Granulocyte-macrophage colony-stimulating factor and interleukin-3 cause basophil histamine release by a common pathway: downregulation by sodium.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are recognized as enhancers, but not as inducers, of histamine release from normal human basophils. However, when extracellular Na+ is removed IL-3 acquires the capacity to induce histamine release. The aim of this study was to evaluate whether GM-CSF can induce basophil histamine release using the same pathway of IL-3. Leucocyte suspensions from normal human subjects were stimulated with GM-CSF, IL-3 and anti-IgE, and histamine release was evaluated by an automated fluorometric method. In a physiological medium, GM-CSF (10 ng/ml) and IL-3 (10 ng/ml) did not provoke histamine release, in spite of an efficient response to anti-IgE (10 micrograms/ml). However, when extracellular Na+ was substituted iso-osmotically with N-methyl-d-glucamine+ or with choline+, GM-CSF and IL-3 were able to trigger histamine release from either mixed leucocyte suspensions or purified human basophils. The effect of GM-CSF on basophil histamine release was dose dependent, with optimal release at a dose of 1 ng/ml after incubation at 37 degrees for 60-120 min. The kinetics of IL-3-induced histamine release were similar, whereas anti-IgE-induced histamine release was more rapid, being almost maximal after incubation for 30 min. A good correlation was found between GM-CSF-induced and IL-3-induced histamine release; furthermore, the combined effects of the two cytokines were less than additive, suggesting that they share the same pathways leading to histamine release. When extracellular Na+ concentration was increased from 0 to 140 mm, histamine release induced by GM-CSF, IL-3 and anti-IgE was reduced progressively. In contrast, histamine release induced by these stimuli was upregulated when the concentration of extracellular Ca2+ was increased. These results provide indirect evidence that GM-CSF and IL-3 can induce basophil histamine release by a common pathway that is downregulated by Na+.