Selective Inhibition of Cyclooxygenase-2 Expression by 15-Deoxy-Δ12,1412,14-prostaglandin J2 in Activated Human Astrocytes, But Not in Human Brain Macrophages

Abstract

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-Δ12,14-PGJ2 (15d-PGJ2) is a ligand for the peroxisome proliferator-activated receptor (PPAR)γ. 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 PPARα ligands (clofibrate and WY14643) enhanced IL-1β-induced COX-2 expression in human astrocytes and microglia, while inhibiting IL-1β plus IFN-γ 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-κB binding to the COX-2 promoter through a new pathway that is the repression of NF-κBp50 induction by IL-1β. In contrast, 15d-PGJ2 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-κBp65/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-PGJ2 in terms of COX-2 inhibition.