Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation
Open accessAbstract
Phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3) is essential for the induction of promoters which contain the interferon-stimulated response element (ISRE). IRF3 can be activated by Toll-like receptor 3 (TLR3) in response to the double-stranded RNA mimic poly(I-C) and by TLR4 in response to lipopolysaccharide (LPS). Here we have analyzed the effect of the glucocorticoid dexamethasone on this response. Dexamethasone inhibited the induction of the ISRE-dependent gene RANTES (regulated on activation normal T cell expressed and secreted) in both U373-CD14 cells and human peripheral blood mononuclear cells and also an ISRE luciferase construct, activated by either TLR3 or TLR4. It also inhibited increased phosphorylation of IRF3 in its N terminus in response to LPS and in its C terminus on Ser-396 in response to either poly(I-C) or LPS. Several dexamethasone-induced phosphatases were tested for possible involvement in these effects; MKP1 did not appear to be involved, although MKP2 and MKP5 both partially inhibited induction of the ISRE, pointing to their possible involvement in the effect of dexamethasone. Importantly, we found that dexamethasone could inhibit TBK1 kinase activity and TBK1 phosphorylation on Ser-172, both of which are required for IRF3 phosphorylation downstream of TLR3 and TLR4 stimulation. Our study, therefore, demonstrates that TBK1 is a target for dexamethasone, common to both TLR3 and TLR4 signaling.
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The liganded GR prevents the recruitment of IRF3 to p65 on NF-kappaB target genes upon TLR4 stimulation by LPS.
“The liganded GR was also found to prevent the recruitment of IRF3 (which then acts as a co-activator) to p65 on NF-κB target genes upon TLR4 stimulation by LPS (94, 123).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [123]
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“Repression of the interferon pathway by glucocorticoids is known (Diez et al., 2012; Flammer et al., 2010; McCoy et al., 2008) but there is no literature to suggest that the interferon pathway can repress GR function.”
BackgroundTranscripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells
Rodrigues, C. P., Collins, J. M., Yang, S. P., Martinez, C., Kim, J. W., Lama, C., Nam, A. S., Alt, C., Lin, C. P., & Zon, L. I. (2024) · Science · doi:10.1126/science.adn1629 · Cited by 20 · see citing works
“These data suggest an operative molecular network of Tlr3 activation cascades that promote Irf3 activation ( 36 ), which could promote the transcription of b2m .”
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“Mammalian IRF3 is activated by phosphorylation of TBK1 mediated by TLR or RLR signaling [28].”
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The role of stress mediators in modulation of cytokine production by ethanol
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Impaired Dual-Specificity Protein Phosphatase DUSP4 Reduces Corticosteroid Sensitivity
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“DUSP4 is also involved in regulation of immune system and inflammatory responses (McCoy et al., 2008; Al-Mutairi et al., 2010; Lubos et al., 2011).”
BackgroundMdkhana, B., Sharif‐Askari, N. S., Ramakrishnan, R. K., Al-Sheakly, B. K. S., Hafezi, S., Sharif‐Askari, F. S., Bajbouj, K., Hamid, Q. A., & Halwani, R. (2023) · PLoS ONE · doi:10.1371/journal.pone.0284061 · Cited by 14 · see citing works
“In LPS stimulated primary macrophages, dexamethasone treat-ment suppressed TBK1 activation; inhibiting IRF3 phosphorylation [49], disrupted IRF3-glu-cocorticoid receptor protein complex [50], and decreased IFN-I secretion [17, 51].”
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Mitophagy Regulated by the PINK1-Parkin Pathway
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“Tubulin was used as the loading controls, and data are represe In addition to inflammatory cytokines, GCs also decrease TLR3- and TLR4-induced interferon-stimulated response element (ISRE)-dependent gene RANTES expression by inhibiting the activation of TBK1/ IRF3 signaling [11].”
BackgroundMethodInfluentialMolecular Cross-Talk Between Nuclear Receptors and Nuclear Factor-κB
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Epigenome-wide effects of vitamin D on asthma bronchial epithelial cells
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“Furthermore, deficiency of MKP5 results in reduced influenza virus replication in the lung, which is associated with increased type I IFN production [13] while overexpression of MKP2 and MKP5 inhibited IFNβ promoter activity in response to LPS or poly (I:C) stimulation [14].”
BackgroundProteomic meta-analysis unveils new frontiers for biomarkers research in pancreatic carcinoma
Marco, F. D., Cufaro, M. C., Damiani, V., Dufrusine, B., Pizzinato, E., Ferdinando, F. D., Sala, G., Lattanzio, R., Dainese, E., Federici, L., et al. (2025) · Oncogenesis · doi:10.1038/s41389-025-00547-4 · Cited by 7 · see citing works
“…possible to notice, also as a proof of concept, that we fi nd in fl uid biomarkers functional analysis all pathways related to cancer and in fl ammation signaling as signi fi cantly activated and those related to anti-proliferative and anti-in fl ammatory functions as signi fi cantly inhibited pathways.”
Modelling the interactions between TLR4 and IFNβ pathways
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“IRF3 phosphorylation does not only function in positive regulation; it is also required for negative regulation (McCoy et al., 2008).”
BackgroundThe STING-IRF3 pathway contributes to paraquat-induced acute lung injury
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“(McCoy et al. 2008), dexamethasone can inhibit IRF3 phosphorylation by targeting TBK1, which is an intermediate regulator of the STING-IRF3 pathway activation.”
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Zinc pyrithione functions as a small-molecule STING agonist to exert antitumor immunotherapy effects
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“In addition to the STING adapter, other pattern recognition receptors can also phosphorylate and activate TBK1 and IRF3, including TLR3/4-TRIF [44 – 46] and RIG-I-MAVS [47, 48] pathway.”
Glucose Metabolism in Immune Regulation: From Mechanisms to Therapeutic Opportunities
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Housing conditions affect enterocyte death mode and turnover rate in mouse small intestine
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“Following internalization to endosomes, TLR4 also signals via the adaptor TICAM1 (TIR domain containing adaptor molecule 1) to activate TBK1 (Tank-binding kinase 1) promoting phosphorylation of the transcription factor IRF3 (interferon response factor 3), which in turn induces expression of the type I interferon IFNβ.”
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Balancing Strategies: GC and GILZ Axis
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Frk positively regulates innate antiviral immunity by phosphorylating TBK1
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Characterisation of the anti-inflammatory effects of marine extracts
McCarthy, C. (2011) · Arrow@dit (Dublin Institute of Technology)
- Authors
- McCoy, C. E., Carpenter, S., Pålsson-McDermott, E. M., Gearing, L. J., & O'Neill, L. A. J.
- Affiliations
- Trinity College Dublin (IE)
- Corresponding author
- McCoy, Claire E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 283
- Issue
- 21
- Pages
- 14277-14285
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1985083242
- Cited by
- 82
- References
- 34
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 8 · 2015: 3 · 2014: 2 · 2013: 8 · 2012: 6
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Science Foundation Ireland
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- glucocorticoids, dexamethasone, IRF3 phosphorylation, TBK1, TLR3, TLR4, IRF3, interferon-stimulated response element, RANTES, lipopolysaccharide, poly(I:C), MKP-1, protein phosphatase, Toll-like receptor signaling
- MeSH terms
- Cells, Cultured, Dextroamphetamine, Enzyme Activation, Gene Expression Regulation, Glucocorticoids, Humans, Lipopolysaccharides, Phosphorylation, Poly I-C, Protein Serine-Threonine Kinases, Genes, Reporter, Chemokine CCL5, Dimerization, Interferon Regulatory Factor-3, Toll-Like Receptor 3, Toll-Like Receptor 4
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