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

J Clin Invest. 1995 Apr;95(4):1669-75. doi: 10.1172/JCI117842.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Base Sequence
  • Enzyme Induction / drug effects
  • Free Radical Scavengers / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / metabolism*
  • Hot Temperature
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Molecular Sequence Data
  • NADH, NADPH Oxidoreductases / metabolism
  • NADPH Oxidases
  • Oxidative Stress / physiology
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Protein Tyrosine Phosphatases / biosynthesis
  • Protein Tyrosine Phosphatases / genetics
  • Rats
  • Reactive Oxygen Species / metabolism*
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antioxidants
  • Free Radical Scavengers
  • Interleukin-1
  • Lipopolysaccharides
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Prostaglandin-Endoperoxide Synthases
  • NADH, NADPH Oxidoreductases
  • NADPH Oxidases
  • Protein Tyrosine Phosphatases