A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response.
Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Colonic epithelial cells, which express high levels of PPAR-gamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report here that PPAR-gamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-kappaB via an IkappaB-alpha-dependent mechanism. Moreover, thiazolidinedione ligands for PPAR-gamma markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-gamma may be a therapeutic target in humans suffering from IBD.
Su
C G
CG
Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Wen
X
X
Bailey
S T
ST
Jiang
W
W
Rangwala
S M
SM
Keilbaugh
S A
SA
Flanigan
A
A
Murthy
S
S
Lazar
M A
MA
Wu
G D
GD
D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016209:Interleukin-8 / Q000235:genetics; D008024:Ligands; D051379:Mice; D008830:Microbodies / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D008024:Ligands; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000072000:NF-KappaB Inhibitor alpha; D015230:Prostaglandin D2