Role of reactive oxygen species in LPS‐induced production of prostaglandin E2 in microglia

Abstract

We determined the roles of reactive oxygen species (ROS) in the expression of cyclooxygenase‐2 (COX‐2) and the production of prostaglandin E₂ (PGE₂) in lipopolysaccharide (LPS)‐activated microglia. LPS treatment increased intracellular ROS in rat microglia dose‐dependently. Pre‐treatment with superoxide dismutase (SOD)/catalase, or SOD/catalase mimetics that can scavenge intracellular ROS, significantly attenuated LPS‐induced release in PGE₂. Diphenylene iodonium (DPI), a non‐specific NADPH oxidase inhibitor, decreased LPS‐induced PGE₂ production. In addition, microglia from NADPH oxidase‐deficient mice produced less PGE₂ than those from wild‐type mice following LPS treatment. Furthermore, LPS‐stimulated expression of COX‐2 (determined by RT‐PCR analysis of COX‐2 mRNA and western blot for its protein) was significantly reduced by pre‐treatment with SOD/catalase or SOD/catalase mimetics. SOD/catalase mimetics were more potent than SOD/catalase in reducing COX‐2 expression and PGE₂ production. As a comparison, scavenging ROS had no effect on LPS‐induced nitric oxide production in microglia. These results suggest that ROS play a regulatory role in the expression of COX‐2 and the subsequent production of PGE₂ during the activation process of microglia. Thus, inhibiting NADPH oxidase activity and subsequent ROS generation in microglia can reduce COX‐2 expression and PGE₂ production. These findings suggest a potential therapeutic intervention strategy for the treatment of inflammation‐mediated neurodegenerative diseases.