Selective Inhibition of Cyclooxygenase-2 Expression by 15-Deoxy-#DELTA#~(12,14)-prostaglandin J_2 in Activated Human Astrocytes, But Not in Human Brain Macrophages

摘要

Overexpression of the inducible cyclooxygenase (COX-2) and inducible NO synthase (iNOS) in activated brain macrophages (microglia) and astrocytes appears central to many neutroinflammatory conditions. 15-Deoxy-#DELTA#~(12,14) -PGJ_2 (15d-PGJ_2) is a ligand for the peroxisome proliferator-activated receptor (PPAR)#gamma#. It ahs 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-PGJ_2 and other PPAR agonists on human microglia and astrocytes, using COX-2 induction as an index of activation. We found that PPAR#alpha# ligands (clofibrate and WY1463) enhanced IL-1#beta#-induced COX-2 expression in human astrocytes and microglia, while inhibiting IL-1#beta# plus IFN-#gamma# induction of iNOS astrocytes. This is the first description of an inhibition of iNOS uncoupled from that of COX-2. 15d-PGJ_2 suppressed COX-2 induction in human astrocytes. It prevented NF-#kappa#B binding to the COX-2 promoter through a new pathway that is the repression of NF-#kappa#Bp50 induction by IL-1#beta#. In contrast, 15d-PGJ_2 increased c-Jun and c-Fos DNA-binding activity in astrocytes, which may result in the actiation of other inflammatory pathways. In human microglia, no effect of 15d-PGJ_2 on COX-2 and NF-#kappa#Bp65/p50 induction was observed. However, the entry of 15d-PGJ_2 occurred in microglia because STAT-1 and c-Jun expression was modulated. Our data suggest the existence of novel pathways mediated by 15d-PGJ_2 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.