Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL

Previous studies showed that following acute carbon tetrachloride (CCl4) tr eatment, interleukin-6 null (IL6-/-) mice develop increased hepatocellular injury, defective regeneration, delayed wound healing, and increased hepato cyte apoptosis, Pretreatment with IL-6 prior to CCl4 reduces injury, hepato cyte 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 wit h the Fas agonist, Jo-2 mAb. At low Fas agonist doses, IL-6+/+ mice develop ed mild hepatic injury and survived, whereas IL-6-/-mice developed severe a poptotic hepatitis within 12 h and died. Pretreatment with IL-6 improved su rvival in IL-6-/- mice and reduced injury in both IL-6-/- and +/+ livers. T he direct anti-apoptotic effects of IL-6 were demonstrated in vitro as IL-6 decreased Fas-mediated apoptosis in both IL-6-/- and +/+ primary hepatocyt e cultures, and suggested that IL-6-/- hepatocytes have a pre-existing defe ct in anti-apoptotic pathways. After Fas activation, IL-6-/- livers demonst rated evidence of both proximal and distal alterations in the apoptotic pat hways including elevated caspase 8 and 3 activation-associated fragments, a nd loss of cytochrome c staining. IL-6-/- livers had reduced pre-existing p rotein 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 ap optosis, 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 abi lity to establish and maintain an adequate level of FLIP and downstream ant i-apoptotic factors.