Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor γ (PPARγ) heterodimer: A basis for new therapeutic strategies

Pierre Desreumaux, Laurent Dubuquoy, Sophie Nutten, Michel Peuchmaur, Walter Englaro, Kristina Schoonjans, Benoit Derijard, Beatrice Desvergne, Walter Wahli, Pierre Chambon, Mark D. Leibowitz, Jean Frédéric Colombel, Johan Auwerx

Research output: Contribution to journalArticlepeer-review

397 Scopus citations

Abstract

The peroxisome proliferator-activated receptor γ (PPARγ) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARγ and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARγ+/- and RXRα+/- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARγ heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARγ agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARγ and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor α and interleukin 1β mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor KB DNA binding activity, c-Jun NH2-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARγ and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARγ heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARγ ligands might hold promise in the clinic due to their synergistic effects.

Original languageEnglish
Pages (from-to)827-838
Number of pages12
JournalJournal of Experimental Medicine
Volume193
Issue number7
DOIs
StatePublished - 2 Apr 2001
Externally publishedYes

Keywords

  • Colitis
  • Inflammatory bowel disease
  • Nuclear receptors
  • Signal transduction pathway
  • Tumor necrosis factor α

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