Tumor necrosis factor-α generates reactive oxygen species via a cytosolic phospholipase A2-linked cascade

Chang Hoon Woo, Young Woo Eom, Min Hyuk Yoo, Hae Jin You, Ho Jae Han, Woo Keun Song, Yung Joon Yoo, Jang Soo Chun, Jae Hong Kim

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195 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) are important regulatory molecules implicated in the signaling cascade triggered by tumor necrosis factor (TNF)-α, although the events through which TNF-α induces ROS generation are not yet well characterized. We therefore investigated selected candidates likely to mediate TNF-α-induced ROS generation. Consistent with the role of Rac in that process, stable expression of Rac(Asn-17), a dominant negative Rac1 mutant, completely blocked TNF-α-induced ROS generation. To understand better the mediators downstream of Rac, we investigated the involvement of cytosolic phospholipase A2 (cPLA2) activation and metabolism of the resultant arachidonic acid (AA) by 5-lipoxygenase (5-LO). TNF-α-induced ROS generation was blocked by inhibition of cPLA2 or 5-LO, but not cyclooxygenase, suggesting that TNF-α-induced ROS generation is dependent on synthesis of AA and its subsequent metabolism to leukotrienes. Consistent with that hypothesis, TNF-α Rac-dependently stimulated endogenous production of leukotriene B4 (LTB4), while exogenous application of LTB4 increased levels of ROS. In contrast, application of leukotrienes C4, D4, and E4 or prostaglandin E2 had little effect. Our findings suggest that LTB4 production by 5-LO is situated downstream of the Rac-cPLA2 cascade, and we conclude that Rac, cPLA2, and LTB4 play pivotal roles in the ROS-generating cascade triggered by TNF-α.

Original languageEnglish
Pages (from-to)32357-32362
Number of pages6
JournalJournal of Biological Chemistry
Volume275
Issue number41
DOIs
Publication statusPublished - 2000 Oct 13
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Woo, C. H., Eom, Y. W., Yoo, M. H., You, H. J., Han, H. J., Song, W. K., Yoo, Y. J., Chun, J. S., & Kim, J. H. (2000). Tumor necrosis factor-α generates reactive oxygen species via a cytosolic phospholipase A2-linked cascade. Journal of Biological Chemistry, 275(41), 32357-32362. https://doi.org/10.1074/jbc.M005638200