INVOLVEMENT OF REACTIVE OXYGEN INTERMEDIATES IN CYCLOOXYGENASE-2 EXPRESSION INDUCED BY INTERLEUKIN-1, TUMOR-NECROSIS-FACTOR-ALPHA, AND LIPOPOLYSACCHARIDE

Reactive oxygen intermediates (ROIs) play an important role in inflammatory processes as mediators of injury and potentially in signal transduction leading to gene expression. Cyclooxygenase (COX) is a rate-limiting enzyme in prostanoid biosynthesis, and its recently cloned inducible form, COX-2, is induced by proinflammatory cytokines, This study linked ROIs to the signaling pathways that induce COX-2 expression, The hydroxyl radical scavengers DMSO (1%), as well as di- and tetramethylthiourea, inhibited IL-1-, TNF alpha-, and LPS-induced COX-2 expression in rat mesangial cells, The suppression of COX-2 mRNA expression correlated with the COX-2 protein level, In comparison with the prolonged induction of the inducible gene encoding protein-tyrosine phosphatase by hydrogen peroxide, the COX-2 gene was only transiently induced, Protein-tyrosine phosphatase is also induced by heat shock and chemical stress, whereas COX-2 is not, Superoxide was a more potent inducer for COX-2 than hydrogen peroxide, In addition, NADPH stimulated COX-2 expression, and an inhibitor of NADPH oxidase blocked COX-2 expression induced by TNF alpha. COX-2 and KC gene expression costimulated by IL-1 were inhibited differentially by the scavengers, These studies demonstrate that oxidant stress is a specific and important inducer of COX-2 gene expression, This induction may contribute to the deleterious amplification of prostanoids in inflammation and compound the direct effects of ROI production,