Affiliation:
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
Abstract
AbstractCalcium 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-α in macrophages. Selective inhibition or RNA interference of CaMKII significantly suppresses TLR4, 9, 3-triggered production of interleukin-6 (IL-6), tumor necrosis factor-α, and interferon-α/β (IFN-α/β) in macrophages. Coincidently, overexpression of constitutively active CaMKII-α significantly enhances production of the above cytokines. In addition to the activation of mitogen-activated protein kinase and nuclear factor κB pathways, CaMKII-α 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.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
152 articles.
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