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

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-, 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.

• Authors: L Feng, Y Xia, G E Garcia, D Hwang, C B Wilson
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 95 Issue 4 Pg. 1669-75 (Apr 1995) ISSN: 0021-9738 [Print] United States
• PMID: 7706475 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

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