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Tumor necrosis factor

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**Discovery and Gene Structure of TNF:**
– William B. Coley recognized the anti-tumoral response theory.
– Gale A Granger discovered lymphotoxin in 1968.
– Lloyd J. Old identified TNF in 1975.
– TNF gene was cloned in 1985 and maps to chromosome 6p21.3.
– The gene spans about 3 kilobases and contains 4 exons.
– The last exon shares similarity with lymphotoxin alpha (LTA).
– The three prime untranslated region (3-UTR) of TNF contains an AU-rich element (ARE).

**TNF Structure and Cell Signaling:**
– TNF is produced as a 233-amino acid-long type II transmembrane protein.
– Soluble homotrimeric cytokine (sTNF) is released via proteolytic cleavage.
– TNF can bind to two receptors: TNFR1 and TNFR2.
– TNFR1 is expressed in most tissues and fully activated by both forms of TNF.
– TNFR2 is found in immune cells and responds to membrane-bound TNF.
– TNF receptors form trimers upon ligand contact, leading to downstream signaling.

**TNF Signaling Pathways and Regulation:**
– TNF utilizes the morpheein model of allosteric regulation.
– Activation of NF-κB pathway involves TRADD, TRAF2, and RIP.
– NF-κB mediates cell survival, proliferation, and inflammatory response.
– Activation of MAPK pathways includes JNK, p38-MAPK, and ERKs.
– TNF-induced cell death involves TNFR1, TRADD, and caspase-8.

**Clinical Significance and Pharmacology of TNF:**
– TNF is produced by various cell types in response to bacterial products and interleukin-1.
– TNF induces insulin resistance, inflammation, and shock-like symptoms.
– TNF inhibitors like infliximab and adalimumab are used in autoimmune disorders.
– Anti-TNF therapy shows effects in cancer treatment and disease stabilization.
– TNF may have an immunosuppressive facet affecting regulatory T cells.

**TNFα in Diseases and Biological Functions:**
– TNFα plays a role in liver diseases, obesity-induced inflammation, and immune regulation.
– TNFα contributes to liver fibrosis, steatosis, and insulin resistance.
– TNFα influences T cell activation, interleukin regulation, and endothelial dysfunction.
– TNFα affects adipose tissue, muscle-fat crosstalk, and sensory perception.
– TNFα promotes a proinflammatory environment and influences various diseases.

Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.

Available structures
PDBOrtholog search: PDBe RCSB
AliasesTNF, DIF, TNF-alpha, TNFA, TNFSF2, Tumour necrosis factor, TNF-α, tumor necrosis factor, TNLG1F, Tumor necrosis factor alpha
External IDsOMIM: 191160 MGI: 104798 HomoloGene: 496 GeneCards: TNF
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 6: 31.58 – 31.58 MbChr 17: 35.42 – 35.42 Mb
PubMed search
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TNF signaling occurs through two receptors: TNFR1 and TNFR2. TNFR1 is constitutively expressed on most cell types, whereas TNFR2 is restricted primarily to endothelial, epithelial, and subsets of immune cells. TNFR1 signaling tends to be pro-inflammatory and apoptotic, whereas TNFR2 signaling is anti-inflammatory and promotes cell proliferation. Suppression of TNFR1 signaling has been important for treatment of autoimmune diseases, whereas TNFR2 signaling promotes wound healing.

TNF-α exists as a transmembrane form (mTNF-α) and as a soluble form (sTNF-α). sTNF-α results from enzymatic cleavage of mTNF-α, by a process called substrate presentation. mTNF-α is mainly found on monocytes/macrophages where it interacts with tissue receptors by cell-to-cell contact. sTNF-α selectively binds to TNFR1, whereas mTNF-α binds to both TNFR1 and TNFR2. TNF-α binding to TNFR1 is irreversible, whereas binding to TNFR2 is reversible.

The primary role of TNF is in the regulation of immune cells. TNF, as an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, and inflammation, inhibit tumorigenesis and viral replication, and respond to sepsis via IL-1 and IL-6-producing cells. Dysregulation of TNF production has been implicated in a variety of human diseases including Alzheimer's disease, cancer, major depression, psoriasis and inflammatory bowel disease (IBD). Though controversial, some studies have linked depression and IBD to increased levels of TNF.

As an adipokine, TNF promotes insulin resistance, and is associated with obesity-induced type 2 diabetes. As a cytokine, TNF is used by the immune system for cell signaling. If macrophages (certain white blood cells) detect an infection, they release TNF to alert other immune system cells as part of an inflammatory response. Certain cancers can cause overproduction of TNF. TNF parallels parathyroid hormone both in causing secondary hypercalcemia and in the cancers with which excessive production is associated. Under the name tasonermin, TNF is used as an immunostimulant drug in the treatment of certain cancers. Drugs that counter the action of TNF are used in the treatment of various inflammatory diseases such as rheumatoid arthritis.

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