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 rele ase from normal human basophils. However, when extracellular Na+ is removed IL-3 acquires the capacity to induce histamine release. The aim of this st udy was to evaluate whether GM-CSF can induce basophil histamine release us ing the same pathway of IL-3. Leucocyte suspensions from normal human subje cts were stimulated with GM-CSF, IL-3 and anti-IEE, and histamine release w as 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 mu g/ml). However, when e xtracellular Na+ was substituted iso-osmotically with N-methyl-D-glucamine( +) or with choline(+), GM-CSF and IL-3 were able to trigger histamine relea se from either mixed leucocyte suspensions or purified human basophils. The effect of GM-CSF on basophil histamine release was dose dependent, with op timal release at a dose of 1 ng/ml after incubation at 37 degrees for 60-12 0 min. The kinetics of IL-3-induced histamine release were similar, whereas anti-IgE-induced histamine release was more rapid, being almost maximal af ter incubation for 30 min. A good correlation was found between GM-CSF-indu ced and IL-3-induced histamine release; furthermore, the combined effects o f the two cytokines were less than additive, suggesting that they share the same pathways leading to histamine release. When extracellular Na+ concent ration was increased from 0 to 140mM, 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 extrace llular 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+.