EXPRESSION AND REGULATION OF CYCLOOXYGENASE-2 IN RAT MICROGLIA

Increased levels of prostanoids have been implicated in various neurop athological diseases, although little is known about their cellular so urces inside the brain. In this study, we analyzed the expression of c yclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, in rat microglia. COX-2 mRNA and protein as well as prostaglandin E(2) formation were almost undetectable in unstimulated microglial culture s but were found to be strongly upregulated in response to lipopolysac charide. However, in contrast to most peripheral cells, proinflammator y cytokines such as tumor necrosis factor alpha, interleukin-1 beta or interleukin-6 failed to markedly induce COX-2 expression. Similar eff ects were observed by analyzing transcription nuclear factor-kappa B ( NF-kappa B) which was strongly activated in microglia by lipopolysacch aride but not by incubation with cytokines. Moreover, known inhibitors of NF-kappa B activation, such as dexamethasone and the antioxidant p yrrolidine dithiocarbamate, as well as the protein kinase C (PKC) inhi bitor Go6976, strongly reduced lipopolysaccharide-induced COX-2 transc ription, indicating the involvement of NF-kappa B and PKC in COX-2 exp ression. Our results suggest that microglia may represent an important source of prostanoids in the brain, thus reinforcing their prominent role in cerebral inflammatory processes.