Protein catabolism after injury or infection results in multiple complications which prolong recovery and cause death. Normally, GH induces circulating insulin-like growth factor-l (IGF-I) synthesis by liver, which stimulates muscle protein synthesis. During sepsis, a 2-4 fold increase in circulating GH is seen with a 50% decrease in plasma IGF-I and concomitant reductions in both muscle protein synthesis and mass. TNF and IL-1 antagonists attenuate the reductions in plasma IGF-I and muscle catabolism observed during the septic insult. The goal of this project is to elucidate the mechanisms responsible for cytokine-mediated hepatic GH resistance, one of the major metabolic derangements during systemic inflammation. We are in a unique position to perform these studies based on the novel cell culture model of cytokine-mediated GH resistance developed in our laboratory. CWSV1 hepatocytes have been utilized to characterize the effects of TNF, IL-1, and IL-6 on GH signaling and GH-inducible gene expression. Postreceptor defects in GH-inducible gene expression appear to represent the predominant mechanism for cytokine-mediated GH resistance. Preliminary data suggest NFkB activation by TNF inhibits the expression of over forty GH-inducible genes involved in regulating intermediary metabolism. The proposed research will characterize the molecular mechanisms by which cytokines and NFkB inhibit GH-inducible gene expression, and will investigate .the. : metabolic consequences of hepatic GH resistance. Our hypothesis is that cytokine-mediated activation of NFkB inhibits anabolic gene transcription by GH during sepsis resulting in hepatic GH resistance and muscle catabolism.
The specific aims are to: 1) Investigate the signaling pathways by which cytokines and sepsis inhibit GH-inducible gene expression, 2) Determine the mechanisms by which NFkB inihbits GH-inducible gene expression, 3) Identify and characterize the promoter regions and transcription factors involved in regulating GH-inducible hepatic genes that are inhibited by cytokines during sepsis. The loss of normal metabolic regulation in patients with injury and infection is associated with increased mortality and prolonged recovery. This problem is caused in part by the inhibitory effects of cytokines (TNF, IL-1, IL-6) on the anabolic actions of GH. An improved understanding of how cytokines and growth factors regulate protein catabolism is important to provide better care for these patients. ? ? ?
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