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

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Version: author
Serval ID
serval:BIB_20497
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.
Journal
Journal of Experimental Medicine
Author(s)
Desreumaux P., Dubuquoy L., Nutten S., Peuchmaur M., Englaro W., Schoonjans K., Derijard B., Desvergne B., Wahli W., Chambon P., Leibowitz M.D., Colombel J.F., Auwerx J.
ISSN
0022-1007[print], 0022-1007[linking]
Publication state
Published
Issued date
2001
Volume
193
Number
7
Pages
827-838
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- 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/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma 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 alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.
Keywords
Animals, Colitis/chemically induced, Colitis/drug therapy, Dimerization, Drug Synergism, Mice, Mice, Mutant Strains, Receptors, Cytoplasmic and Nuclear/agonists, Receptors, Cytoplasmic and Nuclear/genetics, Receptors, Retinoic Acid/agonists, Receptors, Retinoic Acid/genetics, Retinoid X Receptors, Tetrahydronaphthalenes/therapeutic use, Thiazoles/therapeutic use, Thiazolidinediones, Transcription Factors/agonists, Transcription Factors/genetics, Transcriptional Activation, Trinitrobenzenesulfonic Acid/adverse effects
Pubmed
Web of science
Open Access
Yes
Create date
19/11/2007 12:15
Last modification date
20/08/2019 12:56
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