Cited by 210Immune Response and Inflammationinterferon and immune responsesGene Regulatory Network Analysis

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Investigating the Role of TNF-α and IFN-γ Activation on the Dynamics of iNOS Gene Expression in LPS Stimulated Macrophages

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Salim, Taha, Sershen, Cheryl L., May, Elebeoba E.·2016·PLOS ONE

DOI 10.1371/journal.pone.0153289PMC PMC4898755

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Abstract

Macrophage produced inducible nitric oxide synthase (iNOS) is known to play a critical role in the proinflammatory response against intracellular pathogens by promoting the generation of bactericidal reactive nitrogen species. Robust and timely production of nitric oxide (NO) by iNOS and analogous production of reactive oxygen species are critical components of an effective immune response. In addition to pathogen associated lipopolysaccharides (LPS), iNOS gene expression is dependent on numerous proinflammatory cytokines in the cellular microenvironment of the macrophage, two of which include interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). To understand the synergistic effect of IFN-γ and TNF-α activation, and LPS stimulation on iNOS expression dynamics and NO production, we developed a systems biology based mathematical model. Using our model, we investigated the impact of pre-infection cytokine exposure, or priming, on the system. We explored the essentiality of IFN-γ priming to the robustness of initial proinflammatory response with respect to the ability of macrophages to produce reactive species needed for pathogen clearance. Results from our theoretical studies indicated that IFN-γ and subsequent activation of IRF1 are essential in consequential production of iNOS upon LPS stimulation. We showed that IFN-γ priming at low concentrations greatly increases the effector response of macrophages against intracellular pathogens. Ultimately the model demonstrated that although TNF-α contributed towards a more rapid response time, measured as time to reach maximum iNOS production, IFN-γ stimulation was significantly more significant in terms of the maximum expression of iNOS and the concentration of NO produced.

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1 retracted

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Authors: Salim, T., Sershen, C. L., & May, E. E.
Affiliations: University of Houston (US)
Corresponding author: May, Elebeoba E.
Venue: PLOS ONE
Publisher: Public Library of Science (PLoS)
Published: 2016-06-08
Volume: 11
Issue: 6
Pages: e0153289
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0153289
PMC: PMC4898755
OpenAlex: W2415587673
Cited by: 210
References: 94
Citations by year: 2026: 22 · 2025: 24 · 2024: 29 · 2023: 22 · 2022: 26 · 2021: 31 · 2020: 26 · 2019: 14 · 2018: 10 · 2017: 5 · 2016: 1
FWCI: 6.05
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Figshare (submittedVersion, cc-by)
Funders: Defense Threat Reduction Agency (FA8650-10-2-6062 subaward #2381 (Henry M. Jackson Foundation))
Sandia National Laboratories, National Nuclear Security Administration (LDRD 151348)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords: inducible nitric oxide synthase, iNOS expression, macrophages, lipopolysaccharide stimulation, interferon-gamma, TNF-α, nitric oxide production, IRF1, cytokine priming, intracellular pathogens, reactive nitrogen species, systems biology models, pro-inflammatory response
MeSH terms: Humans, Interferon-gamma, Lipopolysaccharides, Macrophages, Nitric Oxide, Tumor Necrosis Factor-alpha, Gene Expression Regulation, Enzymologic, Models, Immunological, Nitric Oxide Synthase Type II

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Investigating the Role of TNF-α and IFN-γ Activation on the Dynamics of iNOS Gene Expression in LPS Stimulated Macrophages

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