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Am J Physiol Cell Physiol 282: C125-C133, 2002;
0363-6143/02 $5.00
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Vol. 282, Issue 1, C125-C133, January 2002

PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts

Marie-Agnès Simonin1, Karim Bordji1, Sandrine Boyault1, Arnaud Bianchi2, Elvire Gouze1, Philippe Bécuwe2, Michel Dauça2, Patrick Netter1, and Bernard Terlain1

1 Laboratoire de Pharmacologie, Unite Mixte de Recherche Centre National de la Recherche Scientifique 7561, 54505 Vandoeuvre-lès-Nancy; and 2 Laboratoire de Biologie du Développement, Unite propre de l'enseignement superieur 2402, 54500 Vandoeuvre-lès-Nancy, France

This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-gamma expression induced by 10 µg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-alpha mRNA expression was not modified. 15-Deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (-80%) and inducible nitric oxide synthase (iNOS) mRNA expression (-80%), whereas troglitazone (10 µM) only inhibited iNOS mRNA expression (-50%). 15d-PGJ2 decreased LPS-induced interleukin (IL)-1beta (-25%) and tumor necrosis factor (TNF)-alpha (-40%) expression. Interestingly, troglitazone strongly decreased TNF-alpha expression (-50%) but had no significant effect on IL-1beta expression. 15d-PGJ2 was able to inhibit DNA-binding activity of both nuclear factor (NF)-kappa B and AP-1. Troglitazone had no effect on NF-kappa B activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ2 and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-alpha and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-gamma ligands and underline different mechanisms of action of 15d-PGJ2 and troglitazone in synovial fibroblasts.

peroxisome proliferator-activated receptor-gamma ligands; rat synovial fibroblasts; proinflammatory cytokines


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