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Expression of peroxisome proliferator-activated receptor- in macrophage suppresses experimentally induced colitis

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Submitted 16 August 2006 ; accepted in final form 2 November 2006

Peroxisome proliferator-activated receptor- (PPAR-) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR- is expressed in several different cell types, and mice with a targeted disruption of the PPAR- gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium (DSS)-induced IBD. However, the highly selective PPAR- ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR- intestinal specific null mice and wild-type littermates. Therefore the role of PPAR- in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR- in macrophages (PPAR-^M) and wild-type littermates (PPAR-^F/F) were administered 2.5% DSS in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis, and proinflammatory cytokine analysis was performed. PPAR-^M mice displayed an increased susceptibility to DSS-induced colitis compared with wild-type littermates, as defined by body weight loss, diarrhea, rectal bleeding score, colon length, and histology. IL-1, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR-^M mice treated with DSS were higher than in similarly treated PPAR-^F/F mice. The present study has identified a novel protective role for macrophage PPAR- in the DSS-induced IBD model. The data suggest that PPAR- regulates recruitment of macrophages to inflammatory foci in the colon.

CC chemokine receptor 2; macrophages

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