Selective inhibition of cyclooxygenase-2 expression by 15-deoxy-Δ12,14-prostaglandin J2 in activated human astrocytes, but not in human brain macrophages

Overexpression of the inducible cyclooxygenase (COX-2) and inducible NO synthase (iNOS) in activated brain macrophages (microglia) and astrocytes appears central to many neuroinflammatory conditions. 15-Deoxy-Delta(12.14)-PGJ(2) (15d-PGJ(2)) is a ligand for the peroxisome proliferator-activated receptor (PPAR)gamma. It has been proposed as an inhibitor of microglial activation, based on the study of iNOS down-regulation in rodent microglia. Because iNOS induction after cytokine activation remains controversial in human microglia, we examined the effect of 15d-PGJ2 and other PPAR agonists on human microglia and astrocytes, using COX-2 induction as an index of activation. We found that PPARalpha ligands (clofibrate and WY14643) enhanced IL-1beta-induced COX-2 expression in human astrocytes and microglia, while inhibiting IL-1beta plus IFN-gamma induction of iNOS in astrocytes. This is the first description of an inhibition of iNOS uncoupled from that of COX-2. 15d-PGJ2 suppressed COX-2 induction in human astrocytes. It prevented NF-kappaB binding to the COX-2 promoter through a new pathway that is the repression of NF-kappaBp50 induction by IL-1beta. In contrast, 15d-PGJ(2) increased c-Jun and c-Fos DNA-binding activity in astrocytes, which may result in the activation of other inflammatory pathways. In human microglia, no effect of 15d-PGJ2 on COX-2 and NF-kappaBp65/p50 induction was observed. However, the entry of 15d-PGJ2 occurred in microglia because STAT-1 and c-Jun expression was modulated. Our data suggest the existence of novel pathways mediated by 15d-PGJ2 in human astrocytes. They also demonstrate that, unlike astrocytes and peripheral macrophages or rodent brain macrophages, human microglia are not subject to the anti-inflammatory effect of 15d-PGJ(2) in terms of COX-2 inhibition.