ATP Activates a Reactive Oxygen Species-dependent Oxidative Stress Response and Secretion of Proinflammatory Cytokines in Macrophages
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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.
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Published findings indicate that ROS help activate caspase-1 after ATP treatment and contribute to Nalp3 activation by MSU and R837.
“Recent data also suggest a role for ROS in activating caspase-1 upon ATP treatment (18) and in Nalp3 inflammasome activation by MSU and R837 (13).”
From Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica (2008) · cites this paper as [18]
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Multiple cathepsins promote pro-IL-1β synthesis and NLRP3-mediated IL-1β activation
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Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome
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Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation
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Sensing pathogens and danger signals by the inflammasome
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The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal
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The Inflammasome in Atherosclerosis and Type 2 Diabetes
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The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis
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- Authors
- Cruz, C. M., Rinna, A., Forman, H. J., Ventura, A. L. M., Persechini, P. M., & Ojcius, D. M.
- Affiliations
- Universidade Federal do Rio de Janeiro (BR)
- University of California, Merced (US)
- Universidade Federal Fluminense (BR)
- Corresponding author
- Ojcius, David M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 282
- Issue
- 5
- Pages
- 2871-2879
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2693903
- OpenAlex
- W2054571187
- Cited by
- 786
- References
- 60
- Citations by year
- 2026: 22 · 2025: 26 · 2024: 39 · 2023: 37 · 2022: 39 · 2021: 50 · 2020: 50 · 2019: 44 · 2018: 33 · 2017: 52 · 2016: 45 · 2015: 57 · 2014: 45 · 2013: 62 · 2012: 50
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Scholarly Commons (University of the Pacific) (submittedVersion)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL037556, HL 37556)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ATP, reactive oxygen species, oxidative stress response, macrophages, inflammatory cytokines, IL-1β, IL-18, caspase-1, NLRP3 inflammasome, purinergic receptors, PI3K/Akt signaling, ERK1/2, cytokine production
- MeSH terms
- Adenosine Triphosphate, Animals, Cells, Cultured, Flow Cytometry, Inflammation, Interleukin-1, Phosphorylation, Cytokines, Macrophages, Alveolar, Rats, Sprague-Dawley, Reactive Oxygen Species, DNA Primers, Oxidative Stress, Caspase 1, Interleukin-18, Mitogen-Activated Protein Kinase 3, Rats
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