Non-classical Effects of TZDs on Chemokine Produciton

Boston Medical Center, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) are characterized by episodes of intestinal inflammation. Recent evidence suggests that activation of a nuclear receptor, PPAR-gamma, with a synthetic TZD ligand, BRL, offers protection against inflammation, at least in part by regulating inflammatory chemokine production from intestinal epithelial cells, both at the transcriptional and post-transcriptional levels. Interestingly, the chemokine promoters do not have PPAR-gamma response elements, indicating that the activated PPAR-gamma, or possibly BRL itself, affect chemokine production in "non-classical" ways. In addition, BRL affects numerous rapid phosphorylation events after cellular stimulation, including many molecules involved in MAP kinase signaling. To test the hypothesis that activated PPAR-gamma or BRL itself regulate chemokine production by modulating MAP kinase signaling, the mechanisms of regulation of a representative chemokine, IP-10, will be determined. The effects of BRL on IP-10 regulation in the presence and absence of PPAR-gamma will be determined, and the signaling pathways affected by BRL delineated in detail. The results of these experiments will further understanding of the mechanism of action of synthetic PPAR-gamma ligands and help in the development of IBD therapies.