期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 276, 期 28, 页码 26605-26613出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M100740200
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资金
- NIDDK NIH HHS [P30 DK50306, DK 49629, 1 K08 DK 02667-01, 1 F32 DK09732-01] Funding Source: Medline
Previous studies showed that following acute carbon tetrachloride (CCl4) treatment, interleukin-6 null (IL6-/-) mice develop increased hepatocellular injury, defective regeneration, delayed wound healing, and increased hepatocyte apoptosis, Pretreatment with IL-6 prior to CCl4 reduces injury, hepatocyte apoptosis, and accelerates regeneration in both IL-6-/- and +/+ livers. To demonstrate whether IL-6 can prevent liver injury that involves direct stimulation of hepatocyte apoptosis, IL-6-/- and +/+ mice were treated with the Fas agonist, Jo-2 mAb. At low Fas agonist doses, IL-6+/+ mice developed mild hepatic injury and survived, whereas IL-6-/-mice developed severe apoptotic hepatitis within 12 h and died. Pretreatment with IL-6 improved survival in IL-6-/- mice and reduced injury in both IL-6-/- and +/+ livers. The direct anti-apoptotic effects of IL-6 were demonstrated in vitro as IL-6 decreased Fas-mediated apoptosis in both IL-6-/- and +/+ primary hepatocyte cultures, and suggested that IL-6-/- hepatocytes have a pre-existing defect in anti-apoptotic pathways. After Fas activation, IL-6-/- livers demonstrated evidence of both proximal and distal alterations in the apoptotic pathways including elevated caspase 8 and 3 activation-associated fragments, and loss of cytochrome c staining. IL-6-/- livers had reduced pre-existing protein expression of the anti-apoptotic factors Bcl-2 and Bcl-xL as well as more rapid degradation of FLIP following Fas treatment that appeared to be post-transcriptionally regulated. FLIP is a crucial proximal inhibitor of caspase 8 activation in Fas, tumor necrosis factor, and DR3/DR4-mediated apoptosis, and Bcl-2 and Bcl-xL more downstream anti-apoptotic regulators. IL-6 may function as a critical anti-apoptotic factor in the liver by its ability to establish and maintain an adequate level of FLIP and downstream anti-apoptotic factors.
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