was caused not by endotoxin, but by a mediating factor produced by the host in response to endotoxin, termed cachectin. The authors also discovered that endotoxin-incubated 6319: 56: 6304: 6349: 6334: 2258: 391: 290: 2925: 2774: 6274: 3480:, and infiltrating immune cells secrete TNF. TNF is hypothesized to contribute to NAFLD by promoting fat accumulation in the liver, prolonged inflammation, and insulin resistance. Clinical studies have shown that TNF levels are correlated with the severity of NAFLD, although some studies have shown otherwise. Pharmacological strategies that downregulate TNF have shown favorable effects on NAFLD, while the efficacy of TNF blockers is yet to be evaluated. 2765:, a less controlled death causing inflammation and interference in surrounding tissue. TNF induces cell survival by default, but cell death can be induced by factors such as disruption of inflammatory pathways by pathogens, co-stimulation with other cytokines, and cross-talk between TNFR1 and TNFR2. Additionally, transmembrane TNF (tmTNF) acts as a reverse signaler, triggering a variety of responses in its own cell depending on cell type and stimulant. 8126: 3027:, tmTNF has been shown to play a dual role in mediating the monocyte's inflammatory response to sTNF. If tmTNF reverse signaling occurs before a monocyte is activated by sTNF, then the monocyte's inflammatory response to sTNF is enhanced. If tmTNF reverse signaling occurs after a monocyte is activated by sTNF, then the inflammatory response is reduced. Meanwhile, tmTNF reverse signaling reduces a monocyte's inflammatory response to 1977:(BCG), upon exposure to endotoxin, produced serum that could kill sarcomas in other mice. Meanwhile, uninfected mice, upon exposure to endotoxin, produced serum that did not kill tumors. This led the authors to conclude that the tumor-killing serum contained a separate cytotoxic factor that was not endotoxin, but instead produced by the host, termed tumor necrosis factor (TNF). Since BCG-infected mice had enlarged 2672: 8138: 2551:(HSSs), regions of chromatin that are uncondensed and thus accessible to DNA-binding proteins. Several studies have shown that HSSs are present at the TNF promoter and gene region in cells that express TNF, and absent in cells that do not express TNF. Other studies have also shown that HSSs are present in the TNF promoter and gene regions depending on the stimulant used to induct the cell. 2100:, and blood clotting, while also releasing mediators including TNF. Uninfected mice did not release these mediators when injected with endotoxin. These results, combined with evidence of endotoxins in the serum of malaria patients, led the authors to propose that mediators such as TNF are present in acute malaria infections, and that they play a role in causing malaria symptoms. 2481:, that is critical for the activation of TNF in all cell-types and conditions. The CRE and nearby transcription factors form the core composite complexes, while distant transcription factors form anchor complexes. Together, the core complex and the anchor complexes stabilize interactions with coactivators and transcription machinery. The proximal promoter region also contains a 3601:(TRAPS), genetic mutations in TNFR1 lead to defective binding of TNFR1 to TNF, as well as defective shedding of TNFR1, a mechanism that attenuates TNFR1 signaling. This causes periodic inflammation, though the exact mechanism is unknown. TNF blockers such as etanercept have shown partial efficacy in reducing symptoms, while other TNF blockers such as 2068:, constructed by guessing the codons of a portion of the TNF amino acid sequence, was used to screen the cDNA library. The matching cDNA was sequenced, revealing a presequence of 76 amino acids followed by the 157 amino acids of mature TNF. The authors deduced that TNF is first synthesized into a larger precursor form containing a 3448:(IRS1). Under normal circumstances, IRS1, upon activation by insulin, undergoes tyrosine phosphorylation and increases glucose uptake in the cell. This process is disrupted when TNF induces the serine phosphorylation of IRS1, converting IRS1 into an insulin inhibitor. TNF-induced insulin resistance is common in cases of 636: 3588:

hyperphosphorylation found in the brains of Alzheimer's patients. TNF blockers have been associated with reduced risk of developing Alzheimer's. Some studies have shown TNF blockers to slightly improve cognition in Alzheimer's patients, though larger studies are needed. Since TNF blockers cannot pass

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In the third checkpoint, non-lethal caspase 8 is activated by TNFR1 signaling, which binds to complex IIb and cleaves RIPK1, disabling it. It is unknown why this form of caspase 8 does not cause cell death. The disabling of this checkpoint, via inactivation of caspase 8, causes RIPK1 from complex IIb

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tmTNF consists of 233 amino acids, weighs 26 kDa, and is arranged as a homotrimer. tmTNF signals bidirectionally, both into the target cell and into its own cell, by binding to TNF receptors upon cell-to-cell contact. tmTNF binds to both TNFR1 and TNFR2, but its activities are mainly mediated through

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The first exon contains the 5' untranslated region and the majority of the transmembrane portion. The second exon contains a minority of the transmembrane portion and a minority of the soluble portion. The third exon contains a minority of the soluble portion. The fourth exon contains the majority of

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and soluble TNF receptors, both of which also inhibit TNF. While moderate exercise does not increase TNF levels, strenuous exercise has been shown to increase TNF levels two-fold, causing a pro-inflammatory effect. However, this proinflammatory effect is outweighed by the anti-inflammatory effect of

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TNFR2 can indirectly induce cell death by degrading cIAP1/2 as part of the non-canonical NF-κB pathway. The degradation of cIAP1/2 affects the ubiquitination of the TNFR1 signaling complex, which inhibits the function of IKK. This disables the IKK cell death checkpoint in TNFR1, inducing cell death.

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which activates the non-canonical NF-κB pathway, leading to cell proliferation. The expression of p100 and RelB is potentiated by the activation of the canonical NF-κB pathway by TNFR1. Thus, TNFR2 non-canonical NF-κB activation is dependent on the canonical NF-κB activation by TNFR1, as well as the

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Much of TNF's functions are mediated through inflammatory signaling pathways, such as MAPK and NF-κB. Many pathogens attempt to prevent an immune response by hijacking cells and disrupting their inflammatory pathways. In response to this, the TNFR1 signaling pathway has cell death pathways that are

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TNFR2 can also activate the canonical NF-κB pathway, though this is less common than non-canonical NF-κB activation. The details of TNFR2's activation of the canonical NF-κB pathway are unknown. Presumably, TAK1 and IKK are recruited by the TRAF2 / TRAF1/3 / cIAP1/2 signaling complex, which in turn

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while it is attached to complex I. This disables complex IIb, which is dependent on RIPK1. Since IKK is dependent on the ubiquitination of complex I, conditions that affect ubiquitination, such as inhibition of cIAP1/2 and LUBAC, mutation of the RIPK1 ubiquitin acceptor site, or deficiencies of A20

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in its cytoplasmic tail, enabling it to trigger cell death. Whether TNFR1 activation triggers cell survival or cell death is mediated by the formation of protein complexes: complex I, which leads to cell survival, and complex II, which leads to cell death. By default, TNFR1 activation triggers cell

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have been discovered that form stable TNF dimers with a shape that inhibits the transition to TNF trimers. Inhibiting the formation of TNF trimers by altering the shape of inactive TNF monomers and dimers presents an alternative mechanism for inhibiting TNF, in contrast to current TNF blockers that

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Paradoxically, TNF-blockers can cause demyelination of neurons and worsen multiple sclerosis symptoms. This is believed to be due to the homeostatic role of TNF in the central nervous system, especially on neuron myelination via TNFR2. The selective blockade of TNFR1 has shown positive outcomes in

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in the skin or intestine may affect barrier integrity, allowing microbes to infiltrate tissue and induce inflammation. It is believed that TNF triggers cell death in inflammatory diseases due to elevated levels of interfering cytokines, elevated levels of TNFR2 signaling, or genetic mutations that

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has been shown to play an important role in regulating the gene expression of TNF. However, it is unclear whether NF-κB activates TNF transcription by binding directly to sites in the promoter region, or through secondary effects. Of the six sequences identified as potential NF-κB binding sites in

2877:, leading to cell death. Complex IIa includes TRADD and can activate caspase 8 without RIPK1, while complex IIb does not include TRADD, so it is dependent on RIPK1 for the activation of caspase 8. The pathways of complex I induce three checkpoints that prevent complex II from inducing cell death. 2718:

The disassembly of TNF trimers happens at a constant rate independent of TNF concentration, whereas the assembly of TNF trimers increases with TNF concentration. Thus, at high TNF concentrations, the concentration of TNF trimers is higher, while at low TNF concentrations, the concentration of TNF

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the human TNF promoter region, only 1 is in the proximal promoter region. Furthermore, the deletion or mutation of these binding sites does not affect the activation of the TNF gene by endotoxin induction, indicating that NF-κB may not influence TNF expression by directly binding to the promoter.

3306:. However, TNF is now known to play a dual role in cancer, both as a promoter and inhibitor, due its ability to induce either proliferation or death in tumor cells. The exact mechanisms determining which role TNF plays in cancer are unclear. In general, TNF is considered to be a cancer promoter. 1877:

TNFR1 can trigger inflammatory pathways, producing effects such as cell survival and proliferation, as well as cell death if the inflammatory pathways are disrupted. TNFR2 can only trigger cell survival and proliferation, but can indirectly induce cell death by disrupting TNFR1. tmTNF also sends

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Although TNF blockers showed efficacy in treating sepsis in mice, they showed mixed results in treating sepsis in humans. This is believed to be due to the dual role that TNF plays in the immune system; blocking TNF reduces the severe inflammation that causes sepsis, but also hinders the immune

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In some cancers, TNF has been shown to play an inhibitory role, primarily when injected locally, repeatedly, and at high concentrations. Due to TNF's adverse side effects, potential TNF cancer treatments seek to maximize cytotoxicity to tumors while minimizing exposure to the entire body. Some

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Long range intrachromosomal and interchromosomal interactions have also been found to regulate TNF gene expression. For example, in activated T cells, the TNF promoter interacts with HSS+3 and HSS-9, bringing distal enhancers closer to the TNF promoter and increasing the local concentration of

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Similar to tmTNF, sTNF is also arranged as a homotrimer, forming a conical shape. The three sTNF monomers join together using edge-to-face packing. The upper sheets of the sTNF monomers form the outer surface of the trimer cone, while the lower sheets form the inner surface. The outer surface

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In 1985, Beutler et al. demonstrated that mouse cachectin has similar cytotoxicity against L-929 cells as TNF, as well as a near identical N-terminal amino acid sequence to human TNF, indicating that cachectin and TNF were the same protein. Since cachectin (now TNF) is known to suppress the

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In 1991, Michael Goodman demonstrated that mice injected with TNF released increased levels of tyrosine and 3-methyl-L-histidine in their skeletal muscles, indicating that TNF induces muscle breakdown. In 1996, Stefferl et al. demonstrated that mice injected with mouse TNF develop fevers,

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assemble into high-order structures to activate transcription. The proximal promoter region, spanning approximately 200 base pairs before the transcribed region, contains multiple transcription factor binding sites, many of which can recognize more than one type of transcription factor.

1962:, when injected into mice with sarcomas, could inhibit tumor growth or cause tumor regression. However, tumor regression was highly variable, with smaller doses of endotoxin often having more potency than larger doses, or entire batches of mice being resistant to the endotoxin. 82: 3131:

inhibited by the activities of the inflammatory pathways. If a cell's inflammatory pathways are disrupted, the cell death pathways are uninhibited, triggering cell death. This prevents the pathogen from replicating within the cell, as well as alerting the immune system.

2190:; and both proteins shared significant genetic and amino acid homology. The similarities between TNF and lymphotoxin led to the unofficial renaming of TNF to TNF-α and lymphotoxin to TNF-β, with the published rationale being that both were detected with the same method. 3288:

TNF contributes to inflammatory disease both by activating inflammatory pathways in target cells, as well as by triggering cell death. Cell death triggers inflammation by exposing the intracellular components of dying cells to neighboring cells. Additionally, death of

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disable cell death checkpoints. In animal models, the activation of cell death alone is enough to trigger autoinflammatory diseases. Drugs that target specifically the cell death pathway of TNF are being evaluated for their efficacy against autoinflammatory diseases.

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ENSG00000230108, ENSG00000223952, ENSG00000204490, ENSG00000228321, ENSG00000232810, ENSG00000228849, ENSG00000206439 GRCh38: Ensembl release 89: ENSG00000228978, ENSG00000230108, ENSG00000223952, ENSG00000204490, ENSG00000228321, ENSG00000232810, ENSG00000228849,

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Rarely, the suppression of TNF can lead to the development of a new form of "paradoxical" autoimmunity. The absence of TNF is hypothesized to promote paradoxical autoimmunity by causing overexpression of other cytokines and amplifying the prevalence of T cells.

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due to its ability to upregulate the innate immune system and blood coagulation. In animals, the injection of TNF can produce heart, lung, kidney, and liver dysfunction similar to sepsis. However, in humans suffering sepsis, TNF is not consistently elevated.

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Thus, while the TNF / lymphotoxin-α ancestor gene is found across a variety of gnathostome species, only a subset of gnathostome species contain a TNF gene. The TNF gene has been found in fish, mammals, birds, and amphibians. Some fish species, such as

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TNF is the principal cytokine for regulating acute inflammation, though many of its functions are shared with other cytokines, especially IL-1. By binding to TNF receptors, TNF can perform functions including: stimulating endothelial cells to induce

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In many cancers, TNF is believed to play a supportive role. High TNF expression levels are associated with more advanced cancers, and TNF expression is found in tumor cells from early stages of disease. TNF expression can lead to the recruitment of

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tmTNF can act as a receptor, activating pathways within its own cell upon binding to TNFR1 or TNFR2. tmTNF reverse signaling can induce apoptosis, apoptosis resistance, inflammation, or inflammation resistance depending on the ligand and cell type.

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in and around the tumors, causing the tumors to hemorrhage. However, the effectiveness of this treatment was inconsistent and repeated injections caused severe side effects such as chills and fevers, causing the treatment to be discontinued.

2733:. However, it is not established whether TNF fully satisfies the criteria of a morpheein, such as the requirement that transitions between oligomeric forms involve dissociating into subunits before reassociating into the new oligomeric form. 2643:

tmTNF consists of an intracellular portion of 30 amino acids, a transmembrane portion of 26 amino acids, and an extracellular portion of 177 amino acids. The cysteine residue at the boundary of the intracellular and transmembrane portions is

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IL-6, which can increase 50-fold. Regular exercise has been shown to reduce base TNF levels in the long-term. Thus, exercise is generally considered to inhibit TNF, which contributes to the overall anti-inflammatory effect of exercise.

1913:, although TNF inhibition has yet to show definitive benefits. Due to the important role of TNF in innate immunity and homeostasis, the inhibition of TNF can lead to increased risk of infections and new "paradoxical" autoimmunities. 2648:, making it more hydrophobic and attracted to the cell membrane. The intracellular portion contains serine residues that are highly conserved between species and essential for signaling into the cell. These serine residues are also 3624:

TNF blockers operate by binding to one or both forms of TNF to prevent it from binding to its receptors. Additionally, they can trigger tmTNF reverse signaling to induce apoptosis, eliminating TNF-expressing cells. Some are

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split. This ancestor gene was dropped from the Agnatha ancestor, but persisted in the Gnathostomata ancestor. During the evolution of gnathostomes, this ancestor gene was duplicated into the TNF and lymphotoxin-α genes.

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pathway. The MAPK pathways and the NF-κB pathway activate multiple transcription factors in the nucleus, which result in cell survival, proliferation, and an inflammatory response. Complex I is negatively regulated by

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Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, et al. (March 1993). "Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface".

2213:, distinguishing its biological function from TNF. As a result of these developments, TNF-β was renamed to lymphotoxin-α, and TNF-α was renamed back to TNF. Nevertheless, some papers continue to use the term TNF-α. 2458:. If NFAT levels are high, such as in T cells upon ionomycin stimulation, the enhanceosome will consist mostly of NFATs bound at NFAT binding sites. If NFAT levels are low, the enhanceosome will consist mostly of 2004:

became the standard technique for detecting TNF. TNF was cytotoxic to cancerous and transformed cell lines, but not to normal, untransformed cell lines, raising hopes that it could be used as a cancer therapy.

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Upon binding to tmTNF, TNFR2 trimerizes and directly recruits TRAF2, as well as TRAF1 or TRAF3. TRAF2 is central to the TNFR2 signaling complex, and recruits cIAP1/2. If there is an accumulation of

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Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, et al. (December 1985). "Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin".

3500:, which are responsible for protein regeneration. However, TNF blockers have had limited effect on muscle wasting in clinical studies, likely due to the multifactorial nature of muscle wasting. 3425:

infection, TNF induces hepatocyte death and acute liver failure. The remnants of dead hepatocytes are consumed by HSCs and Kupffer cells, which then secrete fibrosis-promoting factors, such as

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treatments increase cytotoxicity by inhibiting the cell survival pathways of tumors before treatment with TNF. Other treatments localize TNF activity using antibody-TNF fusions, also known as

3281:. In these diseases, TNF is erroneously secreted by immune cells in response to environmental factors or genetic mutations. TNF then triggers an inflammatory response, damaging normal tissue. 2715:, which then folds its tertiary structures into the compact, bioactive TNF trimer. The assembly and disassembly of TNF trimers are reversible, and includes the accumulation of TNF dimers. 4373:

Shear MJ, Perrault A (April 1944). "Chemical Treatment of Tumors. IX. Reactions of Mice with Primary Subcutaneous Tumors to Injection of a Hemorrhage-Producing Bacterial Polysaccharide".

6288: 2182:, was discovered. TNF and lymphotoxin shared several similarities: both were detected based on their ability to kill L-929 cells; both were able to bind to the two known TNF receptors, 2162:

cells, consisting mostly of macrophages, produced a medium that also lowered LPL activity in mice. This indicated that cachectin was secreted by macrophages in response to endotoxin.

2041:, whereas TNF purified using TSK-HPLC under nondenaturing conditions was determined to have an approximate molecular weight of 45,000 kDa, suggesting that TNF naturally exists as an 2587:

The TNF gene is very similar among mammals, ranging from 233 to 235 amino acids. The TNF proximal promoter region is also highly conserved among mammals, and nearly identical among

1862:. It is expressed in response to pathogens, other cytokines, and environmental stressors. TNF is initially produced as a type II transmembrane protein (tmTNF) and assembled as a 3417:

death, the initial event that drives liver injury and fibrosis, may be induced by TNF, though this connection is uncertain. TNF injection alone does not induce hepatocyte death

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reverse signals into its own cell, leading to cell death or survival depending on circumstances. TNF's effects on the immune system include the activation of white blood cells,

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Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, et al. (August 1985). "Identity of tumour necrosis factor and the macrophage-secreted factor cachectin".

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either through circulation in the bloodstream, or through secretion by macrophages and endothelial cells near the hypothalamus. TNF can also induce fever by stimulating the

3123:. In addition to inducing the secretion of cytokines, TNF itself can be induced by cytokines, enabling a cascade of inflammatory signals. Excessive amounts of TNF can cause 2786:

proliferation and inflammation rather than cell death. These inflammatory pathways contain three cell death checkpoints, each of which is critical in preventing cell death.

2466: 2422:, which translocate to the nucleus to begin TNF transcription. The transcription factors that regulate TNF expression vary depending on the cell type and stimulus involved. 3221:, a zinc-binding protein, by astrocytes. The modulation of excitation and inhibition of neurons by TNF indicates that TNF plays a role in synaptic scaling and plasticity. 3346:

TNF plays a critical role in the innate immune response to infections. Accordingly, the use of TNF blockers is associated with increased risks of infection, such as with

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has also been shown to regulate TNF gene expression, such as the methylation of lysine 4 of histone H3 at the TNF promoter following stimulation of TNF-expressing cells.

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were resistant to the lethal effects of endotoxin, indicating that TNF is one of the mediators of endotoxin lethality. In 1986, this was confirmed by Kevin J. Tracy and

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system's ability to resist the infection. It is hypothesized that TNF blockers are more beneficial in cases of severe sepsis, where the probability of death is higher.

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within the cell, TRAF2/3 and cIAP1/2 may be formed as a complex with inactive NIK. When TRAF2/3 binds to TNFR2, the attached NIK is activated, which in turn activates

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and reduced food intake. It is hypothesized that TNF reduces food intake by increasing sensitivity to bitter taste, though the exact mechanisms of this are unknown.

2591:. The similarity of the TNF gene among fish is lower, ranging from 226 to 256 amino acids. Like mammalian TNF, the fish TNF gene has been shown to be stimulated in 4715:

Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, et al. (October 1986). "Shock and tissue injury induced by recombinant human cachectin".

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Shear MJ, Perrault A (August 1943). "Chemical Treatment of Tumors. VI. Method Employed in Determining the Potency of Hemorrhage-Producing Bacterial Preparations".

2556: 2904:, as well as by the disabling of the IKK complex, which controls the NF-κB pathway. The disabling of this checkpoint activates complex IIa, leading to apoptosis. 2281:, which is not included in the TNF protein; the transmembrane portion, which is present in transmembrane TNF but not in soluble TNF; the soluble portion; and the 2757:

in a target cell. The cell survival response includes cell proliferation and the activation of inflammatory signals, while the cell death response can either be

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Beutler B, Milsark IW, Cerami AC (August 1985). "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin".

2072:, before being processed and released as a smaller mature form. The authors also synthesized TNF in E. coli and verified its cytotoxicity against L-929 cells 2659:, causing the intracellular domain to translocate to the nucleus, where it is believed to regulate cytokine production, such as triggering the expression of 6318: 4108:"Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications" 1499: 7892: 5301: 1480: 220: 7497: 3311: 2893:. The disabling of the IKK checkpoint can also indirectly activate complex IIa by disabling the NF-κB pathway, which controls the second checkpoint. 2655:

Upon cleavage by TACE, the tailing 157 amino acids of the extracellular portion, forming sTNF, are secreted. The remaining tmTNF is cleaved again by

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In September 1981, Masanobu Kawakami and Anthony Cerami investigated the tendency of endotoxins to cause high levels of fat in the blood, known as

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The TNF and lymphotoxin-α genes are believed to be descended from a common ancestor gene that developed early in vertebrate evolution, before the

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in HIV-infected people. TNF blockage has reportedly led to clinical improvement in HIV without worsening the infection, though data is limited.

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around nerve cells. On the other hand, TNF becomes cytotoxic to oligodendrocyte progenitor cells when the cells are in contact with astrocytes.

8103: 7633: 7623: 7597: 7587: 7557: 6965: 3741: 6303: 3723: 8083: 7953: 7948: 7732: 7692: 7490: 6348: 6333: 7712: 3512:, a TNF inhibitor, rapidly increases, leading to an anti-inflammatory effect. This is followed by a subsequent increase in the levels of 7717: 7628: 7592: 2524:

TNF gene expression is regulated by modifications to histones, around which DNA is wrapped. TNF activation is associated with multiple

3557:. As a result, TNF is seen to play an important role in central nervous system disorders associated with neuroinflammation, including 3432:

TNF blockers are not used to treat liver fibrosis. In clinical trials of alcoholic hepatitis, TNF blockers had no significant effect.

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sTNF consists of 157 amino acids, weighs 17kDa, and is shaped like a triangular wedge. The secondary structure of sTNF consists of 10

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families, as well as endotoxin-induced TNF-α factor (LIPAF). However, their effect on TNF gene expression is yet to be fully studied.

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biosynthesis of a specific protein, lipoprotein lipase, the authors deduced that TNF's cytotoxic mechanism operated in a similar way.

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Hlodan R, Pain RH (July 1995). "The folding and assembly pathway of tumour necrosis factor TNF alpha, a globular trimeric protein".

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TNF is activated in response to signals of infection, inflammation, or stress. Such stimuli are often pathogenic, such as bacterial

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consisting of 1,669 nucleotides. The proximal promoter region is approximately 200 base pairs long. TNF is denoted as TNFSF2 in the

2237:. It is 250 kilobases centromeric of the HLA-B locus, 850 kilobases telomeric of the HLA-DR, and 1,100 base pairs downstream of the 3589:

through the blood–brain barrier, it is believed that reducing TNF levels across the body also reduces TNF levels within the brain.

2296:(ARE) that regulates translational repression and mRNA stability. Deletion of this sequence in mice leads to increased TNF levels, 2900:, which counteracts the activation of caspase 8 in complex IIa. This checkpoint can be disabled by translation inhibitors such as 2025:, a human cell line, with phorbol myristate acetate (PMA), a phagocyte stimulant similar to endotoxin. The TNF was purified using 6969: 1938:. Coley was able to successfully treat cancer patients by injecting them with a mixture of bacterial toxins from heat-sterilized 1901:, and the inhibition of TNF is often an effective treatment. TNF is also implicated in the pathology of other diseases including 2559:

the TNF gene and allow for the recycling of transcription machinery, enabling the rapid and early expression of TNF in T cells.

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and OUTLIN, can disable this checkpoint. The disabling of the IKK checkpoint activates complex IIb, leading to apoptosis, or

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The observation that TNF induces wasting and endotoxic shock led to rethinking about its potential role as a cancer therapy.

3706: 8158: 79: 3684: 3410:, which should inhibit liver fibrosis. In general, TNF is considered to promote liver fibrosis by promoting HSC survival. 2996:, tmTNF reverse signaling has been shown to increase NF-κB activity, enhancing cell survival and apoptosis resistance. In 7788: 6389: 5772:"The evolving experience with therapeutic TNF inhibition in sepsis: considering the potential influence of risk of death" 4795:"The role of TNF-alpha in fever: opposing actions of human and murine TNF-alpha and interactions with IL-beta in the rat" 3167: 3103:, which obstructs blood flow to prevent the spread of microbes; stimulating endothelial cells and macrophages to secrete 191:, DIF, TNF-alpha, TNFA, TNFSF2, Tumour necrosis factor, TNF-α, tumor necrosis factor, TNLG1F, Tumor necrosis factor alpha 3330:, as well as direct activation of pathways that promote tumor survival, invasion, and metastasis. TNF-blockers such as 2729:

The ability of TNF to form functionally distinct dimers and trimers that coexist in equilibrium suggests that TNF is a

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did not induce a response in most advanced or metastatic cancers, but some studies have shown disease stabilization.

2474: 2407: 2246: 1828: 3908:"The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics" 2488:

The flexibility of the enhanceosome enables the TNF gene to be activated by a wide range of cell types and stimuli.

7612: 7576: 5478:"Expanding the Concepts in Protein Structure-Function Relationships and Enzyme Kinetics: Teaching using Morpheeins" 3469: 2234: 2187: 2183: 361: 2504:

Other transcription factors have been found to potentially influence TNF gene expression, such as proteins of the

7813: 6785: 3710: 3689: 3119:; inducing catabolism of muscles and fat to produce energy; and stimulating scar tissue formation, also known as 2282: 1886:, among others. The activity of TNF extends beyond the immune system, such as contributing to homeostasis in the 3240:

Excessive levels of inflammatory cytokines, such as during infection or autoimmunity, have been associated with

7567: 5898:"The Role of Tumor Necrosis Factor-Alpha in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease" 2537: 2278: 2119:, when they demonstrated that mice injected with TNF exhibited common symptoms of endotoxin poisoning, such as 1950:

In the 1930s and 1940s, Shear et al. isolated the active tumor-hemorrhaging agent from the bacterial toxins of

1574: 6562: 6297:: THE STRUCTURE OF TUMOR NECROSIS FACTOR-ALPHA AT 2.6 ANGSTROMS RESOLUTION. IMPLICATIONS FOR RECEPTOR BINDING 3064: 2675:

Structure of a single TNF monomer. α-helix in red, β-strands in blue, disulphide bridge in yellow (PDB: 1TNF)

2513: 2034: 4153: 1555: 1551: 1547: 1537: 1533: 1529: 1525: 1521: 3445: 2368: 283: 258: 200: 3566: 3460:

tissue of humans and animals with obesity, though it remains unclear why obesity induces high TNF levels.

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Previous studies showed inconclusive results due to the use of human TNF, rather than mouse TNF, on mice.

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of human TNF. A cDNA library was constructed from the mRNA of HL-60 cells induced by PMA. A 42-base long

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Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, et al. (September 1985).

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the soluble portion and the 3' untranslated region, and shares significant homology with lymphotoxin-α.

1839:. Excess production of TNF plays a critical role in the pathology of several inflammatory diseases, and 8116: 7431: 7233: 6943: 6200: 3266: 2525: 1898: 3107:

that attract white blood cells; stimulating the secretion of other cytokines such as IL-1; activating

3067:(PRRs) of immune cells, causing them to secrete immune-regulating cytokines. These cytokines, such as 1846:

TNF is expressed primarily by macrophages, but is also expressed in several other cell types, such as

397: 296: 8168: 7864: 7527: 7352: 7037: 6246: 5368:"Therapeutic TNF Inhibitors can Differentially Stabilize Trimeric TNF by Inhibiting Monomer Exchange" 5082:"Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization" 3848:"Tumor Necrosis Factor Superfamily: Ancestral Functions and Remodeling in Early Vertebrate Evolution" 3403: 3402:(HSCs), believed to be the primary contributors of liver fibrosis. On the other hand, TNF suppresses 2711:

TNF monomers form TNF trimers by first forming a partially unfolded trimer, also known as a trimeric

2096:-causing parasite, upon exposure to endotoxin, developed malaria-like symptoms such as liver damage, 187: 6046:"Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders" 4178:"Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders" 3314:. Local TNF treatment has been shown to induce tumor regression, though they rarely induce complete 2603:

module known as the TNF homology domain, due to its important role in binding TNF to its receptors.

2505: 2037:. TNF purified using reversed-phase HPLC was determined to have a molecular weight of 17,000 kDa by 390: 289: 7859: 7513: 7387: 6814: 6790: 6204: 3017: 2459: 2419: 1974: 1716: 1665: 208: 5990:"The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review" 4758:

Goodman MN (May 1991). "Tumor necrosis factor induces skeletal muscle protein breakdown in rats".

2896:

In the second checkpoint, the NF-κB pathway promotes the expression of pro-survival genes such as

17: 6382: 5538:"Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects" 3554: 3488:

Conditions that cause inflammation, such as cancer, can elevate TNF levels, which contributes to

2916:, forming complex IIc, also referred to as the necrosome. The necrosome then causes necroptosis. 2851: 1720: 1695: 1669: 1644: 8073: 6715: 3577: 3526: 3351: 3347: 3179: 3138:

to help the body fight infections. TNF can induce fever by triggering the release of cytokines

2443: 1887: 1808: 5366:

van Schie KA, Ooijevaar-de Heer P, Dijk L, Kruithof S, Wolbink G, Rispens T (September 2016).

3209:

in neurons, strengthening synaptic transmission. TNF also decreases the surface expression of

2619:(TACE) into the soluble form, denoted sTNF. Both tmTNF and sTNF are bioactive and arranged as 1893:

The excessive production of TNF is known to be a key factor in inflammatory disorders such as

5295: 4545:

Aggarwal BB, Kohr WJ, Hass PE, Moffat B, Spencer SA, Henzel WJ, et al. (February 1985).

3626: 3399: 2612: 2356: 2194: 1832: 2703:

contains charged and polar side chains, and the inner surface is mainly polar in character.

7241: 6239: 5379: 5230: 4902: 4724: 4681: 4443: 3315: 3262: 3112: 3068: 3048: 2997: 2742: 2372: 2337: 2151: 1943: 1934:, theorized that bacterial infections had a beneficial effect against tumors, particularly 1894: 272: 31: 3421:. However, when TNF injection is coupled with survival pathway inhibition, such as during 8: 7968: 7083: 3492:. TNF contributes to muscle wasting by activating the NF-κB pathway, which activates the 3270: 3258: 3060: 2541: 2321: 2065: 1985:, the authors deduced that TNF was released by macrophages upon exposure to endotoxins. 1955: 1871: 830:

positive regulation of cysteine-type endopeptidase activity involved in apoptotic process

228: 6072: 6045: 5924: 5897: 5383: 5234: 4906: 4728: 4685: 4447: 4299: 4272: 4204: 4177: 3986:

Falvo JV, Tsytsykova AV, Goldfeld AE (2010). "Transcriptional control of the TNF gene".

2430: 8163: 7771: 7667: 7519: 7250: 7207: 7122: 6829: 6375: 6174: 6147: 6123: 6096: 6016: 5989: 5854: 5827: 5798: 5771: 5744: 5717: 5690: 5663: 5564: 5537: 5504: 5477: 5453: 5426: 5402: 5367: 5343: 5316: 5278: 5195: 5168: 4870: 4845: 4821: 4811: 4794: 4522: 4497: 4074: 4047: 4014: 3934: 3907: 3874: 3847: 3814: 3787: 3630: 3562: 3441: 3116: 3000:, tmTNF reverse signaling increases cytotoxic activity by increasing the expression of 2869:

Complex II is formed when RIPK1 and/or TRADD disassociate from complex I and bind with

2274: 2155: 2154:, when injected into animals. This condition was known to be caused by a deficiency of 2124: 2089: 232: 7482: 5185: 5106: 5081: 4649: 4622: 4563: 4546: 4466: 4431: 4350: 4323: 1414: 1409: 1404: 1399: 1394: 1389: 1384: 1379: 1374: 1369: 1364: 1359: 1354: 1349: 1344: 1339: 1334: 1329: 1324: 1319: 1314: 1309: 1304: 1299: 1294: 1289: 1284: 1279: 1274: 1269: 1264: 1259: 1254: 1249: 1244: 1239: 1234: 1229: 1224: 1219: 1214: 1209: 1204: 1199: 1194: 1189: 1184: 1179: 1174: 1169: 1164: 1159: 1154: 1149: 1144: 1139: 1134: 1129: 1124: 1119: 1114: 1109: 1104: 1099: 1094: 1089: 1084: 1079: 1074: 1069: 1064: 1059: 1054: 1049: 1044: 1039: 1034: 1029: 1024: 1019: 1014: 1009: 1004: 999: 994: 989: 984: 979: 974: 969: 964: 959: 954: 949: 944: 939: 934: 929: 924: 919: 914: 909: 904: 899: 894: 889: 884: 879: 874: 869: 864: 859: 854: 849: 844: 839: 834: 829: 824: 819: 814: 809: 804: 799: 794: 789: 784: 768: 763: 758: 753: 748: 743: 738: 733: 728: 723: 718: 713: 697: 692: 687: 682: 677: 7542: 7114: 6733: 6599: 6220: 6211: 6179: 6128: 6077: 6021: 5970: 5929: 5878: 5859: 5803: 5749: 5695: 5610: 5569: 5509: 5458: 5407: 5348: 5283: 5246: 5200: 5149: 5111: 5043: 4999: 4954: 4950: 4918: 4875: 4826: 4775: 4740: 4697: 4654: 4603: 4568: 4527: 4471: 4355: 4304: 4250: 4209: 4129: 4079: 4019: 3999: 3939: 3879: 3819: 3542: 3538: 3422: 3213:, reducing the activity of inhibitory synapses. TNF can also modulate the release of 3092: 3088: 2933: 2814: 2238: 2128: 2050: 2046: 1879: 1185:

positive regulation of humoral immune response mediated by circulating immunoglobulin

180: 72: 38: 6148:"Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives" 4771: 4639: 3020:

pathway by tmTNF reverse signaling can lead to cell cycle inhibition and apoptosis.

2528:, proteins that relax the DNA structure to increase gene expression, such as ATF-2, 2394:

These stimuli trigger the activation of a variety of transcription factors, such as

7546: 7426: 7347: 7215: 6904: 6738: 6169: 6159: 6118: 6108: 6067: 6057: 6011: 6001: 5960: 5919: 5909: 5849: 5839: 5793: 5783: 5739: 5729: 5685: 5675: 5637: 5600: 5559: 5549: 5499: 5489: 5448: 5438: 5397: 5387: 5338: 5328: 5273: 5238: 5190: 5180: 5141: 5101: 5093: 5033: 4989: 4985: 4981: 4946: 4910: 4865: 4857: 4816: 4806: 4767: 4732: 4689: 4644: 4634: 4595: 4558: 4517: 4509: 4461: 4451: 4409: 4382: 4345: 4335: 4294: 4284: 4240: 4199: 4189: 4119: 4069: 4059: 4048:"Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents" 4009: 3991: 3929: 3919: 3869: 3859: 3809: 3799: 3558: 3453: 3290: 3225: 2830: 2781:

TNFR1 exists in most cell types and binds to both tmTNF and sTNF. TNFR1 contains a

2210: 2206: 1973:

of endotoxin-treated mice into other mice. They discovered that mice infected with

1951: 1927: 477: 408: 352: 307: 212: 4513: 4064: 2340:; its activation is rapid and does not depend on the synthesis of other proteins. 8142: 7908: 7888: 7854: 6953: 6639: 5788: 5221:

Jones E, Stuart D, Walker N (March 1989). "Structure of tumour necrosis factor".

4430:

Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (September 1975).

3641: 3638: 3581: 3497: 3355: 3084: 2993: 2881: 2722: 2649: 2588: 2329: 2293: 2104: 2014: 1855: 1245:

negative regulation of extrinsic apoptotic signaling pathway in absence of ligand

452: 236: 5443: 3746:

National Center for Biotechnology Information, U.S. National Library of Medicine

3728:

National Center for Biotechnology Information, U.S. National Library of Medicine

3318:. Body-wide administration of TNF has shown low efficacy and high side effects. 2632:

TNFR2. Like all type II transmembrane proteins, tmTNF is arranged such that the

2209:. Lymphotoxin was also discovered to play a critical role in the development of 1285:

activation of cysteine-type endopeptidase activity involved in apoptotic process

8130: 7923: 7803: 7467: 7462: 7317: 7313: 7295: 7290: 7093: 7088: 7078: 7073: 7068: 7063: 7058: 7054: 7023: 7018: 7013: 6992: 6987: 6982: 6977: 6932: 6927: 6922: 6917: 6865: 6850: 6841: 6398: 6062: 6006: 5914: 4436:

Proceedings of the National Academy of Sciences of the United States of America

4245: 4228: 4194: 4124: 4107: 3906:

Jang DI, Lee AH, Shin HY, Song HR, Park JH, Kang TB, et al. (March 2021).

3804: 3652: 3648: 3546: 3513: 3489: 3395: 3229: 3210: 3163: 3159: 2712: 2660: 2645: 2108: 2069: 1969:

et al. investigated the tumor-killing properties of endotoxin by injecting the

1910: 1906: 1874:. Both tmTNF and sTNF can activate TNFR1, while only tmTNF can activate TNFR2. 1840: 553: 6097:"Therapeutic Potential of TNF-α Inhibition for Alzheimer's Disease Prevention" 6095:

Torres-Acosta N, O'Keefe JH, O'Keefe EL, Isaacson R, Small G (November 2020).

5965: 5948: 5844: 5680: 5642: 5629: 5554: 5333: 5145: 4152:

Kaiser G (21 November 2013). "11.3C: Cytokines Important in Innate Immunity".

8152: 7457: 7452: 7447: 7393: 7342: 7008: 6912: 6888: 6883: 6860: 6855: 6846: 6837: 6619: 5734: 5097: 4547:"Human tumor necrosis factor. Production, purification, and characterization" 3619: 3509: 3477: 3282: 3206: 3202: 3143: 3139: 3076: 3072: 2901: 2572: 2388: 2376: 2352: 2230: 2198: 2116: 1970: 1939: 664: 55: 6367: 6327:: CONFORMATIONAL CHANGES IN THE (ALA-84-VAL) MUTANT OF TUMOR NECROSIS FACTOR 5038: 5021: 4736: 4693: 3990:. Current Directions in Autoimmunity. Vol. 11. Karger. pp. 27–60. 2834: 2692: 2450:

The composition of the enhanceosome depends on the ambient concentration of

2434:

Enhanceosome composition for human TNF for example cell types and stimulants

613: 491: 8068: 7993: 7849: 7808: 7793: 7722: 7687: 6938: 6770: 6183: 6132: 6094: 6081: 6025: 5974: 5933: 5863: 5807: 5753: 5699: 5614: 5573: 5513: 5462: 5411: 5352: 5204: 5153: 5047: 5003: 4531: 4456: 4386: 4359: 4308: 4254: 4213: 4133: 4083: 4023: 3943: 3883: 3823: 3656: 3151: 3124: 3039:

production, which then interferes with the signaling pathway of endotoxin.

2945: 2789:

Upon activation by TNF, TNFR1 trimerizes and forms complex I by recruiting

2782: 2509: 2455: 2439: 2226: 2202: 2097: 2026: 1375:

positive regulation of vascular associated smooth muscle cell proliferation

470: 249: 5770:

Qiu P, Cui X, Barochia A, Li Y, Natanson C, Eichacker PQ (November 2011).

5287: 5250: 5115: 4958: 4922: 4879: 4861: 4830: 4779: 4744: 4701: 4658: 4607: 4572: 4475: 4413: 4273:"Focus on Anti-Tumour Necrosis Factor (TNF)-α-Related Autoimmune Diseases" 3864: 3224:

Through TNFR2 signaling, TNF promotes the proliferation and maturation of

2371:, and silica particles. TNF is also activated by other cytokines, such as 1784: 1779: 1000:

positive regulation of chronic inflammatory response to antigenic stimulus

8048: 8043: 8038: 8013: 8008: 8003: 7978: 7973: 7913: 7826: 7762: 7682: 7538: 7359: 7305: 7046: 6805: 6728: 6164: 5317:"Dynamic dissociating homo-oligomers and the control of protein function" 4289: 3924: 3585: 3302:

TNF was initially discovered as an agent that kills tumors, particularly

3183: 3155: 3108: 3100: 3080: 2968: 2937: 2859: 2822: 2762: 2592: 2470: 2333: 2309: 2277:

and 1,669 base pairs in the mRNA. The mRNA consists of four regions: the

2179: 2175: 2120: 2054: 1982: 1930:, based on anecdotes of cancer patients being cured by sudden attacks of 1812: 1619: 1600: 635: 5132:

Goetz FW, Planas JV, MacKenzie SI (May 2004). "Tumor necrosis factors".

4340: 2680: 2257: 2088:

In June 1981, Ian A. Clark et al. found that healthy mice infected with

2021:

purified and characterized human TNF. The TNF was produced by culturing

8093: 8063: 8058: 8023: 7998: 7988: 7898: 7742: 7707: 7697: 7677: 7662: 7657: 7412: 7105: 6795: 6755: 6113: 5664:"Tumor Necrosis Factor α: Taking a Personalized Road in Cancer Therapy" 4994: 4046:

Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T (July 2010).

3651:

that can specifically target TNF, and monoclonal antibodies with lower

3602: 3493: 3414: 3335: 3331: 3327: 3323: 3191: 3104: 3056: 3009: 3005: 2924: 2886: 2773: 2754: 2637: 2633: 2620: 2600: 2360: 2348: 2344: 2325: 1931: 1870:(TACE) into a soluble form (sTNF), allowing it to be secreted into the 1863: 1859: 369: 266: 216: 5494: 5427:"Impact of quaternary structure dynamics on allosteric drug discovery" 5392: 5365: 4846:"Studies of endotoxin-induced decrease in lipoprotein lipase activity" 4623:"Possible importance of macrophage-derived mediators in acute malaria" 3995: 3394:

TNF is a key player in liver injury and inflammation, but its role in

2688: 2684: 2136: 1345:

positive regulation of leukocyte adhesion to vascular endothelial cell

1340:

positive regulation of leukocyte adhesion to arterial endothelial cell

1165:

epithelial cell proliferation involved in salivary gland morphogenesis

945:

negative regulation of cytokine production involved in immune response

157: 153: 149: 145: 141: 137: 133: 129: 125: 121: 117: 113: 109: 105: 101: 8028: 7983: 7963: 7756: 7747: 7672: 6417: 5242: 4914: 4599: 3634: 3550: 3530: 3473: 3274: 3214: 3187: 3079:, and TNF, are primarily secreted by mononuclear phagocytes, such as 3028: 3024: 2874: 2758: 2730: 2384: 2297: 2112: 2018: 1966: 1959: 1836: 1444: 436: 423: 335: 322: 224: 4972:

Grimstad Ø (May 2016). "Tumor Necrosis Factor and the Tenacious α".

3398:

is controversial. TNF contributes to the activation and survival of

3201:

Through TNFR1 signaling, TNF can increase the surface expression of

2241:

gene. The TNF gene is 2,762 base pairs long and results in a mature

2060:

In that same month, Pennica et al, also at Genentech, sequenced the

8125: 8053: 8018: 7782: 7778: 7766: 7752: 7407: 6402: 5605: 5588: 4498:"Lymphotoxin and TNF: How it all began- A tribute to the travelers" 3303: 3241: 3120: 3001: 2596: 2482: 2364: 2042: 2038: 1996: 1935: 1816: 1768: 5657: 5655: 5653: 4432:"An endotoxin-induced serum factor that causes necrosis of tumors" 4271:

Lopetuso LR, Cuomo C, Mignini I, Gasbarrini A, Papa A (May 2023).

3426: 3036: 2932:

Unlike TNFR1, TNFR2 is expressed in limited cell types, including

2928:

TNFR2 cell signaling. Dashed arrows indicate cross-talk with TNFR1

2846: 2497: 2395: 1994:, TNF was also cytotoxic to L-929 cells, a transformed cell line, 1005:

positive regulation of chemokine (C-X-C motif) ligand 2 production

7933: 7903: 6225: 6215: 3534: 3457: 3449: 3366: 3278: 3257:

Excessive production of TNF plays a key role in the pathology of

3195: 3170:

in the hypothalamus to raise the target temperature of the body.

3013: 2952: 2941: 2863: 2855: 2568: 2317: 2313: 2270: 2159: 2093: 1990: 1978: 1851: 1847: 1819:, and activates inflammatory pathways through its two receptors, 1586: 1511: 1429: 1425: 6312:: Crystal Structure of TNF-alpha with a small molecule inhibitor 5718:"Tumor necrosis factor blockade and the risk of viral infection" 4045: 3496:

pathway to degrade protein, and by inhibiting the activation of

2845:

pathways, as well as IKK, which in turn activates the canonical

1315:

extrinsic apoptotic signaling pathway via death domain receptors

1040:

positive regulation of DNA-binding transcription factor activity

895:

regulation of branching involved in salivary gland morphogenesis

204: 7285: 7182: 7177: 7172: 7167: 7162: 7157: 6875: 6680: 6664: 6659: 6654: 6649: 6644: 6634: 6629: 6357:: HIGH RESOLUTION CRYSTAL STRUCTURE OF A HUMAN TNF-ALPHA MUTANT 6342:: HIGH RESOLUTION CRYSTAL STRUCTURE OF A HUMAN TNF-ALPHA MUTANT 5870: 5650: 4793:

Stefferl A, Hopkins SJ, Rothwell NJ, Luheshi GN (August 1996).

3378: 2818: 2696: 2656: 2623:. Monomer TNF is also bioactive, but to a much smaller degree. 2616: 2383:, and TNF itself, as well as by environmental stresses such as 2359:, and viral RNA. Stimuli can also be non-pathogenic, including 1902: 1867: 1752: 1466: 955:

negative regulation of branching involved in lung morphogenesis

850:

intrinsic apoptotic signaling pathway in response to DNA damage

644: 6231: 5988:

Docherty S, Harley R, McAuley JJ, et al. (January 2022).

4935: 4792: 4714: 4270: 1325:

positive regulation of NF-kappaB transcription factor activity

1180:

positive regulation of membrane protein ectodomain proteolysis

1095:

negative regulation of myosin-light-chain-phosphatase activity

930:

regulation of tumor necrosis factor-mediated signaling pathway

7928: 7918: 7879: 7874: 7821: 7321: 7280: 7275: 7270: 7265: 7260: 7197: 7187: 7152: 7147: 7142: 7137: 7132: 7127: 6780: 6775: 6765: 6750: 6745: 6624: 6614: 6609: 6604: 6594: 6589: 6583: 6567: 6557: 6552: 6547: 6542: 6537: 6532: 6527: 6522: 6516: 6511: 6506: 6501: 6496: 6491: 6486: 6481: 3218: 3135: 2960: 2909: 2897: 2890: 2838: 2810: 2806: 2802: 2798: 2794: 2790: 2750: 2746: 2671: 2581: 2478: 2403: 2266: 2022: 1883: 1824: 1820: 1807:, is an inflammatory protein and a principal mediator of the 1230:

positive regulation of protein-containing complex disassembly

1215:

negative regulation of protein-containing complex disassembly

6210:

Overview of all the structural information available in the

4585: 3576:

TNF-induced neuroinflammation has also been associated with

3285:

are used to treat these diseases, often with high efficacy.

3095:

in blood vessels to promote an early inflammatory response.

2777:

TNFR1 cell signaling. Red arrows show cell death checkpoints

7869: 7245: 7192: 6760: 6701: 6696: 6476: 6471: 6466: 6461: 6455: 6449: 6443: 6437: 6432: 6145: 5981: 5022:"Tumor necrosis factor: biology and therapeutic inhibitors" 4892: 4621:

Clark IA, Virelizier JL, Carswell EA, Wood PR (June 1981).

4620: 3147: 2964: 2956: 2913: 2870: 2842: 2826: 2533: 2451: 2415: 2411: 2399: 2242: 2222: 2061: 2049:, revealing a sequence of 157 amino acids with significant 855:

positive regulation of protein localization to cell surface

5127: 5125: 5079: 2547:

TNF gene expression is also controlled by the presence of

1295:

positive regulation of I-kappaB kinase/NF-kappaB signaling

1150:

positive regulation of protein-containing complex assembly

7798: 5586: 5580: 5063:"TNF (tumor necrosis factor (TNF superfamily, member 2))" 3362: 2584:, have been found to contain duplicates of the TNF gene. 1410:

positive regulation of calcineurin-NFAT signaling cascade

1335:

positive regulation of transcription by RNA polymerase II

1320:

negative regulation of transcription by RNA polymerase II

1225:

negative regulation of bicellular tight junction assembly

805:

positive regulation of calcidiol 1-monooxygenase activity

5054: 4101: 4099: 4097: 4095: 4093: 3553:

levels, activating microglial cells, and disrupting the

3198:, and plays a critical role in maintaining homeostasis. 3031:. This effect is caused by tmTNF activating the JNK and 2462:

and Ets/Elk proteins bound at compatible binding sites.

2008: 1170:

positive regulation of nitric oxide biosynthetic process

460: 7512: 5587:

Netea MG, Kullberg BJ, Van der Meer JW (October 2000).

5122: 4147: 4145: 4143: 3985: 1125:

positive regulation of smooth muscle cell proliferation

1055:

regulation of reactive oxygen species metabolic process

990:

positive regulation of translational initiation by iron

5169:"The active form of tumor necrosis factor is a trimer" 4544: 4429: 3781: 3779: 3777: 3775: 3162:. All of these pathways culminate in the synthesis of 2833:

that forms M1-linked ubiquitin chains, which attracts

2687:. The tertiary structure consists of two antiparallel 2465:

Additionally, the proximal promoter region contains a

950:

positive regulation of peptidyl-serine phosphorylation

8114: 5987: 5630:"Why illness might leave a bitter taste in the mouth" 4090: 3981: 3979: 3977: 3975: 3973: 3773: 3771: 3769: 3767: 3765: 3763: 3761: 3759: 3757: 3755: 2817:

that form K63-linked ubiquitin chains, which recruit

2519: 1360:

positive regulation of heterotypic cell-cell adhesion

1355:

negative regulation of endothelial cell proliferation

1200:

positive regulation of vitamin D biosynthetic process

625: 5131: 4671: 4140: 3971: 3969: 3967: 3965: 3963: 3961: 3959: 3957: 3955: 3953: 1350:

positive regulation of blood microparticle formation

1145:

positive regulation of ceramide biosynthetic process

1135:

positive regulation of superoxide dismutase activity

880:

negative regulation of alkaline phosphatase activity

4220: 3605:and infliximab have been shown to worsen symptoms. 3463: 3361:Conversely, TNF plays a role in the progression of 2201:by forming a complex with a separate transmembrane 2045:. The TNF amino acid sequence was determined using 1330:

positive regulation of transcription, DNA-templated

1100:

negative regulation of transcription, DNA-templated

1020:

chronic inflammatory response to antigenic stimulus

6146:Cudrici C, Deuitch N, Aksentijevich I (May 2020). 5947:Zhou J, Liu B, Liang C, Li Y, Song YH (May 2016). 5711: 5709: 3752: 3702: 3700: 3698: 3680: 3678: 3676: 3377:TNF is believed to be an important contributor to 3158:in the liver, which signals to neurons to secrete 3111:and macrophages; stimulating the liver to produce 2695:, similar to the "jelly-roll" structural motif of 2555:enhancer complexes. These interactions would also 1260:regulation of establishment of endothelial barrier 1190:positive regulation of interferon-gamma production 6039: 6037: 6035: 5895: 5220: 5216: 5214: 4226: 3950: 3541:, and immune cells. Excessive TNF contributes to 3472:(NAFLD). When fat builds up in the liver, termed 3429:, as well as promoting further hepatocyte death. 1205:positive regulation of mononuclear cell migration 940:positive regulation of osteoclast differentiation 915:positive regulation of protein kinase B signaling 885:regulation of I-kappaB kinase/NF-kappaB signaling 825:negative regulation of osteoblast differentiation 407: 306: 8150: 5769: 4266: 4264: 3647:New TNF blockers are being developed, including 2880:In the first checkpoint, IKK disables RIPK1 via 2145: 1390:positive regulation of protein catabolic process 1290:tumor necrosis factor-mediated signaling pathway 1015:positive regulation of hair follicle development 5949:"Cytokine Signaling in Skeletal Muscle Wasting" 5821: 5819: 5817: 5765: 5763: 5706: 5531: 5529: 5527: 5525: 5523: 5160: 5019: 5015: 5013: 4491: 4489: 4487: 4485: 4321: 3905: 3901: 3899: 3897: 3895: 3893: 3785: 3695: 3673: 2652:, although it is unclear what role this plays. 1175:negative regulation of interleukin-6 production 980:positive regulation of interleukin-6 production 910:negative regulation of myoblast differentiation 905:negative regulation of fat cell differentiation 845:positive regulation of interleukin-8 production 835:negative regulation of viral genome replication 6032: 5946: 5621: 5300:: CS1 maint: DOI inactive as of August 2024 ( 5211: 4843: 4425: 4423: 4229:"Metabolic Messengers: tumour necrosis factor" 4041: 4039: 4037: 4035: 4033: 3841: 3839: 3837: 3835: 3833: 3707:GRCm38: Ensembl release 89: ENSMUSG00000024401 3456:. TNF has been found to be upregulated in the 2491: 1988:In addition to causing sarcomas to hemorrhage 1415:positive regulation of NIK/NF-kappaB signaling 1255:negative regulation of lipid catabolic process 1130:positive regulation of protein kinase activity 790:positive regulation of protein phosphorylation 7514: 7498: 6397: 6383: 6247: 5589:"Circulating Cytokines as Mediators of Fever" 5475: 5166: 4399: 4372: 4261: 2611:Human TNF is initially produced as a type II 2425: 1120:lipopolysaccharide-mediated signaling pathway 6139: 6088: 5940: 5814: 5760: 5520: 5469: 5418: 5359: 5314: 5308: 5010: 4482: 4315: 4105: 3890: 3468:TNF plays a key role in the pathogenesis of 1843:are often employed to treat these diseases. 1025:cellular response to organic cyclic compound 860:positive regulation of ERK1 and ERK2 cascade 810:positive regulation of programmed cell death 5257: 5073: 4929: 4886: 4837: 4786: 4751: 4708: 4665: 4614: 4579: 4538: 4420: 4171: 4169: 4167: 4165: 4030: 3830: 2706: 2442:, where multiple transcription factors and 2111:found that mice immunized from TNF via TNF 2033:chromatography, Mono Q chromatography, and 1235:regulation of cell population proliferation 1080:positive regulation of chemokine production 890:defense response to Gram-positive bacterium 7505: 7491: 6390: 6376: 6282:: TUMOR NECROSIS FACTOR ALPHA, R31D MUTANT 6254: 6240: 5715: 5661: 5535: 5263: 4965: 4227:Sethi JK, Hotamisligil GS (October 2021). 3091:, also known as leukocytes, as well as on 1160:positive regulation of cytokine production 1010:positive regulation of JUN kinase activity 795:positive regulation of MAP kinase activity 30:"TNF" redirects here. For other uses, see 7919:RANKL (TRANCE, OPGL, ODF, CD254, TNFSF11) 6203:at the U.S. National Library of Medicine 6173: 6163: 6122: 6112: 6071: 6061: 6015: 6005: 5964: 5923: 5913: 5879:"TNF short-circuits the insulin receptor" 5853: 5843: 5797: 5787: 5743: 5733: 5689: 5679: 5641: 5604: 5563: 5553: 5503: 5493: 5452: 5442: 5401: 5391: 5342: 5332: 5277: 5194: 5184: 5105: 5037: 4993: 4869: 4820: 4810: 4648: 4638: 4562: 4521: 4465: 4455: 4349: 4339: 4322:Lundin JI, Checkoway H (September 2009). 4298: 4288: 4244: 4203: 4193: 4123: 4073: 4063: 4013: 3933: 3923: 3873: 3863: 3813: 3803: 3599:TNF receptor associated periodic syndrome 3178:TNF is expressed in various cells in the 3173: 2753:, TNF can induce either cell survival or 2438:TNF gene expression is regulated through 2273:, for a total of 2,762 base pairs in the 2135:definitively demonstrating that TNF is a 1395:regulation of signaling receptor activity 1365:negative regulation of mitotic cell cycle 965:death-inducing signaling complex assembly 5953:Trends in Endocrinology & Metabolism 5889: 5825: 5134:Development & Comparative Immunology 5020:Papadakis KA, Targan SR (October 2000). 4971: 4402:Journal of the National Cancer Institute 4375:Journal of the National Cancer Institute 4162: 3580:, and is suspected to contribute to the 3247: 2923: 2772: 2741:TNF is a central mediator of the body's 2670: 2599:. All TNF genes have a highly conserved 2429: 2256: 2083: 1275:positive regulation of apoptotic process 1240:cellular response to amino acid stimulus 1105:cortical actin cytoskeleton organization 1060:positive regulation of protein transport 1050:positive regulation of podosome assembly 970:regulation of osteoclast differentiation 6043: 5896:Vachliotis ID, Polyzos SA (July 2023). 4844:Kawakami M, Cerami A (September 1981). 4757: 4175: 2976:activates the canonical NF-κB pathway. 2761:, the controlled death of the cell, or 2308:The TNF gene is expressed primarily in 2292:The 3' untranslated region contains an 1385:protein localization to plasma membrane 1250:cellular response to lipopolysaccharide 1030:positive regulation of fever generation 14: 8151: 5876: 5627: 5476:Lawrence SH, Jaffe EK (January 2013). 4495: 4151: 3788:"Death by TNF: a road to inflammation" 3217:, an excitatory neurotransmitter, and 3053:pathogen-associated molecular patterns 2197:, was discovered to be present on the 1380:negative regulation of gene expression 1305:positive regulation of gene expression 688:tumor necrosis factor receptor binding 7486: 6371: 6235: 5424: 3845: 3637:, while others, like etanercept, are 3435: 3150:. TNF or its mediators can reach the 2972:accumulation of NIK within the cell. 2626: 2615:, denoted tmTNF, which is cleaved by 2252: 2193:In 1993, lymphotoxin, which is not a 2009:Isolation, sequencing, and expression 1958:. They demonstrated that this agent, 1310:extrinsic apoptotic signaling pathway 1110:embryonic digestive tract development 1065:negative regulation of glucose import 785:regulation of protein phosphorylation 739:integral component of plasma membrane 412: 373: 368: 311: 270: 265: 5716:Kim SY, Solomon DH (February 2010). 5067:Atlas Genet Cytogenet Oncol Haematol 5060: 4502:Cytokine & Growth Factor Reviews 3644:that contain TNFR2 binding regions. 3533:, a type of macrophage, but also by 3520: 2983: 2636:is pointed into the cell, while the 1265:positive regulation of cell adhesion 1090:negative regulation of lipid storage 5536:Gough P, Myles IA (November 2020). 4106:Szondy S, Pallai A (January 2017). 3786:van Loo G, Bertrand MJ (May 2023). 3235: 1405:cytokine-mediated signaling pathway 1400:regulation of inflammatory response 985:I-kappaB kinase/NF-kappaB signaling 900:positive regulation of phagocytosis 24: 5315:Selwood T, Jaffe EK (March 2012). 5279:10.1111/j.1432-1033.1995.tb20710.x 4812:10.1111/j.1476-5381.1996.tb15625.x 3629:, such as infliximab, adalimumab, 3146:, or through other mediators like 3042: 2919: 2768: 2520:Regulation via chromatin structure 2300:, and a "Crohn's-like" phenotype. 2265:The transcribed region contains 4 2261:Map of human TNF exons and introns 1981:due to an increased production of 1370:endothelial cell apoptotic process 1220:multicellular organism development 815:positive regulation of JNK cascade 734:intracellular anatomical structure 25: 8180: 6194: 5826:Yang YM, Seki E (December 2015). 5167:Smith RA, Baglioni C (May 1987). 4328:Environmental Health Perspectives 3483: 3406:expression and HSC proliferation 3389: 2247:tumor necrosis factor superfamily 1829:tumor necrosis factor superfamily 1035:extracellular matrix organization 8136: 8124: 7847:TNF superfamily protein ligands: 6347: 6332: 6317: 6302: 6287: 6272: 4850:Journal of Experimental Medicine 3549:neuronal cell death, increasing 3470:nonalcoholic fatty liver disease 3464:Nonalcoholic fatty liver disease 2235:Major Histocompatibility Complex 1965:In 1975, Elizabeth Carswell and 749:external side of plasma membrane 634: 396: 389: 383: 360: 295: 288: 282: 257: 54: 6261: 6224:(Tumor necrosis factor) at the 5173:Journal of Biological Chemistry 4799:British Journal of Pharmacology 4772:10.1152/ajpendo.1991.260.5.E727 4640:10.1128/iai.32.3.1058-1066.1981 4551:Journal of Biological Chemistry 4393: 4366: 3613: 3608: 3529:, TNF is primarily produced by 3252: 2866:, which destabilize complex I. 2719:monomers and dimers is higher. 2666: 2312:, but can also be expressed in 2169: 1811:. TNF is produced primarily by 1270:regulation of protein secretion 920:regulation of insulin secretion 4986:10.1001/jamadermatol.2015.4322 4760:American Journal of Physiology 3734: 3716: 3508:During exercise, the level of 2485:to assist with transcription. 2469:(CRE), a binding site for the 2053:to the amino acid sequence of 2000:. Cytotoxicity to L-929 cells 1882:, secretion of cytokines, and 1833:type II transmembrane proteins 1075:leukocyte tethering or rolling 724:integral component of membrane 645:More reference expression data 614:More reference expression data 13: 1: 7909:LIGHT (HEVML, CD258, TNFSF14) 5186:10.1016/S0021-9258(18)48183-5 4564:10.1016/S0021-9258(18)89560-6 4514:10.1016/j.cytogfr.2014.02.001 3666: 3341: 3065:pattern recognition receptors 2338:immediate early response gene 2303: 2146:Identification with cachectin 1300:necroptotic signaling pathway 1045:cellular response to nicotine 975:defense response to bacterium 820:response to organic substance 381: 280: 5789:10.1517/13543784.2011.623125 5593:Clinical Infectious Diseases 4951:10.1016/0092-8674(93)90574-a 3446:insulin receptor substrate 1 2726:bind to active TNF trimers. 2691:arranged as an antiparallel 2640:is pointed out of the cell. 2562: 1921: 995:sequestering of triglyceride 7: 8159:Genes on human chromosome 6 6201:Tumor Necrosis Factor-alpha 5722:Nature Reviews Rheumatology 5444:10.2174/1568026611313010006 4065:10.1093/rheumatology/keq031 3503: 3228:, which produce protective 2736: 2617:TNF alpha converting enzyme 2492:Other transcription factors 2467:cyclic AMP response element 2076:and against mouse sarcomas 1868:TNF alpha converting enzyme 1866:, which is then cleaved by 875:apoptotic signaling pathway 592:subcutaneous adipose tissue 10: 8185: 6063:10.3389/fimmu.2023.1213448 6007:10.1186/s13102-022-00397-2 5994:BMC Sports Sci Med Rehabil 5915:10.1007/s13679-023-00519-y 5776:Expert Opin Investig Drugs 4246:10.1038/s42255-021-00470-z 4195:10.3389/fimmu.2023.1213448 4125:10.1016/j.phrs.2016.11.025 3805:10.1038/s41577-022-00792-3 3617: 3267:inflammatory bowel disease 3166:, which interact with the 3134:Additionally, TNF induces 2745:. By binding to receptors 2606: 2549:DNase-hypersensitive sites 2526:histone acetyltransferases 2426:Enhanceosome transcription 2336:. The TNF gene is also an 2178:, a cytotoxin secreted by 1916: 1899:inflammatory bowel disease 1195:response to glucocorticoid 1155:protein kinase B signaling 925:osteoclast differentiation 870:animal organ morphogenesis 36: 29: 7839: 7647: 7611: 7575: 7566: 7526: 7377: 7353:Colony-stimulating factor 7335: 7304: 7232: 7206: 7113: 7104: 7045: 7036: 7001: 6964: 6902: 6874: 6828: 6813: 6804: 6714: 6689: 6673: 6576: 6425: 6416: 6409: 6267: 5966:10.1016/j.tem.2016.03.002 5845:10.1007/s40139-015-0093-z 5681:10.3389/fimmu.2022.903679 5662:Ben-Baruch A (May 2022). 5643:10.1038/nature.2015.17415 5555:10.3389/fimmu.2020.585880 5425:Jaffe EK (January 2013). 5334:10.1016/j.abb.2011.11.020 5146:10.1016/j.dci.2003.09.008 3846:Marín I (November 2020). 3742:"Mouse PubMed Reference:" 3724:"Human PubMed Reference:" 3372: 3365:by inducing apoptosis of 3297: 3061:double-stranded viral RNA 2496:The transcription factor 1783: 1778: 1774: 1767: 1751: 1732: 1713: 1709: 1692: 1688: 1681: 1662: 1658: 1641: 1637: 1630: 1617: 1613: 1598: 1594: 1585: 1572: 1568: 1545: 1519: 1510: 1497: 1493: 1478: 1474: 1465: 1450: 1443: 1439: 1423: 865:glucose metabolic process 698:identical protein binding 663: 659: 642: 633: 624: 611: 560: 551: 498: 489: 459: 451: 447: 430: 417: 380: 359: 350: 346: 329: 316: 279: 256: 247: 243: 198: 195: 185: 178: 173: 98: 93: 76: 71: 66: 62: 53: 48: 7388:proinflammatory cytokine 6205:Medical Subject Headings 6044:Caldito NG (July 2023). 5828:"TNFα in liver fibrosis" 5735:10.1038/nrrheum.2009.279 4496:Ruddle NH (April 2014). 4176:Caldito NG (July 2023). 4112:Pharmacological Research 3592: 3035:pathways, which induces 3016:, the activation of the 2992:In tumor cells, such as 2707:Assembly and Disassembly 1975:Bacillus Calmette Guerin 1827:. It is a member of the 1745:Chr 17: 35.42 – 35.42 Mb 37:Not to be confused with 7850:4-1BBL (CD137L, TNFSF9) 6050:Frontiers in Immunology 5902:Current Obesity Reports 5668:Frontiers in Immunology 5628:Rogers N (April 2015). 5282:(inactive 2024-08-31). 5039:10.1053/gast.2000.18160 4737:10.1126/science.3764421 4694:10.1126/science.3895437 3404:alpha-1 type-1 collagen 3156:primary vagal terminals 2967:to be processed into a 2216: 1738:Chr 6: 31.58 – 31.58 Mb 840:humoral immune response 800:response to salt stress 8074:Vorsetuzumab mafodotin 7929:TRAIL (CD253, TNFSF10) 7860:BAFF (CD257, TNFSF13B) 7855:APRIL (CD256, TNFSF13) 6519:/PARC/DCCK1/AMAC1/MIP4 5877:Bordon Y (June 2021). 5098:10.1093/nar/13.17.6361 5086:Nucleic Acids Research 4627:Infection and Immunity 4457:10.1073/pnas.72.9.3666 4324:"Endotoxin and Cancer" 3567:Neuro-Behçet's disease 3527:central nervous system 3400:hepatic stellate cells 3348:Varicella-zoster virus 3180:central nervous system 3174:Central Nervous System 2929: 2813:. cIAP1 and cIAP2 are 2778: 2743:innate immune response 2676: 2435: 2283:3' untranslated region 2279:5' untranslated region 2262: 1888:central nervous system 1809:innate immune response 1085:cellular extravasation 600:mesenteric lymph nodes 414:17 B1|17 18.59 cM 7946:Recombinant proteins: 7914:OX40L (CD252, TNFSF4) 7880:CD154 (CD40L, TNFSF5) 7875:CD153 (CD30L, TNFSF8) 5482:Biochem Mol Biol Educ 4862:10.1084/jem.154.3.631 3627:monoclonal antibodies 3279:noninfectious uveitis 3248:Clinical significance 3087:. They mainly act on 2927: 2841:. TAK1 activates the 2776: 2674: 2613:transmembrane protein 2433: 2357:polyhydroxyalkanoates 2260: 2195:transmembrane protein 2084:Physiological effects 2027:controlled pore glass 1803:), formerly known as 1797:Tumor necrosis factor 1280:inflammatory response 568:stroma of bone marrow 375:Chromosome 17 (mouse) 7939:VEGI (TL1A, TNFSF15) 7899:FasL (CD95L, TNFSF6) 7870:CD70 (CD27L, TNFSF7) 7517:receptor superfamily 6165:10.3390/ijms21093263 5321:Arch Biochem Biophys 5061:Chen F (June 2004). 4387:10.1093/jnci/4.5.461 4290:10.3390/ijms24098187 3925:10.3390/ijms22052719 3494:ubiquitin–proteasome 3263:rheumatoid arthritis 3113:acute phase proteins 3049:innate immune system 2998:natural killer cells 2391:, and high glucose. 2322:Natural Killer cells 2152:hypertriglyceridemia 1944:Bacillus prodigiosus 1895:rheumatoid arthritis 754:extracellular region 273:Chromosome 6 (human) 94:List of PDB id codes 67:Available structures 32:TNF (disambiguation) 7969:Brentuximab vedotin 7084:Interferon type III 5384:2016NatSR...632747V 5235:1989Natur.338..225J 4907:1985Natur.316..552B 4766:(5 Pt 1): 727–730. 4729:1986Sci...234..470T 4686:1985Sci...229..869B 4448:1975PNAS...72.3666C 4414:10.1093/jnci/4.1.99 4341:10.1289/ehp.0800439 3988:TNF Pathophysiology 3865:10.1093/gbe/evaa140 3655:potential, such as 3578:Alzheimer's disease 3555:blood–brain barrier 3271:psoriatic arthritis 3259:autoimmune diseases 2697:viral coat proteins 2542:Histone methylation 2107:, Ian Milsark, and 2035:reversed-phase HPLC 1956:Serratia marcescens 1872:extracellular space 1115:leukocyte migration 769:extracellular space 7772:Echinacea purpurea 7730:Enzyme inhibitors: 7668:Certolizumab pegol 6114:10.3233/JAD-200711 5832:Curr Pathobiol Rep 3631:certolizumab pegol 3563:multiple sclerosis 3442:insulin resistance 3436:Insulin resistance 3352:Epstein–Barr virus 3117:C-reactive protein 3051:is activated when 2930: 2829:. LUBAC is also a 2779: 2677: 2627:Transmembrane form 2436: 2275:primary transcript 2263: 2253:Transcribed region 2229:, residing in the 2156:lipoprotein lipase 2125:metabolic acidosis 2090:Plasmodium vinckei 1841:anti-TNF therapies 1575:ENSMUSG00000024401 778:Biological process 729:recycling endosome 707:Cellular component 671:Molecular function 8112: 8111: 8091:Other inhibitors: 7835: 7834: 7816: 7740:Other inhibitors: 7480: 7479: 7373: 7372: 7331: 7330: 7228: 7227: 7224: 7223: 7032: 7031: 6710: 6709: 6365: 6364: 5883:Nature Milestones 5782:(11): 1555–1564. 5495:10.1002/bmb.20211 5431:Curr Top Med Chem 5393:10.1038/srep32747 5229:(6212): 225–228. 5179:(15): 6951–6954. 5092:(17): 6361–6373. 4901:(6028): 552–554. 4723:(4775): 470–474. 4680:(4716): 869–871. 4594:(5996): 724–729. 4239:(10): 1302–1312. 4005:978-3-8055-9384-7 3996:10.1159/000289196 3858:(11): 2074–2092. 3582:amyloid-β plaques 3543:neuroinflammation 3539:endothelial cells 3521:Neuroinflammation 3423:hepatitis C virus 3093:endothelial cells 3089:white blood cells 3055:(PAMPs), such as 2984:Reverse signaling 2940:, and subsets of 2934:endothelial cells 2815:ubiquitin ligases 2797:, which recruits 2227:chromosome 6p21.3 2129:hemoconcentration 2047:Edman degradation 1880:blood coagulation 1835:that function as 1794: 1793: 1790: 1789: 1763: 1762: 1728: 1727: 1703: 1702: 1677: 1676: 1652: 1651: 1626: 1625: 1607: 1606: 1581: 1580: 1562: 1561: 1506: 1505: 1487: 1486: 1435: 1434: 935:response to virus 693:cytokine activity 655: 654: 651: 650: 620: 619: 607: 606: 545: 544: 518:bone marrow cells 443: 442: 342: 341: 169: 168: 165: 164: 77:Ortholog search: 39:lymphotoxin alpha 16:(Redirected from 8176: 8169:Immunostimulants 8141: 8140: 8139: 8129: 8128: 8120: 8081:Decoy receptors: 7814: 7705:Decoy receptors: 7573: 7572: 7555:Decoy receptors: 7516: 7507: 7500: 7493: 7484: 7483: 7111: 7110: 7043: 7042: 6826: 6825: 6811: 6810: 6423: 6422: 6414: 6413: 6392: 6385: 6378: 6369: 6368: 6351: 6336: 6321: 6306: 6291: 6276: 6256: 6249: 6242: 6233: 6232: 6188: 6187: 6177: 6167: 6143: 6137: 6136: 6126: 6116: 6101:J Alzheimers Dis 6092: 6086: 6085: 6075: 6065: 6041: 6030: 6029: 6019: 6009: 5985: 5979: 5978: 5968: 5944: 5938: 5937: 5927: 5917: 5893: 5887: 5886: 5874: 5868: 5867: 5857: 5847: 5823: 5812: 5811: 5801: 5791: 5767: 5758: 5757: 5747: 5737: 5713: 5704: 5703: 5693: 5683: 5659: 5648: 5647: 5645: 5625: 5619: 5618: 5608: 5584: 5578: 5577: 5567: 5557: 5533: 5518: 5517: 5507: 5497: 5473: 5467: 5466: 5456: 5446: 5422: 5416: 5415: 5405: 5395: 5363: 5357: 5356: 5346: 5336: 5312: 5306: 5305: 5299: 5291: 5281: 5261: 5255: 5254: 5243:10.1038/338225a0 5218: 5209: 5208: 5198: 5188: 5164: 5158: 5157: 5129: 5120: 5119: 5109: 5077: 5071: 5070: 5058: 5052: 5051: 5041: 5032:(4): 1148–1157. 5026:Gastroenterology 5017: 5008: 5007: 4997: 4974:JAMA Dermatology 4969: 4963: 4962: 4933: 4927: 4926: 4915:10.1038/316552a0 4890: 4884: 4883: 4873: 4841: 4835: 4834: 4824: 4814: 4805:(8): 1919–1924. 4790: 4784: 4783: 4755: 4749: 4748: 4712: 4706: 4705: 4669: 4663: 4662: 4652: 4642: 4633:(3): 1058–1066. 4618: 4612: 4611: 4600:10.1038/312724a0 4583: 4577: 4576: 4566: 4557:(4): 2345–2354. 4542: 4536: 4535: 4525: 4493: 4480: 4479: 4469: 4459: 4442:(9): 3666–3670. 4427: 4418: 4417: 4397: 4391: 4390: 4370: 4364: 4363: 4353: 4343: 4334:(9): 1344–1350. 4319: 4313: 4312: 4302: 4292: 4268: 4259: 4258: 4248: 4224: 4218: 4217: 4207: 4197: 4173: 4160: 4159: 4149: 4138: 4137: 4127: 4103: 4088: 4087: 4077: 4067: 4058:(7): 1215–1228. 4043: 4028: 4027: 4017: 3983: 3948: 3947: 3937: 3927: 3903: 3888: 3887: 3877: 3867: 3852:Genome Biol Evol 3843: 3828: 3827: 3817: 3807: 3783: 3750: 3749: 3738: 3732: 3731: 3720: 3714: 3704: 3693: 3682: 3559:neurosarcoidosis 3454:Type II Diabetes 3452:and can lead to 3291:epithelial cells 3236:Taste Perception 3226:oligodendrocytes 2994:B lymphoma cells 2831:ubiquitin ligase 2013:In August 1984, 1952:Escherichia coli 1928:William B. Coley 1776: 1775: 1747: 1740: 1723: 1707: 1706: 1698: 1686: 1685: 1682:RefSeq (protein) 1672: 1656: 1655: 1647: 1635: 1634: 1611: 1610: 1592: 1591: 1566: 1565: 1541: 1517: 1516: 1491: 1490: 1472: 1471: 1441: 1440: 1140:defense response 683:protease binding 661: 660: 647: 638: 631: 630: 616: 556: 554:Top expressed in 549: 548: 494: 492:Top expressed in 487: 486: 466: 465: 449: 448: 439: 426: 415: 400: 393: 387: 376: 364: 348: 347: 338: 325: 314: 299: 292: 286: 275: 261: 245: 244: 239: 190: 183: 160: 91: 90: 85: 64: 63: 58: 46: 45: 21: 8184: 8183: 8179: 8178: 8177: 8175: 8174: 8173: 8149: 8148: 8147: 8137: 8135: 8123: 8115: 8113: 8108: 7934:TWEAK (TNFSF12) 7904:GITRL (TNFSF18) 7831: 7643: 7607: 7562: 7522: 7511: 7481: 7476: 7442: 7421: 7379: 7369: 7327: 7300: 7220: 7202: 7100: 7028: 6997: 6960: 6898: 6870: 6821: 6819: 6817: 6800: 6706: 6685: 6669: 6572: 6405: 6396: 6366: 6361: 6358: 6352: 6343: 6337: 6328: 6322: 6313: 6307: 6298: 6292: 6283: 6277: 6263: 6260: 6197: 6192: 6191: 6144: 6140: 6093: 6089: 6042: 6033: 5986: 5982: 5945: 5941: 5894: 5890: 5875: 5871: 5824: 5815: 5768: 5761: 5714: 5707: 5660: 5651: 5626: 5622: 5585: 5581: 5534: 5521: 5474: 5470: 5423: 5419: 5364: 5360: 5313: 5309: 5293: 5292: 5262: 5258: 5219: 5212: 5165: 5161: 5130: 5123: 5078: 5074: 5059: 5055: 5018: 5011: 4970: 4966: 4934: 4930: 4891: 4887: 4842: 4838: 4791: 4787: 4756: 4752: 4713: 4709: 4670: 4666: 4619: 4615: 4584: 4580: 4543: 4539: 4494: 4483: 4428: 4421: 4398: 4394: 4371: 4367: 4320: 4316: 4269: 4262: 4225: 4221: 4174: 4163: 4150: 4141: 4104: 4091: 4044: 4031: 4006: 3984: 3951: 3904: 3891: 3844: 3831: 3792:Nat Rev Immunol 3784: 3753: 3740: 3739: 3735: 3722: 3721: 3717: 3705: 3696: 3686:ENSG00000206439 3683: 3674: 3669: 3649:small compounds 3642:fusion proteins 3622: 3616: 3611: 3595: 3573:animal models. 3523: 3506: 3498:satellite cells 3486: 3476:, hepatocytes, 3466: 3438: 3392: 3375: 3356:Cytomegalovirus 3344: 3312:immunocytokines 3300: 3255: 3250: 3238: 3211:GABAA receptors 3176: 3085:dendritic cells 3045: 3043:Immune Response 2986: 2922: 2920:TNFR2 signaling 2882:phosphorylation 2852:deubiquitinases 2771: 2769:TNFR1 signaling 2739: 2723:Small molecules 2709: 2669: 2629: 2609: 2589:higher primates 2565: 2522: 2494: 2428: 2330:dendritic cells 2306: 2294:AU-rich element 2269:separated by 3 2255: 2219: 2211:lymphoid organs 2172: 2148: 2086: 2015:Bharat Aggarwal 2011: 1924: 1919: 1856:dendritic cells 1815:in response to 1785:View/Edit Mouse 1780:View/Edit Human 1743: 1736: 1733:Location (UCSC) 1719: 1715: 1694: 1668: 1664: 1643: 1556:ENSG00000206439 1554: 1552:ENSG00000228849 1550: 1548:ENSG00000232810 1540: 1538:ENSG00000228321 1536: 1534:ENSG00000204490 1532: 1530:ENSG00000223952 1528: 1526:ENSG00000230108 1524: 1522:ENSG00000228978 1520: 1419: 1070:immune response 773: 759:plasma membrane 702: 678:protein binding 643: 612: 603: 598: 594: 590: 586: 582: 578: 574: 570: 566: 552: 541: 536: 532: 528: 524: 520: 516: 512: 508: 504: 490: 434: 421: 413: 403: 402: 401: 394: 374: 351:Gene location ( 333: 320: 312: 302: 301: 300: 293: 271: 248:Gene location ( 237:TNF - orthologs 199: 186: 179: 100: 78: 42: 35: 28: 23: 22: 15: 12: 11: 5: 8182: 8172: 8171: 8166: 8161: 8146: 8145: 8133: 8110: 8109: 8107: 8106: 8097: 8096: 8087: 8086: 8077: 8076: 8071: 8066: 8061: 8056: 8051: 8046: 8041: 8036: 8031: 8026: 8021: 8016: 8011: 8006: 8001: 7996: 7991: 7986: 7981: 7976: 7971: 7966: 7957: 7956: 7951: 7942: 7941: 7936: 7931: 7926: 7921: 7916: 7911: 7906: 7901: 7896: 7882: 7877: 7872: 7867: 7862: 7857: 7852: 7843: 7841: 7837: 7836: 7833: 7832: 7830: 7829: 7824: 7819: 7811: 7806: 7804:Pentoxifylline 7801: 7796: 7791: 7786: 7776: 7760: 7750: 7745: 7736: 7735: 7726: 7725: 7720: 7715: 7710: 7701: 7700: 7695: 7690: 7685: 7680: 7675: 7670: 7665: 7660: 7651: 7649: 7645: 7644: 7642: 7641: 7636: 7631: 7626: 7617: 7615: 7609: 7608: 7606: 7605: 7600: 7595: 7590: 7581: 7579: 7570: 7564: 7563: 7561: 7560: 7551: 7550: 7532: 7530: 7524: 7523: 7510: 7509: 7502: 7495: 7487: 7478: 7477: 7475: 7474: 7473: 7472: 7471: 7470: 7465: 7460: 7455: 7450: 7440: 7436: 7435: 7434: 7429: 7419: 7410: 7404: 7403: 7402: 7401: 7396: 7383: 7381: 7375: 7374: 7371: 7370: 7368: 7367: 7362: 7357: 7356: 7355: 7350: 7339: 7337: 7333: 7332: 7329: 7328: 7326: 7325: 7310: 7308: 7302: 7301: 7299: 7298: 7293: 7288: 7283: 7278: 7273: 7268: 7263: 7258: 7253: 7248: 7238: 7236: 7234:Ig superfamily 7230: 7229: 7226: 7225: 7222: 7221: 7219: 7218: 7212: 7210: 7204: 7203: 7201: 7200: 7195: 7190: 7185: 7180: 7175: 7170: 7165: 7160: 7155: 7150: 7145: 7140: 7135: 7130: 7125: 7119: 7117: 7108: 7102: 7101: 7099: 7098: 7097: 7096: 7091: 7081: 7076: 7071: 7066: 7061: 7051: 7049: 7040: 7034: 7033: 7030: 7029: 7027: 7026: 7021: 7016: 7011: 7005: 7003: 6999: 6998: 6996: 6995: 6990: 6985: 6980: 6974: 6972: 6962: 6961: 6959: 6958: 6957: 6956: 6951: 6946: 6941: 6930: 6925: 6920: 6915: 6909: 6907: 6900: 6899: 6897: 6896: 6891: 6886: 6880: 6878: 6872: 6871: 6869: 6868: 6863: 6858: 6853: 6844: 6834: 6832: 6823: 6808: 6802: 6801: 6799: 6798: 6793: 6788: 6783: 6778: 6773: 6768: 6763: 6758: 6753: 6748: 6743: 6742: 6741: 6736: 6726: 6720: 6718: 6712: 6711: 6708: 6707: 6705: 6704: 6699: 6693: 6691: 6687: 6686: 6684: 6683: 6677: 6675: 6671: 6670: 6668: 6667: 6662: 6657: 6652: 6647: 6642: 6637: 6632: 6627: 6622: 6617: 6612: 6607: 6602: 6597: 6592: 6587: 6580: 6578: 6574: 6573: 6571: 6570: 6565: 6560: 6555: 6550: 6545: 6540: 6535: 6530: 6525: 6520: 6514: 6509: 6504: 6499: 6494: 6489: 6484: 6479: 6474: 6469: 6464: 6459: 6453: 6447: 6441: 6435: 6429: 6427: 6420: 6411: 6407: 6406: 6399:Cell signaling 6395: 6394: 6387: 6380: 6372: 6363: 6362: 6360: 6359: 6353: 6346: 6344: 6338: 6331: 6329: 6323: 6316: 6314: 6308: 6301: 6299: 6293: 6286: 6284: 6278: 6271: 6268: 6265: 6264: 6259: 6258: 6251: 6244: 6236: 6230: 6229: 6208: 6196: 6195:External links 6193: 6190: 6189: 6138: 6107:(2): 619–626. 6087: 6031: 5980: 5959:(5): 335–347. 5939: 5908:(3): 191–206. 5888: 5869: 5838:(4): 253–261. 5813: 5759: 5728:(3): 165–174. 5705: 5649: 5620: 5606:10.1086/317513 5579: 5519: 5488:(4): 274–283. 5468: 5417: 5358: 5327:(2): 131–143. 5307: 5272:(2): 381–387. 5256: 5210: 5159: 5140:(5): 487–497. 5121: 5072: 5053: 5009: 4964: 4945:(6): 847–856. 4928: 4885: 4856:(3): 631–639. 4836: 4785: 4750: 4707: 4664: 4613: 4578: 4537: 4481: 4419: 4392: 4381:(5): 461–476. 4365: 4314: 4260: 4219: 4161: 4139: 4089: 4029: 4004: 3949: 3889: 3829: 3798:(5): 289–303. 3751: 3733: 3715: 3694: 3671: 3670: 3668: 3665: 3653:immunogenicity 3618:Main article: 3615: 3612: 3610: 3607: 3594: 3591: 3522: 3519: 3505: 3502: 3490:muscle wasting 3485: 3484:Muscle wasting 3482: 3465: 3462: 3444:by inhibiting 3437: 3434: 3413:Additionally, 3396:liver fibrosis 3391: 3390:Liver fibrosis 3388: 3374: 3371: 3343: 3340: 3299: 3296: 3254: 3251: 3249: 3246: 3237: 3234: 3230:myelin sheaths 3207:NDMA receptors 3203:AMPA receptors 3175: 3172: 3164:prostaglandins 3160:norepinephrine 3063:, bind to the 3044: 3041: 3012:, and TNF. In 2985: 2982: 2959:. This allows 2921: 2918: 2770: 2767: 2738: 2735: 2713:molten globule 2708: 2705: 2668: 2665: 2661:Interleukin-12 2650:phosphorylated 2628: 2625: 2608: 2605: 2564: 2561: 2521: 2518: 2493: 2490: 2427: 2424: 2389:osmotic stress 2305: 2302: 2254: 2251: 2233:region of the 2221:The human TNF 2218: 2215: 2171: 2168: 2147: 2144: 2109:Anthony Cerami 2105:Kevin J. Tracy 2085: 2082: 2070:signal peptide 2010: 2007: 1926:In the 1890s, 1923: 1920: 1918: 1915: 1907:liver fibrosis 1831:, a family of 1792: 1791: 1788: 1787: 1782: 1772: 1771: 1765: 1764: 1761: 1760: 1758: 1756: 1749: 1748: 1741: 1734: 1730: 1729: 1726: 1725: 1711: 1710: 1704: 1701: 1700: 1690: 1689: 1683: 1679: 1678: 1675: 1674: 1660: 1659: 1653: 1650: 1649: 1639: 1638: 1632: 1628: 1627: 1624: 1623: 1615: 1614: 1608: 1605: 1604: 1596: 1595: 1589: 1583: 1582: 1579: 1578: 1570: 1569: 1563: 1560: 1559: 1543: 1542: 1514: 1508: 1507: 1504: 1503: 1495: 1494: 1488: 1485: 1484: 1476: 1475: 1469: 1463: 1462: 1457: 1452: 1448: 1447: 1437: 1436: 1433: 1432: 1421: 1420: 1418: 1417: 1412: 1407: 1402: 1397: 1392: 1387: 1382: 1377: 1372: 1367: 1362: 1357: 1352: 1347: 1342: 1337: 1332: 1327: 1322: 1317: 1312: 1307: 1302: 1297: 1292: 1287: 1282: 1277: 1272: 1267: 1262: 1257: 1252: 1247: 1242: 1237: 1232: 1227: 1222: 1217: 1212: 1207: 1202: 1197: 1192: 1187: 1182: 1177: 1172: 1167: 1162: 1157: 1152: 1147: 1142: 1137: 1132: 1127: 1122: 1117: 1112: 1107: 1102: 1097: 1092: 1087: 1082: 1077: 1072: 1067: 1062: 1057: 1052: 1047: 1042: 1037: 1032: 1027: 1022: 1017: 1012: 1007: 1002: 997: 992: 987: 982: 977: 972: 967: 962: 957: 952: 947: 942: 937: 932: 927: 922: 917: 912: 907: 902: 897: 892: 887: 882: 877: 872: 867: 862: 857: 852: 847: 842: 837: 832: 827: 822: 817: 812: 807: 802: 797: 792: 787: 781: 779: 775: 774: 772: 771: 766: 761: 756: 751: 746: 744:phagocytic cup 741: 736: 731: 726: 721: 716: 710: 708: 704: 703: 701: 700: 695: 690: 685: 680: 674: 672: 668: 667: 657: 656: 653: 652: 649: 648: 640: 639: 628: 622: 621: 618: 617: 609: 608: 605: 604: 602: 601: 597: 593: 589: 585: 581: 577: 576:wall of uterus 573: 569: 565: 561: 558: 557: 546: 543: 542: 540: 539: 535: 531: 527: 523: 519: 515: 511: 507: 503: 499: 496: 495: 483: 482: 474: 463: 457: 456: 453:RNA expression 445: 444: 441: 440: 432: 428: 427: 419: 416: 411: 405: 404: 395: 388: 382: 378: 377: 372: 366: 365: 357: 356: 344: 343: 340: 339: 331: 327: 326: 318: 315: 310: 304: 303: 294: 287: 281: 277: 276: 269: 263: 262: 254: 253: 241: 240: 197: 193: 192: 184: 176: 175: 171: 170: 167: 166: 163: 162: 96: 95: 87: 86: 75: 69: 68: 60: 59: 51: 50: 26: 9: 6: 4: 3: 2: 8181: 8170: 8167: 8165: 8162: 8160: 8157: 8156: 8154: 8144: 8134: 8132: 8127: 8122: 8121: 8118: 8105: 8102: 8099: 8098: 8095: 8092: 8089: 8088: 8085: 8082: 8079: 8078: 8075: 8072: 8070: 8067: 8065: 8062: 8060: 8057: 8055: 8052: 8050: 8047: 8045: 8042: 8040: 8037: 8035: 8034:Tavolixizumab 8032: 8030: 8027: 8025: 8022: 8020: 8017: 8015: 8012: 8010: 8007: 8005: 8002: 8000: 7997: 7995: 7992: 7990: 7987: 7985: 7982: 7980: 7977: 7975: 7972: 7970: 7967: 7965: 7962: 7959: 7958: 7955: 7952: 7950: 7947: 7944: 7943: 7940: 7937: 7935: 7932: 7930: 7927: 7925: 7924:Siva (CD27BP) 7922: 7920: 7917: 7915: 7912: 7910: 7907: 7905: 7902: 7900: 7897: 7894: 7890: 7886: 7885:Ectodysplasin 7883: 7881: 7878: 7876: 7873: 7871: 7868: 7866: 7863: 7861: 7858: 7856: 7853: 7851: 7848: 7845: 7844: 7842: 7838: 7828: 7825: 7823: 7820: 7818: 7812: 7810: 7807: 7805: 7802: 7800: 7797: 7795: 7792: 7790: 7787: 7784: 7780: 7777: 7774: 7773: 7768: 7764: 7761: 7758: 7754: 7751: 7749: 7746: 7744: 7741: 7738: 7737: 7734: 7731: 7728: 7727: 7724: 7721: 7719: 7716: 7714: 7711: 7709: 7706: 7703: 7702: 7699: 7696: 7694: 7691: 7689: 7686: 7684: 7681: 7679: 7676: 7674: 7671: 7669: 7666: 7664: 7661: 7659: 7656: 7653: 7652: 7650: 7646: 7640: 7637: 7635: 7632: 7630: 7627: 7625: 7622: 7619: 7618: 7616: 7614: 7610: 7604: 7601: 7599: 7596: 7594: 7591: 7589: 7586: 7583: 7582: 7580: 7578: 7574: 7571: 7569: 7565: 7559: 7556: 7553: 7552: 7548: 7544: 7540: 7537: 7534: 7533: 7531: 7529: 7525: 7521: 7518: 7508: 7503: 7501: 7496: 7494: 7489: 7488: 7485: 7469: 7466: 7464: 7461: 7459: 7456: 7454: 7451: 7449: 7446: 7445: 7444: 7437: 7433: 7430: 7428: 7425: 7424: 7423: 7416: 7415: 7414: 7411: 7409: 7406: 7405: 7400: 7397: 7395: 7392: 7391: 7390: 7389: 7385: 7384: 7382: 7376: 7366: 7363: 7361: 7358: 7354: 7351: 7349: 7346: 7345: 7344: 7343:Hematopoietic 7341: 7340: 7338: 7334: 7323: 7319: 7315: 7312: 7311: 7309: 7307: 7303: 7297: 7294: 7292: 7289: 7287: 7284: 7282: 7279: 7277: 7274: 7272: 7269: 7267: 7264: 7262: 7259: 7257: 7254: 7252: 7249: 7247: 7243: 7240: 7239: 7237: 7235: 7231: 7217: 7214: 7213: 7211: 7209: 7205: 7199: 7196: 7194: 7191: 7189: 7186: 7184: 7181: 7179: 7176: 7174: 7171: 7169: 7166: 7164: 7161: 7159: 7156: 7154: 7151: 7149: 7146: 7144: 7141: 7139: 7136: 7134: 7131: 7129: 7126: 7124: 7121: 7120: 7118: 7116: 7112: 7109: 7107: 7103: 7095: 7092: 7090: 7087: 7086: 7085: 7082: 7080: 7077: 7075: 7072: 7070: 7067: 7065: 7062: 7060: 7056: 7053: 7052: 7050: 7048: 7044: 7041: 7039: 7035: 7025: 7022: 7020: 7017: 7015: 7012: 7010: 7007: 7006: 7004: 7000: 6994: 6991: 6989: 6986: 6984: 6981: 6979: 6976: 6975: 6973: 6971: 6967: 6963: 6955: 6952: 6950: 6947: 6945: 6942: 6940: 6936: 6935: 6934: 6931: 6929: 6926: 6924: 6921: 6919: 6916: 6914: 6911: 6910: 6908: 6906: 6901: 6895: 6892: 6890: 6887: 6885: 6882: 6881: 6879: 6877: 6873: 6867: 6864: 6862: 6859: 6857: 6854: 6852: 6848: 6845: 6843: 6839: 6836: 6835: 6833: 6831: 6827: 6824: 6816: 6812: 6809: 6807: 6803: 6797: 6794: 6792: 6789: 6787: 6784: 6782: 6779: 6777: 6774: 6772: 6769: 6767: 6764: 6762: 6759: 6757: 6754: 6752: 6751:TNFSF5/CD40LG 6749: 6747: 6744: 6740: 6737: 6735: 6732: 6731: 6730: 6727: 6725: 6722: 6721: 6719: 6717: 6713: 6703: 6700: 6698: 6695: 6694: 6692: 6688: 6682: 6679: 6678: 6676: 6672: 6666: 6663: 6661: 6658: 6656: 6653: 6651: 6648: 6646: 6643: 6641: 6638: 6636: 6633: 6631: 6628: 6626: 6623: 6621: 6618: 6616: 6613: 6611: 6608: 6606: 6603: 6601: 6598: 6596: 6593: 6591: 6588: 6585: 6582: 6581: 6579: 6575: 6569: 6566: 6564: 6561: 6559: 6556: 6554: 6551: 6549: 6546: 6544: 6541: 6539: 6536: 6534: 6531: 6529: 6526: 6524: 6521: 6518: 6515: 6513: 6510: 6508: 6505: 6503: 6500: 6498: 6495: 6493: 6490: 6488: 6485: 6483: 6480: 6478: 6475: 6473: 6470: 6468: 6465: 6463: 6460: 6457: 6454: 6451: 6448: 6445: 6442: 6439: 6436: 6434: 6431: 6430: 6428: 6424: 6421: 6419: 6415: 6412: 6408: 6404: 6400: 6393: 6388: 6386: 6381: 6379: 6374: 6373: 6370: 6356: 6350: 6345: 6341: 6335: 6330: 6326: 6320: 6315: 6311: 6305: 6300: 6296: 6290: 6285: 6281: 6275: 6270: 6269: 6266: 6257: 6252: 6250: 6245: 6243: 6238: 6237: 6234: 6227: 6223: 6222: 6217: 6213: 6209: 6206: 6202: 6199: 6198: 6185: 6181: 6176: 6171: 6166: 6161: 6157: 6153: 6152:Int J Mol Sci 6149: 6142: 6134: 6130: 6125: 6120: 6115: 6110: 6106: 6102: 6098: 6091: 6083: 6079: 6074: 6069: 6064: 6059: 6055: 6051: 6047: 6040: 6038: 6036: 6027: 6023: 6018: 6013: 6008: 6003: 5999: 5995: 5991: 5984: 5976: 5972: 5967: 5962: 5958: 5954: 5950: 5943: 5935: 5931: 5926: 5921: 5916: 5911: 5907: 5903: 5899: 5892: 5884: 5880: 5873: 5865: 5861: 5856: 5851: 5846: 5841: 5837: 5833: 5829: 5822: 5820: 5818: 5809: 5805: 5800: 5795: 5790: 5785: 5781: 5777: 5773: 5766: 5764: 5755: 5751: 5746: 5741: 5736: 5731: 5727: 5723: 5719: 5712: 5710: 5701: 5697: 5692: 5687: 5682: 5677: 5673: 5669: 5665: 5658: 5656: 5654: 5644: 5639: 5635: 5631: 5624: 5616: 5612: 5607: 5602: 5598: 5594: 5590: 5583: 5575: 5571: 5566: 5561: 5556: 5551: 5547: 5543: 5542:Front Immunol 5539: 5532: 5530: 5528: 5526: 5524: 5515: 5511: 5506: 5501: 5496: 5491: 5487: 5483: 5479: 5472: 5464: 5460: 5455: 5450: 5445: 5440: 5436: 5432: 5428: 5421: 5413: 5409: 5404: 5399: 5394: 5389: 5385: 5381: 5377: 5373: 5369: 5362: 5354: 5350: 5345: 5340: 5335: 5330: 5326: 5322: 5318: 5311: 5303: 5297: 5289: 5285: 5280: 5275: 5271: 5267: 5266:Eur J Biochem 5260: 5252: 5248: 5244: 5240: 5236: 5232: 5228: 5224: 5217: 5215: 5206: 5202: 5197: 5192: 5187: 5182: 5178: 5174: 5170: 5163: 5155: 5151: 5147: 5143: 5139: 5135: 5128: 5126: 5117: 5113: 5108: 5103: 5099: 5095: 5091: 5087: 5083: 5076: 5068: 5064: 5057: 5049: 5045: 5040: 5035: 5031: 5027: 5023: 5016: 5014: 5005: 5001: 4996: 4991: 4987: 4983: 4979: 4975: 4968: 4960: 4956: 4952: 4948: 4944: 4940: 4932: 4924: 4920: 4916: 4912: 4908: 4904: 4900: 4896: 4889: 4881: 4877: 4872: 4867: 4863: 4859: 4855: 4851: 4847: 4840: 4832: 4828: 4823: 4818: 4813: 4808: 4804: 4800: 4796: 4789: 4781: 4777: 4773: 4769: 4765: 4761: 4754: 4746: 4742: 4738: 4734: 4730: 4726: 4722: 4718: 4711: 4703: 4699: 4695: 4691: 4687: 4683: 4679: 4675: 4668: 4660: 4656: 4651: 4646: 4641: 4636: 4632: 4628: 4624: 4617: 4609: 4605: 4601: 4597: 4593: 4589: 4582: 4574: 4570: 4565: 4560: 4556: 4552: 4548: 4541: 4533: 4529: 4524: 4519: 4515: 4511: 4507: 4503: 4499: 4492: 4490: 4488: 4486: 4477: 4473: 4468: 4463: 4458: 4453: 4449: 4445: 4441: 4437: 4433: 4426: 4424: 4415: 4411: 4408:(1): 99–105. 4407: 4403: 4396: 4388: 4384: 4380: 4376: 4369: 4361: 4357: 4352: 4347: 4342: 4337: 4333: 4329: 4325: 4318: 4310: 4306: 4301: 4296: 4291: 4286: 4282: 4278: 4277:Int J Mol Sci 4274: 4267: 4265: 4256: 4252: 4247: 4242: 4238: 4234: 4230: 4223: 4215: 4211: 4206: 4201: 4196: 4191: 4187: 4183: 4182:Front Immunol 4179: 4172: 4170: 4168: 4166: 4158:. LibreTexts. 4157: 4156: 4148: 4146: 4144: 4135: 4131: 4126: 4121: 4117: 4113: 4109: 4102: 4100: 4098: 4096: 4094: 4085: 4081: 4076: 4071: 4066: 4061: 4057: 4053: 4049: 4042: 4040: 4038: 4036: 4034: 4025: 4021: 4016: 4011: 4007: 4001: 3997: 3993: 3989: 3982: 3980: 3978: 3976: 3974: 3972: 3970: 3968: 3966: 3964: 3962: 3960: 3958: 3956: 3954: 3945: 3941: 3936: 3931: 3926: 3921: 3917: 3913: 3912:Int J Mol Sci 3909: 3902: 3900: 3898: 3896: 3894: 3885: 3881: 3876: 3871: 3866: 3861: 3857: 3853: 3849: 3842: 3840: 3838: 3836: 3834: 3825: 3821: 3816: 3811: 3806: 3801: 3797: 3793: 3789: 3782: 3780: 3778: 3776: 3774: 3772: 3770: 3768: 3766: 3764: 3762: 3760: 3758: 3756: 3747: 3743: 3737: 3729: 3725: 3719: 3712: 3708: 3703: 3701: 3699: 3691: 3687: 3681: 3679: 3677: 3672: 3664: 3660: 3658: 3654: 3650: 3645: 3643: 3640: 3636: 3632: 3628: 3621: 3620:TNF inhibitor 3606: 3604: 3600: 3590: 3587: 3583: 3579: 3574: 3570: 3568: 3564: 3560: 3556: 3552: 3548: 3544: 3540: 3536: 3532: 3528: 3518: 3515: 3511: 3501: 3499: 3495: 3491: 3481: 3479: 3478:Kupffer cells 3475: 3471: 3461: 3459: 3455: 3451: 3447: 3443: 3440:TNF promotes 3433: 3430: 3428: 3424: 3420: 3416: 3411: 3409: 3405: 3401: 3397: 3387: 3383: 3380: 3370: 3368: 3364: 3359: 3357: 3353: 3349: 3339: 3337: 3333: 3329: 3326:that promote 3325: 3319: 3317: 3313: 3307: 3305: 3295: 3292: 3286: 3284: 3280: 3276: 3272: 3268: 3264: 3260: 3245: 3243: 3233: 3231: 3227: 3222: 3220: 3216: 3212: 3208: 3204: 3199: 3197: 3193: 3189: 3185: 3181: 3171: 3169: 3165: 3161: 3157: 3153: 3149: 3145: 3144:interleukin-6 3141: 3140:interleukin-1 3137: 3132: 3128: 3126: 3122: 3118: 3114: 3110: 3106: 3102: 3096: 3094: 3090: 3086: 3082: 3078: 3074: 3070: 3066: 3062: 3058: 3054: 3050: 3040: 3038: 3034: 3030: 3026: 3021: 3019: 3015: 3011: 3007: 3003: 2999: 2995: 2990: 2981: 2977: 2973: 2970: 2966: 2962: 2958: 2954: 2949: 2947: 2943: 2939: 2935: 2926: 2917: 2915: 2911: 2905: 2903: 2902:cycloheximide 2899: 2894: 2892: 2888: 2883: 2878: 2876: 2872: 2867: 2865: 2861: 2857: 2853: 2848: 2844: 2840: 2836: 2832: 2828: 2824: 2820: 2816: 2812: 2808: 2804: 2800: 2796: 2792: 2787: 2784: 2775: 2766: 2764: 2760: 2756: 2752: 2748: 2744: 2734: 2732: 2727: 2724: 2720: 2716: 2714: 2704: 2700: 2698: 2694: 2690: 2686: 2683:and a single 2682: 2673: 2664: 2662: 2658: 2653: 2651: 2647: 2646:palmitoylated 2641: 2639: 2635: 2624: 2622: 2618: 2614: 2604: 2602: 2598: 2594: 2590: 2585: 2583: 2577: 2574: 2573:Gnathostomata 2570: 2560: 2558: 2552: 2550: 2545: 2543: 2539: 2535: 2531: 2527: 2517: 2515: 2511: 2507: 2502: 2499: 2489: 2486: 2484: 2480: 2476: 2472: 2468: 2463: 2461: 2457: 2453: 2448: 2445: 2441: 2440:enhanceosomes 2432: 2423: 2421: 2417: 2413: 2409: 2405: 2401: 2397: 2392: 2390: 2386: 2382: 2378: 2377:Interleukin-2 2374: 2373:Interleukin-1 2370: 2366: 2362: 2358: 2354: 2353:superantigens 2350: 2346: 2341: 2339: 2335: 2331: 2327: 2323: 2319: 2315: 2311: 2301: 2299: 2295: 2290: 2286: 2284: 2280: 2276: 2272: 2268: 2259: 2250: 2248: 2244: 2240: 2239:lymphotoxin-α 2236: 2232: 2228: 2225:is mapped to 2224: 2214: 2212: 2208: 2207:lymphotoxin-β 2204: 2200: 2199:cell membrane 2196: 2191: 2189: 2185: 2181: 2177: 2167: 2163: 2161: 2157: 2153: 2143: 2140: 2138: 2132: 2131:, and death. 2130: 2126: 2122: 2118: 2117:Bruce Beutler 2114: 2110: 2106: 2101: 2099: 2095: 2091: 2081: 2079: 2075: 2071: 2067: 2063: 2058: 2056: 2055:lymphotoxin-α 2052: 2048: 2044: 2040: 2036: 2032: 2028: 2024: 2020: 2016: 2006: 2003: 1999: 1998: 1993: 1992: 1986: 1984: 1980: 1976: 1972: 1968: 1963: 1961: 1957: 1953: 1948: 1945: 1941: 1940:Streptococcus 1937: 1933: 1929: 1914: 1912: 1908: 1904: 1900: 1896: 1891: 1889: 1885: 1881: 1875: 1873: 1869: 1865: 1861: 1857: 1853: 1849: 1844: 1842: 1838: 1834: 1830: 1826: 1822: 1818: 1814: 1810: 1806: 1802: 1798: 1786: 1781: 1777: 1773: 1770: 1766: 1759: 1757: 1754: 1750: 1746: 1742: 1739: 1735: 1731: 1724: 1722: 1718: 1712: 1708: 1705: 1699: 1697: 1691: 1687: 1684: 1680: 1673: 1671: 1667: 1661: 1657: 1654: 1648: 1646: 1640: 1636: 1633: 1631:RefSeq (mRNA) 1629: 1622: 1621: 1616: 1612: 1609: 1603: 1602: 1597: 1593: 1590: 1588: 1584: 1577: 1576: 1571: 1567: 1564: 1558: 1557: 1553: 1549: 1544: 1539: 1535: 1531: 1527: 1523: 1518: 1515: 1513: 1509: 1502: 1501: 1496: 1492: 1489: 1483: 1482: 1477: 1473: 1470: 1468: 1464: 1461: 1458: 1456: 1453: 1449: 1446: 1442: 1438: 1431: 1427: 1422: 1416: 1413: 1411: 1408: 1406: 1403: 1401: 1398: 1396: 1393: 1391: 1388: 1386: 1383: 1381: 1378: 1376: 1373: 1371: 1368: 1366: 1363: 1361: 1358: 1356: 1353: 1351: 1348: 1346: 1343: 1341: 1338: 1336: 1333: 1331: 1328: 1326: 1323: 1321: 1318: 1316: 1313: 1311: 1308: 1306: 1303: 1301: 1298: 1296: 1293: 1291: 1288: 1286: 1283: 1281: 1278: 1276: 1273: 1271: 1268: 1266: 1263: 1261: 1258: 1256: 1253: 1251: 1248: 1246: 1243: 1241: 1238: 1236: 1233: 1231: 1228: 1226: 1223: 1221: 1218: 1216: 1213: 1211: 1208: 1206: 1203: 1201: 1198: 1196: 1193: 1191: 1188: 1186: 1183: 1181: 1178: 1176: 1173: 1171: 1168: 1166: 1163: 1161: 1158: 1156: 1153: 1151: 1148: 1146: 1143: 1141: 1138: 1136: 1133: 1131: 1128: 1126: 1123: 1121: 1118: 1116: 1113: 1111: 1108: 1106: 1103: 1101: 1098: 1096: 1093: 1091: 1088: 1086: 1083: 1081: 1078: 1076: 1073: 1071: 1068: 1066: 1063: 1061: 1058: 1056: 1053: 1051: 1048: 1046: 1043: 1041: 1038: 1036: 1033: 1031: 1028: 1026: 1023: 1021: 1018: 1016: 1013: 1011: 1008: 1006: 1003: 1001: 998: 996: 993: 991: 988: 986: 983: 981: 978: 976: 973: 971: 968: 966: 963: 961: 958: 956: 953: 951: 948: 946: 943: 941: 938: 936: 933: 931: 928: 926: 923: 921: 918: 916: 913: 911: 908: 906: 903: 901: 898: 896: 893: 891: 888: 886: 883: 881: 878: 876: 873: 871: 868: 866: 863: 861: 858: 856: 853: 851: 848: 846: 843: 841: 838: 836: 833: 831: 828: 826: 823: 821: 818: 816: 813: 811: 808: 806: 803: 801: 798: 796: 793: 791: 788: 786: 783: 782: 780: 777: 776: 770: 767: 765: 764:membrane raft 762: 760: 757: 755: 752: 750: 747: 745: 742: 740: 737: 735: 732: 730: 727: 725: 722: 720: 717: 715: 712: 711: 709: 706: 705: 699: 696: 694: 691: 689: 686: 684: 681: 679: 676: 675: 673: 670: 669: 666: 665:Gene ontology 662: 658: 646: 641: 637: 632: 629: 627: 623: 615: 610: 599: 595: 591: 587: 583: 579: 575: 571: 567: 563: 562: 559: 555: 550: 547: 537: 533: 529: 525: 521: 517: 513: 509: 505: 501: 500: 497: 493: 488: 485: 484: 481: 479: 475: 473: 472: 468: 467: 464: 462: 458: 454: 450: 446: 438: 433: 429: 425: 420: 410: 406: 399: 392: 386: 379: 371: 367: 363: 358: 354: 349: 345: 337: 332: 328: 324: 319: 309: 305: 298: 291: 285: 278: 274: 268: 264: 260: 255: 251: 246: 242: 238: 234: 230: 226: 222: 218: 214: 210: 206: 202: 194: 189: 182: 177: 172: 161: 159: 155: 151: 147: 143: 139: 135: 131: 127: 123: 119: 115: 111: 107: 103: 97: 92: 89: 88: 84: 81: 74: 70: 65: 61: 57: 52: 47: 44: 40: 33: 19: 8100: 8090: 8080: 8069:Vorsetuzumab 7994:Enavatuzumab 7960: 7945: 7846: 7809:Pomalidomide 7794:Lenalidomide 7770: 7763:Cannabinoids 7739: 7729: 7723:Pegsunercept 7704: 7688:Ozoralizumab 7654: 7620: 7584: 7554: 7535: 7438: 7417: 7386: 7378:By function/ 7089:IL28/IFNL2+3 6354: 6339: 6324: 6309: 6294: 6279: 6219: 6155: 6151: 6141: 6104: 6100: 6090: 6053: 6049: 5997: 5993: 5983: 5956: 5952: 5942: 5905: 5901: 5891: 5882: 5872: 5835: 5831: 5779: 5775: 5725: 5721: 5671: 5667: 5633: 5623: 5596: 5592: 5582: 5545: 5541: 5485: 5481: 5471: 5437:(1): 55–63. 5434: 5430: 5420: 5375: 5371: 5361: 5324: 5320: 5310: 5296:cite journal 5269: 5265: 5259: 5226: 5222: 5176: 5172: 5162: 5137: 5133: 5089: 5085: 5075: 5066: 5056: 5029: 5025: 4977: 4973: 4967: 4942: 4938: 4931: 4898: 4894: 4888: 4853: 4849: 4839: 4802: 4798: 4788: 4763: 4759: 4753: 4720: 4716: 4710: 4677: 4673: 4667: 4630: 4626: 4616: 4591: 4587: 4581: 4554: 4550: 4540: 4508:(2): 83–89. 4505: 4501: 4439: 4435: 4405: 4401: 4395: 4378: 4374: 4368: 4331: 4327: 4317: 4280: 4276: 4236: 4232: 4222: 4185: 4181: 4155:Microbiology 4154: 4115: 4111: 4055: 4052:Rheumatology 4051: 3987: 3915: 3911: 3855: 3851: 3795: 3791: 3745: 3736: 3727: 3718: 3661: 3657:ozoralizumab 3646: 3623: 3614:TNF blockers 3609:Pharmacology 3596: 3575: 3571: 3524: 3507: 3487: 3467: 3439: 3431: 3418: 3412: 3407: 3393: 3384: 3376: 3360: 3345: 3320: 3308: 3301: 3287: 3283:TNF blockers 3256: 3253:Autoimmunity 3239: 3223: 3200: 3182:, including 3177: 3152:hypothalamus 3133: 3129: 3125:septic shock 3097: 3046: 3022: 2991: 2987: 2978: 2974: 2950: 2946:immune cells 2931: 2906: 2895: 2889:by cleaving 2879: 2873:to activate 2868: 2788: 2783:death domain 2780: 2740: 2728: 2721: 2717: 2710: 2701: 2678: 2667:Soluble form 2654: 2642: 2630: 2610: 2586: 2578: 2566: 2553: 2546: 2523: 2503: 2495: 2487: 2473:of proteins 2464: 2449: 2444:coactivators 2437: 2393: 2342: 2307: 2291: 2287: 2264: 2220: 2203:glycoprotein 2192: 2173: 2170:Nomenclature 2164: 2149: 2141: 2133: 2102: 2098:hypoglycemia 2087: 2077: 2073: 2059: 2012: 2001: 1995: 1989: 1987: 1964: 1949: 1925: 1892: 1876: 1845: 1804: 1800: 1796: 1795: 1717:NP_001265530 1714: 1693: 1666:NM_001278601 1663: 1642: 1618: 1599: 1573: 1546: 1498: 1479: 1459: 1454: 1210:MAPK cascade 719:cell surface 476: 469: 196:External IDs 99: 43: 8104:Tengonermin 8049:Toralizumab 8044:Tigatuzumab 8039:Teneliximab 8014:Mapatumumab 8009:Lucatumumab 8004:Lexatumumab 7979:Dacetuzumab 7974:Conatumumab 7961:Antibodies: 7827:Thalidomide 7683:Nerelimomab 7655:Antibodies: 7634:Tasonfermin 7624:Plusonermin 7598:Tasonfermin 7588:Plusonermin 7558:Baminercept 7539:Lymphotoxin 7306:IL17 family 7047:IL10 family 6966:IL12 family 6818:(grouped by 6806:Interleukin 6729:Lymphotoxin 6262:PDB gallery 6158:(9): 3263. 5599:: 178–184. 4995:10037/10660 4283:(9): 8187. 4118:: 124–132. 3918:(5): 2719. 3586:tau protein 3547:excitotoxic 3545:by causing 3184:glial cells 3109:neutrophils 3101:coagulation 3081:macrophages 2969:heterodimer 2938:fibroblasts 2908:to bind to 2763:necroptosis 2621:homotrimers 2593:macrophages 2557:circularize 2471:heterodimer 2347:, viruses, 2334:fibroblasts 2310:macrophages 2180:lymphocytes 2176:lymphotoxin 2121:hypotension 1983:macrophages 1911:Alzheimer's 1813:macrophages 960:JNK cascade 580:endometrium 564:granulocyte 510:bone marrow 502:granulocyte 435:35,420,983 422:35,418,357 334:31,578,336 321:31,575,565 174:Identifiers 8153:Categories 8094:Blisibimod 8084:Briobacept 8064:Varlilumab 8059:Utomilumab 8024:Ruplizumab 7999:Iratumumab 7989:Drozitumab 7954:Dulanermin 7949:Ardenermin 7743:Apremilast 7733:Apratastat 7708:Etanercept 7698:Placulumab 7693:Remtolumab 7678:Infliximab 7663:Afelimomab 7658:Adalimumab 7639:TNF (TNFα) 7603:TNF (TNFα) 7568:TNF (TNFα) 7528:LTB (TNFβ) 7520:modulators 7413:Lymphokine 7251:IL1B/IL1F2 7246:IL1A/IL1F1 7242:IL1 family 7106:Interferon 7094:IL29/IFNL1 4980:(6): 557. 4233:Nat. Metab 3713:, May 2017 3692:, May 2017 3667:References 3603:adalimumab 3415:hepatocyte 3342:Infections 3336:etanercept 3332:infliximab 3328:metastasis 3324:leukocytes 3261:, such as 3192:astrocytes 3115:, such as 3105:chemokines 3057:endotoxins 3010:Fas ligand 3006:granzyme B 2887:pyroptosis 2755:cell death 2693:β-sandwich 2638:C-terminal 2634:N-terminal 2601:C-terminal 2361:ionophores 2349:protozoans 2345:endotoxins 2326:mast cells 2304:Expression 2017:et al. at 1932:erysipelas 1864:homotrimer 1860:mast cells 526:lymph node 480:(ortholog) 217:HomoloGene 8164:Cytokines 8101:Unsorted: 8029:Tabalumab 7984:Denosumab 7964:Belimumab 7757:green tea 7753:Catechins 7748:Bupropion 7713:Lenercept 7673:Golimumab 7648:Ungrouped 7621:Agonists: 7585:Agonists: 7536:Agonists: 7291:33/IL1F11 7256:1Ra/IL1F3 6903:IL6 like/ 6620:CXCL8/IL8 6418:Chemokine 6410:By family 6403:cytokines 5378:: 32747. 3635:golimumab 3551:glutamate 3531:microglia 3474:steatosis 3316:remission 3275:psoriasis 3215:glutamate 3188:microglia 3029:endotoxin 3025:monocytes 2875:caspase 8 2759:apoptosis 2731:morpheein 2681:β-strands 2563:Evolution 2385:radiation 2298:arthritis 2231:Class III 2205:, termed 2174:In 1968, 2113:antiserum 2103:In 1985, 2066:DNA probe 2019:Genentech 1967:Lloyd Old 1960:endotoxin 1922:Discovery 1837:cytokines 1721:NP_038721 1696:NP_000585 1670:NM_013693 1645:NM_000594 1445:Orthologs 225:GeneCards 8143:Medicine 8054:Urelumab 8019:Oxelumab 7789:LA-SS-Az 7783:turmeric 7779:Curcumin 7767:cannabis 7718:Onercept 7629:Sonermin 7593:Sonermin 7547:β (TNFC) 7543:α (TNFβ) 7408:Monokine 6937:+non IL 6822:subunit) 6820:receptor 6791:TNFSF13B 6739:TNFC/LTB 6734:TNFB/LTA 6184:32380704 6133:33016914 6082:37483590 6073:10360935 6026:34991697 6000:(1): 5. 5975:27025788 5934:37407724 5925:10482776 5864:26726307 5808:21961576 5754:20142812 5700:35663982 5615:11113021 5574:33324405 5514:19578473 5463:23409765 5412:27605058 5353:22182754 5205:20194223 5154:15062645 5048:11040201 5004:27168212 4532:24636534 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