Thrombin Induces IL-6 but Not TNFα Secretion by Mouse Mast Cells: Threshold-Level Thrombin Receptor and Very Low Level FcϵRI Signaling Synergistically Enhance IL-6 Secretion

Mast cells become activated in multiple diseases wherein thrombin generation is often clinically apparent, but the effect of thrombin on cytokine release by mast cells remains unexplored. Thus, we examined IL-6 and TNFα release by thrombin-challenged mast cells. Thrombin and the protease-activated receptor (PAR)-1 peptide TRAP14 induced these cells to secrete IL-6 in a dose-dependent fashion. Mast cells secreted ≥2800 pg IL-6/106 cells over 24 h, but only low levels of serotonin and no significant TNFα. Furthermore, at near-background levels of allergen, threshold doses of α-thrombin synergistically enhanced the IL-6 response (by up to 100-fold), but high-dose costimulation led to a simple additive response. Both the PI3- and sphingosine-kinase signaling pathways contributed importantly to the thrombin response. Our data thus clearly demonstrate that low-level thrombin and FcϵRI signaling can synergize to augment mast cell IL-6 responses, and that thrombin also differentially induces cytokine secretion by mast cells.