Anti-inflammatory actions of 15-deoxy-Delta (12,14)-prostaglandin J(2) andtroglitazone - Evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression

In this study, the anti-inflammatory actions of the peroxisome proliferator -activated receptor (PPAR)-gamma agonists 15-deoxy-Delta (12,14)-prostaglan din J(2) (15-d-Delta (12,14)-PGJ(2)) and troglitazone have been examined. T reatment of RAW 264.7 cells and CD-1 mouse peritoneal macrophages with lipo polysaccharide (LPS) + interferon-gamma (IFN-gamma) results in inducible ni tric oxide synthase (iNOS), inducible cyclooxygenase (COX-2) and interleuki n-1 (IL-1) expression, increased production of nitric oxide, and the releas e of IL-1, In a concentration-dependent manner, 15-d-Delta (12,14)-PGJ(2) i nhibits each of these proinflammatory actions of LPS + IFN-gamma, with half -maximal inhibition at -0.5 mu g/ml and complete inhibition at 1-5 mu g/ml, The inhibitory actions of 15-d-Delta (12,14)-PGJ(2) on LPS + IFN-gamma-ind uced inflammatory events are not associated with the inhibition of iNOS enz ymatic activity or macrophage cell death, but appear to result from an inhi bition of iNOS and IL-1 transcription. In addition, the anti-inflammatory a ctions of 15-d-Delta (12,14)-PGJ(2) are not limited to peritoneal macrophag es, as 15-d-Delta (12,14)-PGJ(2) prevents TNF-alpha + LPS-induced resident islet macrophage expression of IL-1 beta and beta-cell expression of iNOS s timulated by the local release of IL-1 in rat islets, 15-d-Delta (12,14)-PG J(2) appears to be similar to 10-fold more effective at inhibiting resident islet macrophage activation (in response to TNF + LPS) than IL-1-induced n itrite production by beta-cells. Two mechanisms appear to be associated wit h the antiinflammatory actions of both 15-d-Delta (12,14)-PGJ(2) and trogli tazone: 1) the direct inhibition of cytokine- and endotoxin-stimulated iNOS and IL-1 transcription; and 2) the inhibition of IL-1 signaling, an event associated with PPAR-gamma agonist-induced activation of the heat shock res ponse (as assayed by heat shock protein 70 expression). These findings indi cate that the PPAR-gamma agonists, troglitazone and the J series of prostag landins, are potent anti-inflammatory agents that prevent cytokine- and end otoxin-stimulated activation of peripheral and resident tissue macrophages and cytokine-induced iNOS expression by beta-cells by the inhibition of tra nscriptional activation and induction of the heat shock response.