Chemokine gene expression in CD133 cord blood derived human mast cells and modulation by cyclosporin A and dexamethasone

Mast cells are important effector cells in acute IgE-associated allergic reactions and contribute to innate and acquired immunity. We have in vitro differentiated cord blood derived mast cells to investigate the kinetics of expression of their genes encoding the chemokines IL-8, MCP-1, MIP-1alpha and MIP-1beta. Furthermore, modulatory effects were studied on chemokine gene expression by immunosuppressants prior or during mast cell activation. CD133+ cord blood derived, human mast cells (CBMC) were activated via the high-affinity IgE receptor (FcepsilonRI), CXCR4 receptor or pharmacologically with phorbol myristate acetate (PMA) or ionomycin. Modulatory effects of dexamethasone and cyclosporin A on gene induction was investigated. The kinetics of chemokine gene induction was assessed by RNase protection assay and ELISA. Pretreatment of activated CBMC with immunosuppressants demonstrated that chemokine genes are modulated differentially reflecting the targeting of different signal transduction pathways and transcription factors. A novel observation was the ability of immunosuppressants to quench ongoing induction of chemokine genes in activated mast cells. The very rapid induction of chemokines is consistent with a key role of mast cells in early immune responses. Moreover, the expression levels can be differentially modulated by various immunosuppressants. This indicates that the beneficial therapeutic effect of glucocorticoids in allergic diseases may be mediated, at least in part, through inhibition of mast cell chemokine genes.