To evaluate the contribution of human lung mast cells (HLMC) to allergic inflammation, we investigated whether or not cytokines, including stem-cell factor (SCF), monocyte chemotactic and activating factor (MCAF), and RANTES, activate HLMC. SCF induced histamine release from dispersed HLMC in a dose-dependent fashion (P<0.01). The release was 7.8 ± 1.0% at 500 ng/ml SCF (n= 9). This response was also observed in chopped lung tissue. HLMC from which surface IgE molecules had been removed by treatment with lactic acid responded to SCF, while these cells lost their response to anti-IgE. The process was relatively rapid and reached a maximum in 5 min. This response required extracellular calcium, and it was observed at 37°C, but not at 4°C or 20°. A brief preincubation (10 min) with lower concentrations of SCF, which were ineffective in releasing histamine, enhanced anti-IgE-induced histamine release (P<0.05), while its enhancing effect was lost by the longer preincubation (30 min). SCF did not prime basophils to enhance stimulated-histamine release. Interleukin (IL)-1α, IL-1β, IL-3, IL-4, IL-5, granulocyte/macrophage-colony stimulating factor (GM-CSF), MCAF, and RANTES neither induced histamine release nor enhanced the release stimulated by anti-IgE after a 10- or 30-min preincubation. The combination of IL-3 and IL-4 showed no effect on histamine release from HLMC. Leukotriene (LT)C4/D4/E4 production by SCF was negligible, as compared with anti-IgE-induced LT production. SCF at 1.5 ng/ml augmented anti-IgE-induced LT generation significantly (536+ 117 pg/105 mast cells and 1569 ± 258 pg/105 mast cells; P<0.01). These results provide further evidence that numerous aspects of the phenotype of mast cells and basophils are heterogeneous, including structure, relevant secretagogues, and pharmacologic control.