Distinct roles of Ca2+ mobilization and G protein usage on regulation of Toll-Like Receptor Function in Human and Murine Mast Cells

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Departmental Papers (Dental)
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Chemokine; Cytokine; Mast cells; Signal transduction; TLR
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Zaidi, Asifa K.
Thangam, Elden
Ali, Hydar

Toll-like receptors (TLRs) expressed in mast cells play important roles in orchestrating host defence against bacterial pathogens. Previous studies demonstrated that TLR2 agonist tripalmitoyl-S-glycero-Cys-(Lys)4 (Pam3Cys) stimulates both degranulation and cytokine production in human mast cells but only induces cytokine production in murine mast cells. To determine the molecular basis for this difference, we utilized a human mast cell line LAD 2, murine lung and bone marrow-derived mast cells (MLMC and BMMC). We found that Pam3Cys caused a sustained Ca2+ mobilization and degranulation in LAD 2 mast cells but not in MLMC or BMMC. Despite these differences, Pam3Cys stimulated equivalent chemokine CCL2 generation in all mast cell types tested. Cyclosporin A (CsA), an inhibitor of Ca 2+/calcineurin-mediated nuclear factor of activated T cells (NFAT) activation, blocked chemokine production in LAD 2 but not in MLMC or BMMC. In contrast, inhibitors of nuclear factor kappa B (NF-κB) completely blocked CCL2 production in MLMC and BMMC but not in LAD 2 mast cells. Pertussis toxin and U0126, which, respectively, inhibit Gαi, extracellular signal-regulated kinase (ERK) phosphorylation substantially inhibited Pam 3Cys-induced CCL2 generation in LAD 2 mast cells but had little or no effect on chemokine generation in MLMC and BMMC. These findings suggest that TLR2 activation in human LAD 2 mast cells and MLMC/BMMC promotes the release of different classes of mediators via distinct signalling pathways that depend on Ca2+ mobilization and G protein usage. © 2006 Blackwell Publishing Ltd.

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