Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α[5][6]) is a cytokine and member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain. It is the first cytokine to be described as an adipokine as secreted by adipose tissue.[7]
TNF signaling occurs through two receptors: TNFR1 and TNFR2.[8][9] TNFR1 is constitutively expressed on most cell types, whereas TNFR2 is restricted primarily to endothelial, epithelial, and subsets of immune cells.[8][9] TNFR1 signaling tends to be pro-inflammatory and apoptotic, whereas TNFR2 signaling is anti-inflammatory and promotes cell proliferation.[8][9] Suppression of TNFR1 signaling has been important for treatment of autoimmune diseases,[10] whereas TNFR2 signaling promotes wound healing.[9]
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,[11] 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.[11] sTNF-α selectively binds to TNFR1, whereas mTNF-α binds to both TNFR1 and TNFR2.[12] TNF-α binding to TNFR1 is irreversible, whereas binding to TNFR2 is reversible.[13]
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,[14] cancer,[15] major depression,[16] psoriasis[17] and inflammatory bowel disease (IBD).[18] Though controversial, some studies have linked depression and IBD to increased levels of TNF.[19][20]
As an adipokine, TNF promotes insulin resistance, and is associated with obesity-induced type 2 diabetes.[7] 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.[7] 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.
^ abcGRCm38: Ensembl release 89: ENSMUSG00000024401 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Liu CY, Tam SS, Huang Y, Dubé PE, Alhosh R, Girish N, et al. (October 2020). "TNF Receptor 1 Promotes Early-Life Immunity and Protects against Colitis in Mice". Cell Reports. 33 (3): 108275. doi:10.1016/j.celrep.2020.108275. PMC 7682618. PMID 33086075.
^Gravallese EM, Monach PA (January 2015). "The rheumatoid joint: Synovitis and tissue destruction.". Rheumatology. Vol. 1 (Sixth ed.). Mosby. pp. 768–784. doi:10.1016/B978-0-323-09138-1.00094-2. ISBN 978-0-323-09138-1. The simplified name TNF is now preferred over the former designation TNF-α because the corresponding term TNF-β, an alternative name for LT, is now obsolete.
^ abcHeir R, Stellwagen D (2020). "TNF-Mediated Homeostatic Synaptic Plasticity: From in vitro to in vivo Models". Frontiers in Cellular Neuroscience. 14: 565841. doi:10.3389/fncel.2020.565841. PMC 7556297. PMID 33192311.
^ abcdGough P, Myles IA (2020). "Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects". Frontiers in Immunology. 11: 585880. doi:10.3389/fimmu.2020.585880. PMC 7723893. PMID 33324405.
^Rolski F, Błyszczuk P (October 2020). "Complexity of TNF-α Signaling in Heart Disease". Journal of Clinical Medicine. 9 (10): 3267. doi:10.3390/jcm9103267. PMC 7601316. PMID 33053859.
^ abQu Y, Zhao G, Li H (2017). "Forward and Reverse Signaling Mediated by Transmembrane Tumor Necrosis Factor-Alpha and TNF Receptor 2: Potential Roles in an Immunosuppressive Tumor Microenvironment". Frontiers in Immunology. 8: 1675. doi:10.3389/fimmu.2017.01675. PMC 5712345. PMID 29234328.
^Probert L (August 2015). "TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects". Neuroscience. 302: 2–22. doi:10.1016/j.neuroscience.2015.06.038. PMID 26117714.
^Szondy Z, Pallai A (January 2017). "Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: Therapeutic implications". Pharmacological Research. 115: 124–132. doi:10.1016/j.phrs.2016.11.025. PMID 27888159. S2CID 40818956.
^Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (November 2010). "A meta-analysis of cytokines in Alzheimer's disease". Biological Psychiatry. 68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID 20692646. S2CID 6544784.
^Locksley RM, Killeen N, Lenardo MJ (February 2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell. 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407. S2CID 7657797.
^Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. (March 2010). "A meta-analysis of cytokines in major depression". Biological Psychiatry. 67 (5): 446–457. doi:10.1016/j.biopsych.2009.09.033. PMID 20015486. S2CID 230209.
^Victor FC, Gottlieb AB (December 2002). "TNF-alpha and apoptosis: implications for the pathogenesis and treatment of psoriasis". Journal of Drugs in Dermatology. 1 (3): 264–275. PMID 12851985.
^Brynskov J, Foegh P, Pedersen G, Ellervik C, Kirkegaard T, Bingham A, et al. (July 2002). "Tumour necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease". Gut. 51 (1): 37–43. doi:10.1136/gut.51.1.37. PMC 1773288. PMID 12077089.
^Mikocka-Walus AA, Turnbull DA, Moulding NT, Wilson IG, Andrews JM, Holtmann GJ (February 2007). "Controversies surrounding the comorbidity of depression and anxiety in inflammatory bowel disease patients: a literature review". Inflammatory Bowel Diseases. 13 (2): 225–234. doi:10.1002/ibd.20062. hdl:10536/DRO/DU:30091069. PMID 17206706.
^Bobińska K, Gałecka E, Szemraj J, Gałecki P, Talarowska M (2017). "Is there a link between TNF gene expression and cognitive deficits in depression?". Acta Biochimica Polonica. 64 (1): 65–73. doi:10.18388/abp.2016_1276. PMID 27991935.
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