title: PPARbeta/delta protects against experimental colitis through a ligand-independent mechanism.
abstract: Peroxisome proliferator-activated receptors (PPARs) beta/delta and gamma have overlapping roles in the negative regulation of inflammatory response genes. Ligand activation of PPARgamma protects against experimental colitis in mice. PPARbeta/delta can negatively regulate inflammation and is highly expressed in the epithelial cells of the colon, therefore PPARbeta/delta may also have a role in experimental colitis. In these studies, colitis was induced by dextran sodium sulfate (DSS) treatment in wild-type and PPARbeta/delta-null mice, with and without the PPARbeta/delta specific ligand GW0742. PPARbeta/delta-null mice exhibited increased sensitivity to DSS-induced colitis, as shown by marked differences in body weight loss, colon length, colonic morphology, myeloperoxidase activity and increased expression of mRNAs encoding the inflammatory markers interferon gamma, tumor necrosis factor-alpha, and interleukin-6 compared to similarly treated wild-type mice. Interestingly, these differences were not affected by ligand activation of PPARbeta/delta in either genotype. These studies demonstrate that PPARbeta/delta expression in the colonic epithelium inhibits inflammation and protects against DSS-induced colitis through a ligand-independent mechanism.
authors.affiliation: Department of Veterinary and Biomedical Sciences , The Pennsylvania State University, 312 Life Sciences Building, University Park, Pennsylvania 16802, USA.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Hollingshead
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Adachi
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D018450:Disease Progression; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000627:therapeutic use*; D048068:PPAR-beta / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D010952:Plasma Substitutes / Q000633:toxicity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D016264:Dextran Sulfate; D007371:Interferon-gamma; D015850:Interleukin-6; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D009195:Peroxidase; D010952:Plasma Substitutes; D012333:RNA, Messenger; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds