Calcineurin negatively regulates TLR-mediated activation pathways

YJ Kang, B Kusler, M Otsuka, M Hughes… - The Journal of …, 2007 - journals.aai.org
YJ Kang, B Kusler, M Otsuka, M Hughes, N Suzuki, S Suzuki, WC Yeh, S Akira, J Han
The Journal of Immunology, 2007journals.aai.org
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 …
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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