Molecular Mechanisms by which TNFalpha Modulates Fibrosis

University Of California, San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Tumor necrosis factor (TNF) ? is a pleiotropic cytokine that induces cellular responses including proliferation, production of inflammatory mediators, and cell death and plays a major role in the pathophysiology of shock, inflammation, and the wasting syndrome. The initial period of this grant focused on the role of TNF? in inhibiting Type I collagen gene expression and the effect of TNF? on stimulating collagenase-1 gene expression with the net result of inhibiting fibrosis. However, we have subsequently discovered that TNF1 has a wide variety of effects on wound healing, including the induction of apoptosis in parenchymal cells, the induction of JNK with subsequent phosphorylation of Mcl-1 and other targets of apoptosis, the induction of reactive oxygen species, and the induction of the profribrogenic cytokine TGF?. Therefore, the current application will study hepatic fibrosis as a model of wound healing and address the following four specific aims: 1. To determine the role of the 5'Stem Loop of collagen ?1(I) mRNA in fibrosis. 2. To determine the role of TNF? and its receptor signaling in hepatic fibrosis. 3. To investigate how TNF1/TNFR-induced NFkB and JNK activation is coordinated by NOX derived ROS in HSC. 4. To assess the role of TNF1 induced JNK activation on hepatocyte apoptosis. PUBLIC HEALTH RELEVANCE: Tumor necrosis factor (TNF)? is a multifunctional cytokine that is induced during inflammation and wound healing. TNF? has both anti-fibrotic effects on Type I collagen and pro-fibrotic effects on activating myofibroblasts. This proposal uses the wound healing model of hepatic fibrosis to assess how TNF? modulates wound healing through different signal transduction pathways in the whole organism and in specific hepatic cell populations.