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Blood, 15 December 2008, Vol. 112, No. 13, pp. 4961-4970. Prepublished online as a Blood First Edition Paper on September 25, 2008; DOI 10.1182/blood-2008-03-144022. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-03-144022v1 112/13/4961    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Liu, X. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by Liu, X. Articles by Cao, X. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 7, 2008 Accepted September 5, 2008 CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages Xingguang Liu, Ming Yao, Nan Li, Chunmei Wang, Yuanyuan Zheng, and Xuetao Cao* Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China * Corresponding author; email: caoxt{at}public3.sta.net.cn. The full activation of TLR signaling requires contributions of other signal pathways. Calcium and its major downstream effector, calcium/calmodulin-dependent protein kinase II (CaMKII), are found to be important for the functions of immune cells. LPS has been shown to induce intracellular calcium release in macrophages, however, whether and how CaMKII is required for TLR signaling remain unknown. Here we demonstrate that TLR4, 9, 3 ligands markedly induce intracellular calcium fluxes and activate CaMKII in macrophages. Selective inhibitor or RNAi knockdown of CaMKII significantly suppresses TLR4, 9, 3-triggered production of IL-6, TNF-, IFN-/ in macrophages. Coincidently, overexpression of constitutively active CaMKII significantly enhances production of the above cytokines. In addition to the activation of MAPK and NF-B pathways, CaMKII can directly bind and phosphorylate TAK1 and IRF3 (serine on 386) via its N-terminal part of regulatory domain. In vivo administration of CaMKII inhibitor substantially decreases production of serum proinflammatory cytokines, IFN- and increases survival rate of lethal LPS-challenged mice. Therefore, CaMKII can be activated by TLR ligands, and in turn, promotes both MyD88- and TRIF-dependent inflammatory responses by directly activating TAK1 and IRF3. The cross-talk with calcium/CaMKII pathway is needed for full activation of TLR signaling in macrophages. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Zhang, S. Liu, P. Yang, C. Han, J. Wang, J. Liu, Y. Han, Y. Yu, and X. Cao Fibronectin maintains survival of mouse natural killer (NK) cells via CD11b/Src/{beta}-catenin pathway Blood, November 5, 2009; 114(19): 4081 - 4088. [Abstract] [Full Text] [PDF] M. Yao, X. Liu, D. Li, T. Chen, Z. Cai, and X. Cao Late Endosome/Lysosome-Localized Rab7b Suppresses TLR9-Initiated Proinflammatory Cytokine and Type I IFN Production in Macrophages J. Immunol., August 1, 2009; 183(3): 1751 - 1758. [Abstract] [Full Text] [PDF] J. Hou, P. Wang, L. Lin, X. Liu, F. Ma, H. An, Z. Wang, and X. Cao MicroRNA-146a Feedback Inhibits RIG-I-Dependent Type I IFN Production in Macrophages by Targeting TRAF6, IRAK1, and IRAK2 J. Immunol., August 1, 2009; 183(3): 2150 - 2158. [Abstract] [Full Text] [PDF] S. Fischer, M. Nishio, S. C. Peters, M. Tschernatsch, M. Walberer, S. Weidemann, R. Heidenreich, P. O. Couraud, B. B. Weksler, I. A. Romero, et al. Signaling mechanism of extracellular RNA in endothelial cells FASEB J, July 1, 2009; 23(7): 2100 - 2109. [Abstract] [Full Text] [PDF] C. Wang, R. Qi, N. Li, Z. Wang, H. An, Q. Zhang, Y. Yu, and X. Cao Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression J. Biol. Chem., June 12, 2009; 284(24): 16183 - 16190. [Abstract] [Full Text] [PDF]

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