Details

Autor(en) / Beteiligte

• François, Mathias
• Richette, Pascal
• Tsagris, Lydia
• Fitting, Catherine
• Lemay, Cedric
• Benallaoua, Mourad
• Tahiri, Khadija
• Corvol, Marie‐Therese

Titel

Activation of the peroxisome proliferator–activated receptor α pathway potentiates interleukin‐1 receptor antagonist production in cytokine‐treated chondrocytes

Ist Teil von

• Arthritis and rheumatism, 2006-04, Vol.54 (4), p.1233-1245

Ort / Verlag

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

Erscheinungsjahr

2006

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Objective To determine whether peroxisome proliferator–activated receptor α (PPARα) agonists protect chondrocytes against the effects of interleukin‐1β (IL‐1β). Methods PPARα expression and function in cultured rabbit articular chondrocytes were studied by Northern blotting, electrophoretic mobility shift assay, and transient expression of a luciferase reporter construct bearing the human IL‐1 receptor antagonist (Il‐1Ra) gene promoter. Chondrocytes were incubated in vitro with IL‐1β alone or in combination with CloFibrate (CloF) or other PPAR ligands. Proteoglycans were evaluated by 35S‐sulfate incorporation, matrix metalloproteinase (MMP) levels were assessed by zymography and enzyme‐linked immunosorbent assay (ELISA), and MMP messenger RNA (mRNA) levels were measured by Northern blotting and real‐time reverse transcriptase–polymerase chain reaction. IL‐1β and IL‐1Ra soluble contents were measured by ELISA. Results CloF counteracted IL‐1β–induced 35S‐proteoglycan degradation, gelatinolytic activity, and MMP‐1, ‐3, and ‐13 mRNA expression. CloF also maximized IL‐1β–induced endogenous production of soluble IL‐1Ra (sIL‐1Ra). This stimulating effect on IL‐1Ra gene expression was shown, by transient expression assay, to be transcriptional. Inhibition of sIL‐1Ra expression by a specific small interfering RNA suppressed the effect of CloF on IL‐1β–induced MMP expression. The stimulatory effect of CloF was enhanced by cotransfection with wild‐type PPARα and abolished by a dominant‐negative PPARα mutant. Fenofibrate and WY‐14643 displayed a similar stimulating effect on the IL‐1Ra promoter, while rosiglitazone did not. Two PPAR response elements, an NF‐κB–binding site, and a CCAAT/enhancer binding protein–binding site were identified in the IL‐1Ra promoter. All 4 sites were necessary for mediation of the effects of CloF. Conclusion Our findings support the notion that there is a PPARα‐dependent mechanism that inhibits IL‐1β function in chondrocytes, which operates via an increase in sIL‐1Ra production.