Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Abstract

Objective. To study the potency of 2 peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ) 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 (␣, ␤/␦, ␥) were assessed by realtime polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1␤. PPAR levels were assessed by Western blotting and secreted IL-1Ra levels by immunoassay. The potency of PPAR␥ agonists and the PPAR␤/␦ agonist GW-501516 on IL-1Ra levels was tested in the range of 1-10 M and at 100 pM, respectively. The contribution of PPAR␥ 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 M), respectively. The dominant-negative strategy was also performed to investigate the possible contribution of PPAR␤/␦ and NF-B activation.Results. IL-1␤-induced IL-1Ra production was increased by 10 M rosiglitazone but was reduced dose-dependently by 15-deoxy-PGJ 2 . Both agonists lowered IL-1␤ secretion, but rosiglitazone alone reduced the imbalance of IL-1␤/IL-1Ra toward basal levels. Enhancement of IL-1␤-induced IL-1Ra production by rosiglitazone was not affected by PPAR␥ overexpression or by its inhibition with dominant-negative PPAR␥ or GW-9662. Inhibition of NF-B was also ineffective against rosiglitazone but abolished the stimulating effect of IL-1␤ on IL-1Ra. All PPAR isotypes were expressed constitutively in rat synoviocytes, but PPAR␥ decreased dramatically upon IL-1␤ exposure, whereas PPAR␤/␦ remained stable. Dominant-negative PPAR␤/␦ 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 PPAR␤/␦ 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.

Treatment with the PPARγ agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome

“…Similar anti-inflammatory effects on the IL1 system in vitro have also been reported by others in THP-1 monocytes (36) and synovial fibroblasts (37). Thus, although our in vivo data clearly suggest inflammatory net effect on the IL1 system during rosiglitazone therapy, representing the main finding in the present study, our in vitro data illustrate the complex effects of these medications, potentially exhibiting anti-inflammatory effects in certain tissues or cells at least at certain concentrations.…”

IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

“…In fact, the expression pattern of IL-33 was more similar to that of IL-1 receptor antagonist, the natural inhibitor of IL-1β, which is also expressed in non-inflammatory bone [41] and in adipocytes (our unpublished data and [42]). It will be interesting to examine whether the expression of IL-33, like that of IL-1Ra, is also controlled by PPARα [43,44] and PPARβ/δ [45].…”

PPARδ inhibits IL-1β-stimulated proliferation and migration of vascular smooth muscle cells via up-regulation of IL-1Ra

“…Previous studies demonstrated that activation of PPARa and c potentiates IL-1Ra production in cells such as synovial fibroblasts, chondrocytes, and THP-1 that were stimulated by cytokine or phorbol ester [26][27][28]. In IL-1b-treated chondrocytes, this action was mediated via PPRE, which is located in the IL-1Ra promoter region.…”