Recent data suggest that stem cell factor (SCF or c-kit ligand, KL) is a major regulator of human mast cells (MCs). In the present study, MCs derived from the lung (n = 8), uterus (n = 14) and heart (n = 4) were analyzed for expression of c-kit receptor and for responses to recombinant SCF. MCs of all organs tested were recognized by mAbs to c-kit (YB5.B8, SR-1) as assessed by combined toluidine blue/immunofluorescence staining. Activation by rhSCF (10 ng/ml, 60 min) resulted in histamine release from lung MCs (SCF 12.8 +/- 2.7% histamine release; control 2.8 +/- 0.8%, p < 0.01), uterus MCs (SCF 16.8 +/- 5.8%; control 5.2 +/- 2.5%, p < 0.01) and heart MCs (SCF 18.4 +/- 2.6%; control 1.7 +/- 0.23%, p < 0.01). Short-term pre-incubation with rhSCF (15 min) did not result in histamine secretion (p > 0.05), but in an increase (lung 2.4 +/- 1.0 fold; uterus 2.1 +/- 1.1 fold, and heart 2.0 +/- 0.4 fold) of alpha IgE-induced mediator release (p < 0.05). The effects of SCF were dose-dependent (maximum responses at 10-100 ng/ml) and dependent on extracellular calcium. A monoclonal antibody to SCF was found to inhibit the effects of SCF on MCs. Furthermore, MCs could be desensitized specifically by pre-incubation of MCs with rhSCF in Ca-free medium. Together, these data suggest that SCF triggers mediator secretion from MCs in various organs via binding to the c-kit receptor.