Heterogeneity in the responses of human lung mast cells to stem cell factor

摘要

Summary: Background: Stem cell factor (SCF) is a growth factor that is involved in mast cell differentiation and proliferation. SCF primes human lung mast cells for enhanced responses to IgE-directed activation but is not generally recognized as a direct activator. SCF mediates its effects through c-kit. Objective: The aim of this study was to reappraise the effects of SCF on human lung mast cells. Methods: Mast cells were isolated from human lung. Mast cells were challenged with anti-IgE or SCF and the generation of histamine, cysteinyl-leukotrienes (cys-LTs) and prostaglandin D2 (PGD2) was assessed as was expression of the activation marker, CD63. The effects of c-kit inhibitors on mediator release were evaluated. Results: Stem cell factor (10 ng/mL) alone was unable to induce mediator release but primed mast cells for enhanced IgE-dependent secretion. At higher concentrations (≥ 30 ng/mL), SCF had more varied effects and even when used alone was able to drive substantial levels of histamine release in about a third of all preparations studied. Similarly, SCF (100 ng/mL) alone was effective in stimulating the generation of cys-LTs in half of the preparations studied. SCF (100 ng/mL) was even more effective at stimulating PGD2 generation as almost all preparations generated substantial quantities of the prostanoid. Mediator release induced by SCF was accompanied by the up-regulation of the activation marker, CD63. There was a positive correlation between the extent of mediator release induced by SCF and c-kit receptor expression. The effects of SCF on mediator release from mast cells were reversed by the c-kit inhibitor imatinib. Conclusions and clinical relevance: These data demonstrate that the responses of mast cells to SCF are heterogeneous. SCF can drive much greater levels of mediator release from mast cells, especially of PGD2, than hitherto appreciated and this could be important in the context of respiratory diseases.