title: ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages.
abstract: Secretion of the proinflammatory cytokines, interleukin (IL)-1beta 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-1beta 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.
authors.affiliation: School of Natural Sciences, University of California, Merced, California 95344, USA.
authors.forename: Cristiane M
authors.initials: CM
authors.lastname: Cruz
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rinna
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
authors.forename: Ana L M
authors.initials: AL
authors.lastname: Ventura
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Persechini
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D017931:DNA Primers; D005434:Flow Cytometry; D007249:Inflammation / Q000503:physiopathology*; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016207:Cytokines; D017931:DNA Primers; D007375:Interleukin-1; D020382:Interleukin-18; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D048052:Mitogen-Activated Protein Kinase 3; D020170:Caspase 1