Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells

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 gamma-2 (PLC gamma 2), leading to intracellular free Ca2+ mobilization in bone marrow-derived macrophages (BMM phi) and bone marrow-derived dendritic cells (BMDC). PGN- and LPS-induced Ca2+ mobilization was not observed in BMDC from PLC gamma 2 knockout mice. Thus, PLC gamma 2 is essential for TLR2 and TLR4-mediated Ca2+ flux. In PLC gamma 2-knockdown cells, PGN-induced I kappa B-alpha phosphorylation and p38 activation were reduced. Moreover, PLC gamma 2 was necessary for the full production of TNF-alpha and IL-6. These data indicate that the PLC gamma 2 pathway plays an important role in bacterial ligands-induced activation of macrophages and dendritic cells.