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ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2007 Feb 02; Vol. 282 (5), pp. 2871-9. Date of Electronic Publication: 2006 Nov 27. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Caspase 1 metabolism
Cells, Cultured
DNA Primers
Flow Cytometry
Interleukin-1 metabolism
Interleukin-18 metabolism
Macrophages, Alveolar drug effects
Mitogen-Activated Protein Kinase 3 metabolism
Oxidative Stress drug effects
Phosphorylation
Rats
Rats, Sprague-Dawley
Adenosine Triphosphate pharmacology
Cytokines metabolism
Inflammation physiopathology
Macrophages, Alveolar physiology
Oxidative Stress physiology
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 282
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17132626
- Full Text :
- https://doi.org/10.1074/jbc.M608083200