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J. Biol. Chem., Vol. 282, Issue 5, 2871-2879, February 2, 2007

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ATP Activates a Reactive Oxygen Species-dependent Oxidative Stress Response and Secretion of Proinflammatory Cytokines in Macrophages^*

Cristiane M. Cruz, Alessandra Rinna, Henry Jay Forman, Ana L. M. Ventura^¶, Pedro M. Persechini^¶, and David M. Ojcius¹

From the School of Natural Sciences, University of California, Merced, California 95344, the Laboratorio de Imunobiofisica, IBCCF, Federal University of Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil, and the ^¶Laboratório de Neuroquímica, Instituto de Biologia, Universidade Federal Fluminense, Niterói 24030-210, Rio de Janeiro, Brazil

Secretion of the proinflammatory cytokines, interleukin (IL)-1 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-1 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.

Received for publication, August 23, 2006 , and in revised form, November 13, 2006.

^* This work was supported by a fellowship from the Conselho Nacional de Desenvolvimento Cientifico e Technologico do Brasil (CNPq), the University of California, and National Institutes of Health Grant HL37556. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: P. O. Box 2039, Merced, CA 95344. Tel.: 209-724-2948; Fax: 209-724-2912; E-mail: dojcius{at}ucmerced.edu.

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