Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Ligands for PPARgamma include prostanoids such as 15-deoxy-delta 12,14 prostaglandin J, (15d-PGJ,), polyunsaturated fatty acids, a variety of non-steroidal anti-inflammatory drugs (NSAIDS), and a new class of oral antidiabetic agents, the thiazolidinediones (TZDs). Colonic epithelial cells, which express high levels of PPARgamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). In preliminary data, we show that PPARgamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting IkappaB-alpha phosphorylation and activation of Nuclear Factor Kappa B (NF-kappaB); a mechanism that requires the activation of new gene transcription and protein synthesis. These same ligands also induce the expression of the anti-inflammatory protein, annexin I (lipocortin I). Moreover, we show that thiazolidinedione ligands for PPARgamma markedly reduce colonic inflammation in a mouse model of IBD. Ligands for PPARgamma may therefore have promise as novel therapeutic agents for the treatment of patients with IBD. The overall goal of this grant proposal is to identify and characterize candidate molecular mechanisms by which TZD and prostanoid ligands for PPARgamma inhibit the intestinal inflammatory response. We hypothesize that PPARgamma ligands inhibit the intestinal immune response by the activation of gene transcription through a PPARgamma dependent mechanism. Based on this hypothesis, three specific aims will be pursued: 1) To determine the role that PPARgamma and its post-translational modification plays in the regulation of the intestinal epithelial immune response through cell culture models, 2) To clone the PPARgamma Ligand dependent Inhibitor of IkappaB-alpha Phosphorylation (PLIP) as well as identify its kinase target, and 3) To identify the molecular mechanisms by which these ligands activate annexin I expression in vitro as well as determine its pattern of expression in vivo. Ultimately, the studies described in this grant proposal may provide novel insights into mechanisms by which nuclear hormone receptors and their ligands modulate the intestinal inflammatory response.
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