The Journal of Experimental Medicine
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Published online 2 April 2001.
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© The Rockefeller University Press, 0022-1007/2001/4/827/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 7, April 2, 2001 827-838

Original Article

Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (Rxr)/Peroxisome Proliferator–Activated Receptor {gamma} (Ppar{gamma}) Heterodimer: A Basis for New Therapeutic Strategies



Pierre Desreumauxa, Laurent Dubuquoya, Sophie Nuttena, Michel Peuchmaurb, Walter Englaroc, Kristina Schoonjansd, Benoit Derijardc, Beatrice Desvergnee, Walter Wahlie, Pierre Chambond, Mark D. Leibowitzf, Jean-Frédéric Colombela, and Johan Auwerxd

a Equipe Propre Institut National de la Sante et de la Recherche Medicale 0114 sur la Physiopathologie des Maladies Inflammatoires Intestinales, CHU Lille 59037, France
b Service d'Anatomie et de Cytologie pathologiques, Hôpital Robert Debré, Paris 75019, France
c UMR 6548-Centre National de la Recherche Scientifique, Nice 06108, France
d Institut de Génétique et Biologie Moléculaire et Cellulaire, Illkirch 67404, France
e Institut de Biologie Animale, Faculté des Sciences, Université de Lausanne, Lausanne CH1015, Switzerland
f Ligand Pharmaceuticals, San Diego, California 92121
Service de Gastroentérologie, Hôpital Huriez, CHU Lille 59037, France.33-3-20-44-47-1333-3-20-44-47-14

pdesreumaux{at}chru-lille.fr

The peroxisome proliferator–activated receptor {gamma} (PPAR{gamma}) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPAR{gamma} and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPAR{gamma}1/– and RXR{alpha}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/PPAR{gamma} heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPAR{gamma} agonists. TNBS-induced colitis was significantly reduced by the administration of both PPAR{gamma} 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 1β mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor {kappa}B DNA binding activity, c-Jun NH2-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPAR{gamma} and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPAR{gamma} heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPAR{gamma} ligands might hold promise in the clinic due to their synergistic effects.

Key Words: colitis • inflammatory bowel disease • nuclear receptors • tumor necrosis factor {alpha} • signal transduction pathway

P. Desreumaux and L. Dubuquoy contributed equally to this work.

Abbreviations used in this paper: IBD, inflammatory bowel disease; JNK, c-jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MPO, myeloperoxidase; NF, nuclear factor; PPAR{gamma}, peroxisome proliferator–activated receptor {gamma}; RXR, retinoid X receptor; TNBS, 2,4,6-trinitrobenzene sulfonic acid.

© 2001 The Rockefeller University Press


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