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Tumor necrosis factor ligand superfamily member 12 also known as TNF-related weak inducer of apoptosis (TWEAK) is a protein that in humans is encoded by the TNFSF12 gene.[1][2][3]


TWEAK was discovered in 1997.[1] The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is a ligand for the FN14/TWEAKR receptor. This cytokine has overlapping signaling functions with TNF, but displays a much wider tissue distribution. Leukocytes are the main source of TWEAK including human resting and activated monocytes, dendritic cells and natural killer cells.[4] TWEAK can induce apoptosis via multiple pathways of cell death in a cell type-specific manner. This cytokine is also found to promote proliferation and migration of endothelial cells, and thus acts as a regulator of angiogenesis.[3]

Clinical significance

Excessive activation of the TWEAK pathway in chronic injury has been described to promote pathological tissue changes including chronic inflammation, fibrosis and angiogenesis.[5] In chronic liver disease for example TWEAK expression is enhanced and causes hepatic stellate cells, which are key regulators of liver fibrosis, to proliferate.[6] A disease-driving role of the TWEAK pathway has been described in several other diseases as well. For example, NFAT1 regulates the expression of TWEAKR and its ligand TWEAK (this protein) with lipocalin 2 to increase breast cancer cell invasion.[7]


  1. 1.0 1.1 Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I, Browning JL (December 1997). "TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis". The Journal of Biological Chemistry. 272 (51): 32401–10. doi:10.1074/jbc.272.51.32401. PMID 9405449.
  2. Marsters SA, Sheridan JP, Pitti RM, Brush J, Goddard A, Ashkenazi A (April 1998). "Identification of a ligand for the death-domain-containing receptor Apo3". Current Biology. 8 (9): 525–8. doi:10.1016/S0960-9822(98)70204-0. PMID 9560343.
  3. 3.0 3.1 "Entrez Gene: TNFSF12 tumor necrosis factor (ligand) superfamily, member 12".
  4. Maecker H, Varfolomeev E, Kischkel F, Lawrence D, LeBlanc H, Lee W, Hurst S, Danilenko D, Li J, Filvaroff E, Yang B, Daniel D, Ashkenazi A (December 2005). "TWEAK attenuates the transition from innate to adaptive immunity". Cell. 123 (5): 931–44. doi:10.1016/j.cell.2005.09.022. PMID 16325585.
  5. Burkly LC (June 2014). "TWEAK/Fn14 axis: the current paradigm of tissue injury-inducible function in the midst of complexities". Seminars in Immunology. The TNF family - challenges ahead. 26 (3): 229–36. doi:10.1016/j.smim.2014.02.006. PMID 24636536.
  6. Wilhelm A, Shepherd EL, Amatucci A, Munir M, Reynolds G, Humphreys E, Resheq Y, Adams DH, Hübscher S, Burkly LC, Weston CJ, Afford SC (February 2016). "Interaction of TWEAK with Fn14 leads to the progression of fibrotic liver disease by directly modulating hepatic stellate cell proliferation". The Journal of Pathology. 239: 109–21. doi:10.1002/path.4707. PMC 4949530. PMID 26924336.
  7. Gaudineau B, Fougère M, Guaddachi F, Lemoine F, de la Grange P, Jauliac S (October 2012). "Lipocalin 2, the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion" (PDF). Journal of Cell Science. 125 (Pt 19): 4475–86. doi:10.1242/jcs.099879. PMID 22767506.

Further reading

  • Wiley SR, Winkles JA (2004). "TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor". Cytokine & Growth Factor Reviews. 14 (3–4): 241–9. doi:10.1016/S1359-6101(03)00019-4. PMID 12787562.
  • Campbell S, Michaelson J, Burkly L, Putterman C (September 2004). "The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity". Frontiers in Bioscience. 9: 2273–84. doi:10.2741/1395. PMID 15353286.
  • Lynch CN, Wang YC, Lund JK, Chen YW, Leal JA, Wiley SR (March 1999). "TWEAK induces angiogenesis and proliferation of endothelial cells". The Journal of Biological Chemistry. 274 (13): 8455–9. doi:10.1074/jbc.274.13.8455. PMID 10085077.
  • Kaplan MJ, Ray D, Mo RR, Yung RL, Richardson BC (March 2000). "TRAIL (Apo2 ligand) and TWEAK (Apo3 ligand) mediate CD4+ T cell killing of antigen-presenting macrophages". Journal of Immunology. 164 (6): 2897–904. doi:10.4049/jimmunol.164.6.2897. PMID 10706675.
  • Kaptein A, Jansen M, Dilaver G, Kitson J, Dash L, Wang E, Owen MJ, Bodmer JL, Tschopp J, Farrow SN (November 2000). "Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3)". FEBS Letters. 485 (2–3): 135–41. doi:10.1016/S0014-5793(00)02219-5. PMID 11094155.
  • Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V, Liu H, Daniel TO, Smith CA, Fanslow WC (November 2001). "A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis". Immunity. 15 (5): 837–46. doi:10.1016/S1074-7613(01)00232-1. PMID 11728344.
  • Nakayama M, Ishidoh K, Kayagaki N, Kojima Y, Yamaguchi N, Nakano H, Kominami E, Okumura K, Yagita H (January 2002). "Multiple pathways of TWEAK-induced cell death". Journal of Immunology. 168 (2): 734–43. doi:10.4049/jimmunol.168.2.734. PMID 11777967.
  • Jakubowski A, Browning B, Lukashev M, Sizing I, Thompson JS, Benjamin CD, Hsu YM, Ambrose C, Zheng TS, Burkly LC (January 2002). "Dual role for TWEAK in angiogenic regulation". Journal of Cell Science. 115 (Pt 2): 267–74. PMID 11839778.
  • Kaplan MJ, Lewis EE, Shelden EA, Somers E, Pavlic R, McCune WJ, Richardson BC (November 2002). "The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells". Journal of Immunology. 169 (10): 6020–9. doi:10.4049/jimmunol.169.10.6020. PMID 12421989.
  • Harada N, Nakayama M, Nakano H, Fukuchi Y, Yagita H, Okumura K (December 2002). "Pro-inflammatory effect of TWEAK/Fn14 interaction on human umbilical vein endothelial cells". Biochemical and Biophysical Research Communications. 299 (3): 488–93. doi:10.1016/S0006-291X(02)02670-0. PMID 12445828.
  • Nakayama M, Ishidoh K, Kojima Y, Harada N, Kominami E, Okumura K, Yagita H (January 2003). "Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death". Journal of Immunology. 170 (1): 341–8. doi:10.4049/jimmunol.170.1.341. PMID 12496418.
  • Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, Chen Q, Szafranski P, Rao S, Wu L, Housman DE, DiCorleto PE, Driscoll DJ, Borrow J, Wang Q (February 2004). "Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome". Nature. 427 (6975): 640–5. doi:10.1038/nature02320. PMC 1618873. PMID 14961121.
  • Kim SH, Kang YJ, Kim WJ, Woo DK, Lee Y, Kim DI, Park YB, Kwon BS, Park JE, Lee WH (April 2004). "TWEAK can induce pro-inflammatory cytokines and matrix metalloproteinase-9 in macrophages". Circulation Journal. 68 (4): 396–9. doi:10.1253/circj.68.396. PMID 15056843.
  • Jin L, Nakao A, Nakayama M, Yamaguchi N, Kojima Y, Nakano N, Tsuboi R, Okumura K, Yagita H, Ogawa H (May 2004). "Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes". The Journal of Investigative Dermatology. 122 (5): 1175–9. doi:10.1111/j.0022-202X.2004.22419.x. PMID 15140220.