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

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR-γ is expressed in several different cell types, and mice with a targeted disruption of the PPAR-γ gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium (DSS)-induced IBD. However, the highly selective PPAR-γ ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR-γ intestinal specific null mice and wild-type littermates. Therefore the role of PPAR-γ in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR-γ in macrophages (PPAR-γ^ΔMφ) and wild-type littermates (PPAR-γ^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-γ^ΔMφ 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-1β, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR-γ^ΔMφ mice treated with DSS were higher than in similarly treated PPAR-γ^F/F mice. The present study has identified a novel protective role for macrophage PPAR-γ in the DSS-induced IBD model. The data suggest that PPAR-γ regulates recruitment of macrophages to inflammatory foci in the colon.