BACKGROUND: Tumor necrosis factor-α (TNF-α) is a potent proinflammatory cytokine involved in a variety of disease pathologies, including ischemia/reperfusion (I/R) injuries in transplantation. The interaction of TNF-α with its cognate receptor TNF receptor I (TNFRI) results in the activation of signal transduction pathways that regulate either cell survival or cell death. Hepatocytes express TNFRI and respond to TNF-α released by resident Kupffer cells as well as leukocytes that migrate to the liver during I/R injury. Upon binding TNF-α, the hepatocyte proliferates or undergoes apoptosis or necroptosis. The decision by the cell to commit to one path or the other is not understood. The damaged tissue exhibits cell death and hemorrhaging from the influx of immune mediators. TNF-α inhibitors ameliorate the injury in animal models, suggesting that lowering (but not eliminating) TNF-α levels shifts the balance of TNF-α toward its beneficial functions. METHODS: We review TNF-α signal transduction pathways and the role of TNF-α in liver I/R injury. CONCLUSIONS: Because TNF-α plays an important role in hepatocyte proliferation, complete inhibition of TNF-α is not desirable in treating liver I/R injury. The strategy for developing pharmacological therapies may be the identification of specific intermediates in the TNF-α/TNFR1 signal transduction pathway and directed targeting of proapoptotic and pronecroptotic events.
BACKGROUND: Tumor necrosis factor-α (TNF-α) is a potent proinflammatory cytokine involved in a variety of disease pathologies, including ischemia/reperfusion (I/R) injuries in transplantation. The interaction of TNF-α with its cognate receptor TNF receptor I (TNFRI) results in the activation of signal transduction pathways that regulate either cell survival or cell death. Hepatocytes express TNFRI and respond to TNF-α released by resident Kupffer cells as well as leukocytes that migrate to the liver during I/R injury. Upon binding TNF-α, the hepatocyte proliferates or undergoes apoptosis or necroptosis. The decision by the cell to commit to one path or the other is not understood. The damaged tissue exhibits cell death and hemorrhaging from the influx of immune mediators. TNF-α inhibitors ameliorate the injury in animal models, suggesting that lowering (but not eliminating) TNF-α levels shifts the balance of TNF-α toward its beneficial functions. METHODS: We review TNF-α signal transduction pathways and the role of TNF-α in liver I/R injury. CONCLUSIONS: Because TNF-α plays an important role in hepatocyte proliferation, complete inhibition of TNF-α is not desirable in treating liver I/R injury. The strategy for developing pharmacological therapies may be the identification of specific intermediates in the TNF-α/TNFR1 signal transduction pathway and directed targeting of proapoptotic and pronecroptotic events.
Authors: C P Kaudel; M Frink; M van Griensven; U Schmiddem; C Probst; S Bergmann; C Krettek; J Klempnauer; M Winkler Journal: Transplant Proc Date: 2007-03 Impact factor: 1.066
Authors: Young Sik Cho; Sreerupa Challa; David Moquin; Ryan Genga; Tathagat Dutta Ray; Melissa Guildford; Francis Ka-Ming Chan Journal: Cell Date: 2009-06-12 Impact factor: 41.582
Authors: Alessandro Cinti; Marco De Giorgi; Elisa Chisci; Claudia Arena; Gloria Galimberti; Laura Farina; Cristina Bugarin; Ilaria Rivolta; Giuseppe Gaipa; Ryszard Tom Smolenski; Maria Grazia Cerrito; Marialuisa Lavitrano; Roberto Giovannoni Journal: PLoS One Date: 2015-10-29 Impact factor: 3.240
Authors: Ondřej Malý; Ján Zajak; Radomír Hyšpler; Zdeněk Turek; David Astapenko; Daniel Jun; Nela Váňová; Aleš Kohout; Věra Radochová; Jiří Kotek; Jiří Páral Journal: Ann Transl Med Date: 2019-12