1A8M, 1TNF, 2AZ5, 2E7A, 2TUN, 2ZJC, 2ZPX, 3ALQ, 3IT8, 3L9J, 3WD5, 4G3Y, 4TSV, 4TWT, 5TSW712421926ENSG00000232810ENSG00000228849ENSG00000206439ENSMUSG00000024401P01375P06804NM_000594NM_001278601NM_013693NP_000585NP_001265530NP_038721Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation.

[5] TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors on other cells.

[6] It is a member of the tumor necrosis factor superfamily, a family of transmembrane proteins that are cytokines, chemical messengers of the immune system.

[13] In the 1890s, William Coley observed that acute infections could cause tumor regression, leading to his usage of bacterial toxins as a cancer treatment.

[9] TNF gene expression is regulated by a proximal promoter region consisting of approximately 200 base pairs.

Most of the binding sites within the proximal promoter region can recognize multiple transcription factors, enabling TNF to be activated by a variety of signaling pathways.

tmTNF is cleaved by TNF alpha converting enzyme (TACE), which causes the extracellular portion to be secreted.

[10] The secondary structure of sTNF consists primarily of alternating strands that join into two sheets, known as antiparallel β-sheets.

The disabling of the IKK checkpoint activates complex IIb, leading to apoptosis, or pyroptosis by cleaving GSDMD.

[6] In the second checkpoint, the NF-κB pathway promotes the expression of pro-survival genes such as FLIP, which counteracts the activation of caspase 8 in complex IIa.

This allows p100 and RelB to be processed into a heterodimer which activates the non-canonical NF-κB pathway, leading to cell proliferation.

TNF can also induce fever by stimulating the primary vagal terminals in the liver, which signals to neurons to secrete norepinephrine.

All of these pathways culminate in the synthesis of prostaglandins, which interact with the OVLT in the hypothalamus to raise the target temperature of the body.

[12] Through TNFR2 signalling, TNF promotes the proliferation and maturation of oligodendrocytes, which produce protective myelin sheaths around nerve cells.

[8] In these diseases, TNF is erroneously secreted by immune cells in response to environmental factors or genetic mutations.

Drugs that target proteins involved in TNF-induced cell death, such as RIPK1, are being evaluated for their efficacy against autoinflammatory diseases.

However, TNF is now known to play a dual role in cancer, both as a promoter and inhibitor, due to its ability to induce either proliferation or death in tumor cells.

[28] In some cancers, TNF has been shown to play an inhibitory role, primarily when injected locally, repeatedly, and at high concentrations.

TNF-blockers such as infliximab and etanercept did not induce a response in most advanced or metastatic cancers, but some studies have shown disease stabilization.

[29] Conversely, TNF plays a role in the progression of HIV by inducing apoptosis of T cells in HIV-infected people.

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

[29] TNF is believed to be an important contributor to sepsis 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.

TNF contributes to the activation and survival of hepatic stellate cells (HSCs), believed to be the primary contributors of liver fibrosis.

On the other hand, TNF suppresses alpha-1 type-1 collagen expression and HSC proliferation in vitro, which should inhibit liver fibrosis.

[31] Additionally, hepatocyte death, the initial event that drives liver injury and fibrosis, may be induced by TNF, though this connection is uncertain.

Under normal circumstances, IRS1, upon activation by insulin, undergoes tyrosine phosphorylation and increases glucose uptake in the cell.

As a result, TNF is seen to play an important role in central nervous system disorders associated with neuroinflammation, including neurosarcoidosis, multiple sclerosis, Neuro-Behçet's disease.

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

[8] Rarely, the suppression of TNF can lead to the development of a new form of "paradoxical" autoimmunity, caused by the overexpression of other cytokines.