PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts.
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 microg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-alpha mRNA expression was not modified. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (-80%) and inducible nitric oxide synthase (iNOS) mRNA expression (-80%), whereas troglitazone (10 microM) only inhibited iNOS mRNA expression (-50%). 15d-PGJ(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-PGJ(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-PGJ(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-PGJ(2) and troglitazone in synovial fibroblasts.
Simonin
Marie-Agnès
MA
Laboratoire de Pharmacologie, Unite Mixte de Recherche Centre National de la Recherche Scientifique 7561, 54505 Vandoeuvre-lès-Nancy, France.
Bordji
Karim
K
Boyault
Sandrine
S
Bianchi
Arnaud
A
Gouze
Elvire
E
Bécuwe
Philippe
P
Dauça
Michel
M
Netter
Patrick
P
Terlain
Bernard
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D051546:Cyclooxygenase 2; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007375:Interleukin-1 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000166:cytology* / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000970:Antineoplastic Agents; D002839:Chromans; D007375:Interleukin-1; D007527:Isoenzymes; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C037112:9-deoxy-delta-9-prostaglandin D2; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000077288:Troglitazone; D015230:Prostaglandin D2