Rosiglitazone induces interleukin-1 receptor antagonist in interleukin-1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism
David Moulin
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorArnaud Bianchi
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorSandrine Boyault
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorSylvie Sebillaud
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorMeriem Koufany
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorMathias Francois
UMR INSERM 530–Université Paris V, UFR Biomédicale, Paris, France
Search for more papers by this authorPatrick Netter
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorCorresponding Author
Jean-Yves Jouzeau
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
CNRS–Université Henri Poincaré Nancy 1, Avenue de la Forêt de Haye, BP184, 54505 Vandoeuvre-les-Nancy, FranceSearch for more papers by this authorBernard Terlain
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorDavid Moulin
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorArnaud Bianchi
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorSandrine Boyault
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorSylvie Sebillaud
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorMeriem Koufany
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorMathias Francois
UMR INSERM 530–Université Paris V, UFR Biomédicale, Paris, France
Search for more papers by this authorPatrick Netter
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorCorresponding Author
Jean-Yves Jouzeau
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
CNRS–Université Henri Poincaré Nancy 1, Avenue de la Forêt de Haye, BP184, 54505 Vandoeuvre-les-Nancy, FranceSearch for more papers by this authorBernard Terlain
UMR 7561–CNRS–Université Henri Poincaré Nancy 1, Vandoeuvre-les-Nancy, France
Search for more papers by this authorAbstract
Objective
To study the potency of 2 peroxisome proliferator–activated receptor γ (PPARγ) agonists, 15-deoxy-Δ12,14-prostaglandin J2 (15-deoxy-PGJ2) and rosiglitazone, to modulate the expression of interleukin-1 receptor antagonist (IL-1Ra) in rat synovial fibroblasts.
Methods
Levels of messenger RNA for IL-1Ra and PPAR isotypes (α, β/δ, γ) were assessed by real-time polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1β. PPAR levels were assessed by Western blotting and secreted IL-1Ra levels by immunoassay. The potency of PPARγ agonists and the PPARβ/δ agonist GW-501516 on IL-1Ra levels was tested in the range of 1–10 μM and at 100 pM, respectively. The contribution of PPARγ to the effects of rosiglitazone on IL-1Ra secretion was examined either by its overexpression or by inhibition using wild-type or dominant-negative constructs and the antagonist GW-9662 (10 μM), respectively. The dominant-negative strategy was also performed to investigate the possible contribution of PPARβ/δ and NF-κB activation.
Results
IL-1β–induced IL-1Ra production was increased by 10 μM rosiglitazone but was reduced dose-dependently by 15-deoxy-PGJ2. Both agonists lowered IL-1β secretion, but rosiglitazone alone reduced the imbalance of IL-1β/IL-1Ra toward basal levels. Enhancement of IL-1β–induced IL-1Ra production by rosiglitazone was not affected by PPARγ overexpression or by its inhibition with dominant-negative PPARγ or GW-9662. Inhibition of NF-κB was also ineffective against rosiglitazone but abolished the stimulating effect of IL-1β on IL-1Ra. All PPAR isotypes were expressed constitutively in rat synoviocytes, but PPARγ decreased dramatically upon IL-1β exposure, whereas PPARβ/δ remained stable. Dominant-negative PPARβ/δ abolished the enhancement of IL-1Ra by rosiglitazone, whereas GW-501516 reproduced the effect of rosiglitazone on IL-1Ra secretion.
Conclusion
Rosiglitazone stimulates IL-1Ra production by a PPARβ/δ mechanism in activated rat synovial fibroblasts, further contributing to its potential antiarthritic properties and opening new perspectives for the modulation of inflammatory genes by specific PPAR agonists in articular cells.
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