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

J Clin Invest. 1999 Aug;104(4):383-9. doi: 10.1172/JCI7145.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caco-2 Cells
  • Colitis / drug therapy*
  • Colitis / immunology
  • Colitis / pathology
  • Cytokines / genetics
  • DNA-Binding Proteins / metabolism
  • Epithelium / drug effects
  • Epithelium / pathology
  • Gene Expression / drug effects
  • HT29 Cells
  • Humans
  • I-kappa B Proteins*
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / pathology
  • Interleukin-8 / genetics
  • Ligands
  • Mice
  • Microbodies / metabolism
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Rosiglitazone
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors / metabolism*

Substances

  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Cytokines
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Interleukin-8
  • Ligands
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Rosiglitazone
  • NF-KappaB Inhibitor alpha
  • Prostaglandin D2