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
| Autor: | 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. |
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| Rok vydání: | 2001 |
| Předmět: |
Transcriptional Activation
Tetrahydronaphthalenes Receptors Retinoic Acid colitis Receptors Cytoplasmic and Nuclear nuclear receptors signal transduction pathway Drug Synergism tumor necrosis factor α digestive system Animals Colitis/chemically induced Colitis/drug therapy Dimerization 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 Trinitrobenzenesulfonic Acid/adverse effects Rosiglitazone Thiazoles Trinitrobenzenesulfonic Acid inflammatory bowel disease Original Article Transcription Factors |
| Zdroj: | The Journal of Experimental Medicine Journal of Experimental Medicine, vol. 193, no. 7, pp. 827-838 |
| ISSN: | 0022-1007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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