A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response
Chinyu G. Su, Xiaoming Wen, Shannon T. Bailey, Wen Jiang, Shamina M. Rangwala, Sue A. Keilbaugh, Anne Flanigan, Sreekant Murthy, Mitchell A. Lazar, Gary D. Wu
Chinyu G. Su, Xiaoming Wen, Shannon T. Bailey, Wen Jiang, Shamina M. Rangwala, Sue A. Keilbaugh, Anne Flanigan, Sreekant Murthy, Mitchell A. Lazar, Gary D. Wu
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Article

A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response

Abstract

Peroxisome proliferator-activated receptor γ (PPAR-γ), 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-γ protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report here that PPAR-γ ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-κB via an IκB-α–dependent mechanism. Moreover, thiazolidinedione ligands for PPAR-γ markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-γ may be a therapeutic target in humans suffering from IBD.

Authors

Chinyu G. Su, Xiaoming Wen, Shannon T. Bailey, Wen Jiang, Shamina M. Rangwala, Sue A. Keilbaugh, Anne Flanigan, Sreekant Murthy, Mitchell A. Lazar, Gary D. Wu

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15d-PGJ2 inhibits the transcriptional activation of the IL-8 promoter by...
15d-PGJ2 inhibits the transcriptional activation of the IL-8 promoter by preventing the activation of NF-κB via an IκB-α–dependent pathway. (a) Caco-2 cells cotransfected with either an IL-8 promoter luciferase reporter gene or the PPAR-γ–regulated reporter plasmid, acyl-CoA X 3-TK-LUC, were treated with various concentrations of 15d-PGJ2 for 24 hours, followed by stimulation with IL-1β (5 ng/mL). (b) EMSAs of nuclear extracts isolated from Caco-2 cells treated with either 15d-PGJ2 or methyl acetate for 24 hours and followed by IL-1β stimulation (5 ng/mL) for the times indicated. A double-stranded oligonucleotide spanning the NF-κB element in the IL-8 promoter was used as a probe. (c) IκB-α Western blot of proteins isolated from Caco-2 cells treated with 15d-PGJ2 or methyl acetate for 24 hours and followed by IL-1β stimulation (5 ng/mL) for the times indicated.