Expression of peroxisome proliferator-activated receptor-gamma in macrophage suppresses experimentally induced colitis.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR-gamma is expressed in several different cell types, and mice with a targeted disruption of the PPAR-gamma gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium (DSS)-induced IBD. However, the highly selective PPAR-gamma ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR-gamma intestinal specific null mice and wild-type littermates. Therefore the role of PPAR-gamma in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR-gamma in macrophages (PPAR-gamma(DeltaMphi)) and wild-type littermates (PPAR-gamma(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-gamma(DeltaMphi) 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-1beta, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR-gamma(DeltaMphi) mice treated with DSS were higher than in similarly treated PPAR-gamma(F/F) mice. The present study has identified a novel protective role for macrophage PPAR-gamma in the DSS-induced IBD model. The data suggest that PPAR-gamma regulates recruitment of macrophages to inflammatory foci in the colon.
Shah
Yatrik M
YM
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Morimura
Keiichirou
K
Gonzalez
Frank J
FJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018955:CD36 Antigens; D018932:Chemokine CCL2; D016207:Cytokines; D016264:Dextran Sulfate; D050556:Fatty Acid-Binding Proteins; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; D000077154:Rosiglitazone; D045162:Thiazolidinediones; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C515335:Ccr2 protein, mouse; C493411:Fabp4 protein, mouse; C092228:Marco protein, mouse