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.
Chun
Jarin
J
College of Physicians and Surgeons, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
Prince
Alice
A
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D051966:Phospholipase C gamma / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D019869:Phosphatidylinositol 3-Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D051966:Phospholipase C gamma; D002118:Calcium