TLR2-mediated Ca2+ fluxes signal proinflammatory responses in airway epithelial cells. TLR2 ligands stimulate release of Ca2+ by signaling the phosphorylation of TLR2 by c-Src, recruiting PI3K and activating PLCγ. TLR2 or thapsigargin-mediated Ca2+ fluxes signal NF-κB activation and IL-8 expression. Silencing TLR2 by siRNA, blocking TLR2 by overexpression of a TLR2 tyrosine mutant, or using biochemical inhibitors of Src (PP1, PP2), PI3K (LY294002), or PLCγ (U73122) blocks intracellular Ca2+ release, NF-κB activation, and IL-8 expression. Chelating intracellular Ca2+ using BAPTA/AM also blocks NF-κB activation and IL-8 expression.