Calcineurin Negatively Regulates TLR-Mediated Activation Pathways
Open accessAbstract
In innate immunity, microbial components stimulate macrophages to produce antimicrobial substances, cytokines, other proinflammatory mediators, and IFNs via TLRs, which trigger signaling pathways activating NF-κB, MAPKs, and IFN response factors. We show in this study that, in contrast to its activating role in T cells, in macrophages the protein phosphatase calcineurin negatively regulates NF-κB, MAPKs, and IFN response factor activation by inhibiting the TLR-mediated signaling pathways. Evidence for this novel role for calcineurin was provided by the findings that these signaling pathways are activated when calcineurin is inhibited either by the inhibitors cyclosporin A or FK506 or by small interfering RNA-targeting calcineurin, and that activation of these pathways by TLR ligands is inhibited by the overexpression of a constitutively active form of calcineurin. We further found that IκB-α degradation, MAPK activation, and TNF-α production by FK506 were reduced in macrophages from mice deficient in MyD88, Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF), TLR2, or TLR4, whereas macrophages from TLR3-deficient or TLR9 mutant mice showed the same responses to FK506 as those of wild-type cells. Biochemical studies indicate that calcineurin interacts with MyD88, TRIF, TLR2, and TLR4, but not with TLR3 or TLR9. Collectively, these results suggest that calcineurin negatively regulates TLR-mediated activation pathways in macrophages by inhibiting the adaptor proteins MyD88 and TRIF, and a subset of TLRs.
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Many of these pathways involve calcium signaling, and the calcineurin cascade which in macrophages has been shown to down-regulate TLR mediated activation pathways.
“Many of these pathways involve calcium signaling, and the calcineurin cascade which in macrophages has been shown to down-regulate TLR mediated activation pathways [43].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [43]
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- Authors
- Kang, Y. J., Kusler, B., Otsuka, M., Hughes, M., Suzuki, N., Suzuki, S., Yeh, W.-C., Akira, S., Han, J., & Jones, P. P.
- Affiliations
- Stanford University (US)
- Scripps Research Institute (US)
- University Health Network (CA)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Kusler, Brenda
- Hughes, Michael
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-10-01
- Volume
- 179
- Issue
- 7
- Pages
- 4598-4607
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2168532652
- Cited by
- 104
- References
- 61
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 9 · 2018: 3 · 2017: 5 · 2016: 8 · 2015: 4 · 2014: 8 · 2013: 6 · 2012: 8
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- calcineurin, Toll-like receptors, macrophages, innate immunity, NF-κB signaling, MAPK signaling, MyD88, TRIF, TLR2, TLR4, TLR3, TLR9, IκBα degradation, TNF-alpha production, cyclosporine, FK506, protein phosphatase
- MeSH terms
- Animals, Cell Line, Enzyme Activation, Phosphorylation, Signal Transduction, NF-kappa B, Interferon-beta, Receptors, Tumor Necrosis Factor, Calcineurin, Adaptor Proteins, Vesicular Transport, RNA, Small Interfering, Interferon Regulatory Factor-3, Toll-Like Receptors, Mice, I-kappa B Kinase, Myeloid Differentiation Factor 88, Calcineurin Inhibitors
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