Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-α, and lipopolysaccharide

L. Feng, Y. Xia, G. E. Garcia, D. Hwang, C. B. Wilson

Research output: Contribution to journalArticlepeer-review

443 Scopus citations

Abstract

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-, TNFα-, 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 TNFα. 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.

Original languageEnglish (US)
Pages (from-to)1669-1675
Number of pages7
JournalJournal of Clinical Investigation
Volume95
Issue number4
StatePublished - 1995
Externally publishedYes

Keywords

  • KC
  • mesangial cell
  • NADPH
  • PTPase
  • reactive oxygen intermediates

ASJC Scopus subject areas

  • Medicine(all)

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