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• W2099402579 abstract "To determine whether peroxisome proliferator-activated receptor alpha (PPARalpha) agonists protect chondrocytes against the effects of interleukin-1beta (IL-1beta).PPARalpha 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-1beta 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-1beta and IL-1Ra soluble contents were measured by ELISA.CloF counteracted IL-1beta-induced 35S-proteoglycan degradation, gelatinolytic activity, and MMP-1, -3, and -13 mRNA expression. CloF also maximized IL-1beta-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-1beta-induced MMP expression. The stimulatory effect of CloF was enhanced by cotransfection with wild-type PPARalpha and abolished by a dominant-negative PPARalpha 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-kappaB-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.Our findings support the notion that there is a PPARalpha-dependent mechanism that inhibits IL-1beta function in chondrocytes, which operates via an increase in sIL-1Ra production." @default.
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• W2099402579 date "2006-01-01" @default.
• W2099402579 modified "2023-10-18" @default.
• W2099402579 title "Activation of the peroxisome proliferator–activated receptor α pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes" @default.
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• W2099402579 doi "https://doi.org/10.1002/art.21728" @default.
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