Redox regulation of glial inflammatory response to lipopolysaccharide and interferonγ
Abstract
Astrocytes and microglia, the two immune‐regulatory cells of the central nervous system (CNS), are activated by a variety of pathogens and cytokines to elicit rapid transcriptional responses. This program of activation is initiated by a set of intracellular signaling cascades that includes mitogen‐activated protein kinase (MAPK), nuclear factor (NF) κB, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. This study defines the critical role that NADPH oxidase(Phox)‐derived reactive oxygen species (ROS) play in lipopolysaccharide (LPS)‐ and interferon (IFN)γ‐induced signaling cascades leading to gene expression in glial cells. Treatment of rat microglia and astrocytes with LPS and IFNγ resulted in a rapid activation of Phox and the release of ROS followed by an induction of inducible nitric oxide synthase (iNOS) expression. iNOS induction was blocked by inhibitors of Phox, i.e., diphenylene iodonium chloride (DPI) and 4‐(2‐aminoethyl) benzenesulfonylfluoride (AEBSF), suggesting an involvement of ROS signaling in iNOS gene expression. Exogenous catalase but not superoxide dismutase suppressed the basal activity and completely blocked induced levels of NO/iNOS, suggesting that hydrogen peroxide is the ROS involved. Phox inhibitors and catalase also suppressed LPS/IFNγ‐induced expression of cytokines, i.e., interleukin (IL)‐1, IL‐6, and tumor necrosis factor (TNF)α and blocked LPS activation of MAP kinases (i.e., p38 MAPK, c‐Jun N‐terminal kinase and extracellular signal‐regulated kinase), NFκB, and IFNγ‐induced STAT1 phosphorylation. A microglial cell line stably transfected with a mutant form of Phox subunit, i.e., p47 phox W(193)R, and primary astrocytes derived from Phox‐deficient mice showed attenuated ROS production and induction of iNOS in response to LPS/IFNγ, further strengthening the notion that Phox‐derived ROS are crucial for proinflammatory gene expression in glial cells. © 2004 Wiley‐Liss, Inc.
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Nox was implicated in LPS-triggered rat microglial production of NO.
“It was previously shown with Nox inhibitors and ROS scavengers that Nox was implicated in LPS-triggered rat microglial production of NO⅐ (Pawate et al., 2004).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Pawate et al., 2004
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- Authors
- Pawate, S., Shen, Q., Fan, F., & Bhat, N. R.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Bhat, Narayan R.
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2004-06-04
- Volume
- 77
- Issue
- 4
- Pages
- 540-551
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2056311398
- Cited by
- 428
- References
- 5
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 13 · 2023: 17 · 2022: 12 · 2021: 22 · 2020: 21 · 2019: 16 · 2018: 18 · 2017: 20 · 2016: 29 · 2015: 19 · 2014: 23 · 2013: 19 · 2012: 18
- FWCI
- 7.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS41396, NS41035, R01NS041035, R01NS041396, R01NS051575)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- NADPH oxidase, reactive oxygen species, glial inflammation, lipopolysaccharide, interferon-gamma, astrocytes, microglia, inducible nitric oxide synthase, hydrogen peroxide, MAPK signaling, NF-κB, JAK/STAT signaling, STAT1 phosphorylation, cytokine gene expression, p47phox, catalase, diphenyleneiodonium
- MeSH terms
- Animals, Animals, Newborn, Astrocytes, Cells, Cultured, Encephalitis, Enzyme Inhibitors, Gliosis, Interferon-gamma, Lipopolysaccharides, Oxidation-Reduction, Gene Expression Regulation, Enzymologic, Cytokines, NF-kappa B, Reactive Oxygen Species, Microglia, Mice, Knockout, Oxidative Stress, Inflammation Mediators, Nitric Oxide Synthase, NADPH Oxidases, MAP Kinase Signaling System, Mice, Rats, Nitric Oxide Synthase Type II
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