Regulation of human basophil mediator release by cytokines. I. Interaction with antiinflammatory steroids

We have analyzed the effects of overnight culture of human basophils with a variety of cytokines in the presence or absence of the glucocorticoid dexamethasone. The 24-h culture of basophils with a range of concentrations of several cytokines (granulocyte-macrophage-CSF, TNF-alpha, IL-1, IL-2, and IL-4) had no effect either on anti-IgE-induced histamine release or the inhibitory effects of dexamethasone on histamine release. IFN-gamma enhanced postculture releasability of human basophils. The concentration range for this effect was from 50 to 50,000 U/ml and maximal enhancement of anti-IgE-induced basophil histamine release was approximately 200% of control. IFN-gamma did not increase the number of occupied or unoccupied Fc epsilon RI on human basophils, suggesting that the enhancement of histamine release is a result of an intrinsic increase in the releasability mechanism. rIL-3 also augmented basophil releasability (approximately 250% of control) by a mechanism independent of alterations in basophil cell surface IgE density. The increase in post culture releasability occurred in both partially purified basophils (12 to 90% purity) and mixed leukocytes (approximately 1% basophils) although it was more marked in the former. Enhanced postculture releasability after exposure to IL-3 occurred for both IgE-dependent (anti-IgE) and peptide-mediated (fmet-leu-phe) responses and included elevations in the release of both histamine and sulfidopeptide leukotriene, suggesting a global increase in releasability. Basophils cultured in the presence of IL-3 were insensitive to the inhibitory effects of dexamethasone; at 1,000 U/ml IL-3, dexamethasone inhibition of basophil mediator release was completely blocked. None of the other cytokines tested, with the exception of crude or partially purified IL-2 preparations, had this effect. IL-3 contamination may explain the ability of these partially purified "IL-2" preparations to block the inhibitory effects of dexamethasone, because this effect was abolished by a specific anti-IL-3 antibody. These results suggest that IFN-gamma and IL-3 may modulate the response of human basophils in allergic reactions. Furthermore, increased local production of IL-3 may "prime" basophils for increased releasability and override inhibitory effects of elevated systemic glucocorticoids on human basophils. Finally, we conclude that the effects of glucocorticoids on human basophils may be in part mediated indirectly by effects on cells which produce cytokines, such as IFN-gamma and IL-3, that can modulate basophil function.