Activation of Ca2+-dependent signaling by TLR2.

Upon contact with airway epithelial cells, bacterial products activate Ca(2+) fluxes that are required for induction of NF-kappaB-dependent gene expression. TLR2 is apically displayed on airway cells, making it a likely transducer linking bacterial stimuli and kinases that affect Ca(2+) release. Using biochemical and genetic approaches, we demonstrate that TLR2 ligands stimulate release of Ca(2+) from intracellular stores by activating TLR2 phosphorylation by c-Src, and recruiting PI3K and phospholipase Cgamma to affect Ca(2+) release through inositol (1,4,5) trisphosphate receptors. In the absence of TLR2, murine macrophages as well as airway cells do not generate Ca(2+) fluxes or induce proinflammatory signaling. Thus, Ca(2+) participates as a second messenger in TLR2-dependent signaling and provides another target to modulate proinflammatory responses to bacterial infection.