Determining what factors are responsible for ameliorating injury and promoting recovery in response to acute and chronic liver injury are central issues in understanding the molecular basis of hepatic regeneration. Our data thus far has shown that interleukin-6 (IL-6) is a protective factor against acute and chronic toxic liver injury. IL-6 reduces acute carbon tetrachloride-induced liver injury and hepatocyte apoptosis and enhances regeneration. Our preliminary data suggests that IL-6 suppresses Fas-mediated hepatocyte apoptosis. Lastly, after developing a chronic liver injury model which produces relatively rapid and reliable fibrosis in mice, we demonstrated that mice with a targeted disruption of the 1L-6 gene (IL-6 -/-) developed severe liver injury and accelerated fibrosis. The first objective of this research is to continue the study of the role of IL-6 in hepatic injury, hepatocyte apoptosis, and regeneration following acute carbon tetrachloride and Fas-induced injury. Studies of patterns of gene expression in the acute carbon tetrachloride toxicity model will be completed. Differences in histologic injury, transcription factor activation, patterns of gene expression, DNA synthesis, and cell proliferation in IL-6-/- and IL-6 +/+ mice will be studied following Fas-mediated liver injury. We will assess the effect of injected IL-6 in correcting abnormalities in Fas-mediated liver injury. The role of IL-6 in hepatocyte apoptosis will be investigated. We will quantify the differences in apoptosis morphologically and via the in situ detection of fragmented DNA in IL-6 -/- and IL-6 +/+ livers following Fas-mediated injury. We will study differences in gene activation or expression of factors important in the signal transduction and cell death effector pathways using in vivo and cell culture models, and test the ability of IL-6 to reverse any defects in 1L-64- hepatocytes. With these data, further studies into the mechanism of the anti-apoptotic effects of IL-6 in the liver will be developed. Utilizing chronic repetitive injury with carbon tetrachloride, the role of IL-6 in hepatofibrosis will be studied with histologic stains for collagen and patterns of collagen and matrix gene activation. The role of chronic hepatocyte apoptotic injury in chronic hepatitis and fibrosis will be investigated. We will assess the ability of repetitive low doses of agonistic Fas antibody to induce chronic hepatitis and fibrosis. As the study of chronic hepatitis is distinct from prior work in the laboratory, this portion of the proposal is intended to function as a basis for development of an independent research pathway.
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| Kovalovich, K; Li, W; DeAngelis, R et al. (2001) Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J Biol Chem 276:26605-13 |
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