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Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

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Kang, Young Jun, Kusler, Brenda, Otsuka, Motoyuki, Hughes, Michael, Suzuki, Nobutaka, Suzuki, Shinobu, Yeh, Wen-Chen, Akira, Shizuo, Han, Jiahuai, Jones, Patricia P·2007·The Journal of Immunology
DOI 10.4049/jimmunol.179.7.4598
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Abstract

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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Metadata

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
DOI
10.4049/jimmunol.179.7.4598
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
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
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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