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Article
ATP activates a Reactive Oxygen Species-dependent oxidative stress response and secretion of pro-inflammatory cytokines in macrophages
Journal of Biological Chemistry
  • Christiane M. Cruz, University of California, Merced
  • Alessandra Rinna, University of California, Merced
  • Henry Jay Forman, University of California, Merced
  • Ana L. M. Ventura, Universidade Federal Fluminense
  • Pedro M. Persechini, Universidade Federal Fluminense
  • David M. Ojcius, University of California, Merced
ORCiD
David M. Ojcius: 0000-0003-1461-4495
Document Type
Article
DOI
10.1074/jbc.M608083200
Publication Date
2-2-2007
Abstract

Secretion of the proinflammatory cytokines, interleukin (IL)-1β and IL-18, usually requires two signals. The first, due to microbial products such as lipopolysaccharide, initiates transcription of the cytokine genes and accumulation of the precursor proteins. Cleavage and secretion of the cytokines is mediated by caspase-1, in association with an inflammasome containing Nalp3, which can be activated by binding of extracellular ATP to purinergic receptors. We show that treatment of macrophages with ATP results in production of reactive oxygen species (ROS), which stimulate the phosphatidylinositol 3-kinase (PI3K) pathway and subsequent Akt and ERK1/2 activation. ROS exerts its effect through glutathionylation of PTEN (phosphatase and tensin homologue deleted from chromosome 10), whose inactivation would shift the equilibrium in favor of PI3K. ATP-dependent ROS production and PI3K activation also stimulate transcription of genes required for an oxidative stress response. In parallel, ATP-mediated ROS-dependent PI3K is required for activation of caspase-1 and secretion of IL-1β and IL-18. Thus, an increase in ROS levels in ATP-treated macrophages results in activation of a single pathway that promotes both adaptation to subsequent exposure to oxidants or inflammation, and processing and secretion of proinflammatory cytokines.

Citation Information
Christiane M. Cruz, Alessandra Rinna, Henry Jay Forman, Ana L. M. Ventura, et al.. "ATP activates a Reactive Oxygen Species-dependent oxidative stress response and secretion of pro-inflammatory cytokines in macrophages" Journal of Biological Chemistry Vol. 282 Iss. 5 (2007) p. 2871 - 2879 ISSN: 0021-9258
Available at: http://works.bepress.com/david-ojcius/17/