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

PPAR-[gamma] ligands modulate the effects of LPS in stimulated rat synovial fibroblasts. Am J Physiol Cell Physiol 282: C125-C133, 2002.--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 [micro]g/ml lipopolysaccharide (LPS) was observed, whereas PPAR-[alpha] mRNA expression was not modified. 15-Deoxy-[[DELTA].sup.12,14]-prostaglandin [J.sub.2] (15d-PG[J.sub.2]) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (-80%) and inducible nitric oxide synthase (iNOS) mRNA expression (-80%), whereas troglitazone (10 [micro]M) only inhibited iNOS mRNA expression (-50%). 15d-PG[J.sub.2] decreased LPS-induced interleukin (IL)-1[beta] (-25%) and tumor necrosis factor (TNF)-[alpha] (-40%) expression. Interestingly, troglitazone strongly decreased TNF-[alpha] expression (-50%) but had no significant effect on IL-1[beta] expression. 15d-PG[J.sub.2] 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-PG[J.sub.2] 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-PG[J.sub.2] and troglitazone in synovial fibroblasts. peroxisome proliferator-activated receptor-[gamma] ligands; rat synovial fibroblasts; proinflammatory cytokines