PPARbeta/delta protects against experimental colitis through a ligand-independent mechanism.
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.
Hollingshead
Holly E
HE
Department of Veterinary and Biomedical Sciences , The Pennsylvania State University, 312 Life Sciences Building, University Park, Pennsylvania 16802, USA.
Morimura
Keiichirou
K
Adachi
Masahiro
M
Kennett
Mary J
MJ
Billin
Andrew N
AN
Willson
Timothy M
TM
Gonzalez
Frank J
FJ
Peters
Jeffrey M
JM
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
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