FcepsilonRI-mediated mast cell migration: signaling pathways and dependence on cytosolic free Ca2+ concentration.

Department of Medicine, Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Cellular Signalling (Impact Factor: 4.47). 08/2009; 21(11):1698-705. DOI: 10.1016/j.cellsig.2009.07.008
Source: PubMed

ABSTRACT IgE-sensitized rat basophilic leukemia (RBL)-2H3 mast cells have been shown to migrate towards antigen. In the present study we tried to identify the mechanism by which antigen causes mast cell migration. Antigen caused migration of RBL-2H3 cells at the concentration ranges of 1000-fold lower than those required for degranulation and the dose response was biphasic. This suggests that mast cells can detect very low concentration gradients of antigen (pg/ml ranges), which initiate migration until they degranulate near the origin of antigen, of which concentration is in the ng/ml ranges. Similar phenomenon was observed in human mast cells (HMCs) derived from CD34(+) progenitors. As one mechanism of mast cell migration, we tested the involvement of sphingosine 1-phosphate (S1P). Fc epsilon RI-mediated cell migration was dependent on the production of S1P but independent of a S1P receptor or its signaling pathways as determined with S1P receptor antagonist VPC23019 and Gi protein inhibitor pertussis toxin (PTX). This indicated that the site of action of S1P produced by antigen stimulation was intracellular. However, S1P-induced mast cell migration was dependent on S1P receptor activation and inhibited by both VPC23019 and PTX. Cell migration towards antigen or extracellular S1P was dependent on the activation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, while only migration towards antigen was inhibited by the inhibitors of sphingosine kinase and phospholipase C (PLC) and intracellular calcium chelator BAPTA. In summary, our data suggest that the high affinity receptor for IgE (Fc epsilon RI)-mediated mast cell migration is dependent on the production of S1P but independent of S1P receptors. Cell migration mediated by either Fc epsilon RI or S1P receptors involves activation of both PI3K and MAPK.

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