SULFONYLUREAS INHIBIT CYTOKINE-INDUCED EOSINOPHIL SURVIVAL AND ACTIVATION

Eosinophils play a key role ire the pathogenesis of asthma and other a llergic inflammatory diseases. We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits IL-5-induced su rvival. This inhibition cannot be overcome by increasing concentration s of IL-5 and is not due to the blocking of Na+ channels by lidocaine, Here we report that one class of KC channel blockers, the sulfonylure as, inhibits easinophil survival in a manner similar to lidocaine. The sulfonylurea glyburide inhibits eosinophil survival even at high conc entrations of IL-5. In contrast, increasing concentrations of IL-3 or granulocyte-macrophage CSF overcome glyburide inhibition. Glyburide al so blocks cytokine-induced eosinophil superoxide production. Similar r esults were seen with the sulfonylureas tolblatamide and glipizide, In terestingly, the effects of glyburide are not antagonized by the ATP-s ensitive K+ channel openers cromakalim, pinacidil, or diazoxide, Altho ugh Scatchard analysis of [H-3]glyburide binding to eosinophil membran es indicated that the high affinity sulfonylurea receptor (SUR1) is no t present on eosinophils, human eosinophils do express mRNA homologous to the sulfonylurea receptor family, in keeping with the presence of a sulfonylurea receptor. Finally, coculture of eosinaphils with combin ations of glyburide, lidocaine, and dexamethasone resulted in synergis tic inhibition of cytokine-mediated eosinophil survival and superoxide production. These results have intriguing clinical implications for t he treatment of eosinophil-associated diseases.