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¹ Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
² Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
³ Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

In macrophages and monocytes, microbial components trigger the production of pro-inflammatory cytokine through Toll-like receptors (TLRs). Although major TLR signaling pathways are mediated by serine/threonine kinases, including TAK1, IKK and MAP kinases, tyrosine phosphorylation of intracellular proteins by TLR ligands has been suggested in a number of reports. Here, we demonstrated that peptidoglycan (PGN) of a Gram-positive bacterial cell wall component, a TLR2 ligand and lipopoysaccharide (LPS) of a Gram-positive bacterial component, a TLR4 ligand induced tyrosine phosphorylation of phospholipase C-2 (PLC2), leading to intracellular free Ca²⁺ mobilization in bone marrow-derived macrophages (BMM) and bone marrow-derived dendritic cells (BMDC). PGN- and LPS-induced Ca²⁺ mobilization was not observed in BMDC from PLC2 knockout mice. Thus, PLC2 is essential for TLR2 and TLR4-mediated Ca²⁺ flux. In PLC2-knockdown cells, PGN-induced IB- phosphorylation and p38 activation were reduced. Moreover, PLC2 was necessary for the full production of TNF- and IL-6. These data indicate that the PLC2 pathway plays an important role in bacterial ligands-induced activation of macrophages and dendritic cells.

^* Correspondence: E-mail: yakihiko{at}bioreg.kyushu-u.ac.jp

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