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Calcineurin Negatively Regulates TLR-Mediated Activation Pathways¹

Young Jun Kang^2,3,*, Brenda Kusler^*, Motoyuki Otsuka, Michael Hughes^*, Nobutaka Suzuki, Shinobu Suzuki, Wen-Chen Yeh, Shizuo Akira, Jiahuai Han and Patricia P. Jones^3,*

^* Department of Biological Sciences, Stanford University, Stanford, CA 94305; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Advanced Medical Discovery Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

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-B, 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-B, 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 IB- degradation, MAPK activation, and TNF- production by FK506 were reduced in macrophages from mice deficient in MyD88, Toll/IL-1R domain-containing adaptor-inducing IFN- (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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from Stanford University (to P.P.J.).

² Current address: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.

³ Address correspondence and reprint requests to Dr. Young Jun Kang, 10550 North Torrey Pines Road, IMM-32, Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; E-mail address: ykang{at}scripps.edu or Dr. Patricia P. Jones, 371 Serra Mall, Gilbert Building, Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020; E-mail address: patjones{at}stanford.edu

⁴ Abbreviations used in this paper: IRAK, IL-1R-associated kinase; AKAP, A-kinase anchoring protein; CsA, cyclosporin A; IKK, IB kinase; IP-10, IFN--inducible protein-10; IRF, IFN response factor; siRNA, small interfering RNA; TAB, TGF--activated kinase 1-binding protein; TAK, TGF--activated kinase; TRAF, TNFR-associated factor; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-.

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