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

Francois, M., Richette, P., Tsagris, L., Fitting, C., Lemay, C., Benallaoua, M., Tahiri, K. and Corvol, M. T. (2006) Activation of the peroxisome proliferator-activated receptor pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes. Arthritis and Rheumatism, 54 4: 1233-1245. doi:10.1002/art.21728


Author Francois, M.
Richette, P.
Tsagris, L.
Fitting, C.
Lemay, C.
Benallaoua, M.
Tahiri, K.
Corvol, M. T.
Title Activation of the peroxisome proliferator-activated receptor pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes
Journal name Arthritis and Rheumatism   Check publisher's open access policy
ISSN 0004-3591
Publication date 2006
Sub-type Article (original research)
DOI 10.1002/art.21728
Volume 54
Issue 4
Start page 1233
End page 1245
Total pages 13
Place of publication Hoboken. N.J.
Publisher John Wiley & Sons
Language eng
Subject 060405 Gene Expression (incl. Microarray and other genome-wide approaches)
Abstract Objective To determine whether peroxisome proliferator-activated receptor (PPAR) agonists protect chondrocytes against the effects of interleukin-1 (IL-1). Methods PPAR 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-1 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-1 and IL-1Ra soluble contents were measured by ELISA. Results CloF counteracted IL-1-induced 35S-proteoglycan degradation, gelatinolytic activity, and MMP-1, -3, and -13 mRNA expression. CloF also maximized IL-1-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-1-induced MMP expression. The stimulatory effect of CloF was enhanced by cotransfection with wild-type PPAR and abolished by a dominant-negative PPAR 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-B-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 PPAR-dependent mechanism that inhibits IL-1 function in chondrocytes, which operates via an increase in sIL-1Ra production.
Keyword Rheumatism
Arthritis
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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