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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 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 Citation Map 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. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages Xingguang Liu1, Ming Yao2, Nan Li1, Chunmei Wang1, Yuanyuan Zheng1, and Xuetao Cao1,2 1 Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai; and 2 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China Calcium and its major downstream effector, calcium/calmodulin-dependent protein kinase II (CaMKII), are found to be important for the functions of immune cells. Lipopolysaccharide (LPS) has been shown to induce intracellular calcium release in macrophages; however, whether and how CaMKII is required for Toll-like receptor (TLR) signaling remain unknown. Here we demonstrate that TLR 4, 9, and 3 ligands markedly induce intracellular calcium fluxes and activate CaMKII- in macrophages. Selective inhibition or RNA interference of CaMKII significantly suppresses TLR4, 9, 3-triggered production of interleukin-6 (IL-6), tumor necrosis factor-, and interferon-/β (IFN-/β) in macrophages. Coincidently, overexpression of constitutively active CaMKII- significantly enhances production of the above cytokines. In addition to the activation of mitogen-activated protein kinase and nuclear factor B pathways, CaMKII- can directly bind and phosphorylate transforming growth factor β–activated kinase 1 (TAK1) and IFN regulatory factor 3 (IRF3; serine on 386) via the N-terminal part of its regulatory domain. Therefore, CaMKII can be activated by TLR ligands, and in turn promotes both myeloid differentiating factor 88 and Toll/IL-1 receptor domain-containing adaptor protein-inducing IFN-β–dependent inflammatory responses by directly activating TAK1 and IRF3. The cross-talk with the 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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