Sulfonylureas inhibit cytokine-induced eosinophil survival and activation.
Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases. We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits IL-5-induced survival. This inhibition cannot be overcome by increasing concentrations of IL-5 and is not due to the blocking of Na+ channels by lidocaine. Here we report that one class of K+ channel blockers, the sulfonylureas, inhibits eosinophil survival in a manner similar to lidocaine. The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of IL-5. In contrast, increasing concentrations of IL-3 or granulocyte-macrophage CSF overcome glyburide inhibition. Glyburide also blocks cytokine-induced eosinophil superoxide production. Similar results were seen with the sulfonylureas tolbutamide and glipizide. Interestingly, the effects of glyburide are not antagonized by the ATP-sensitive K+ channel openers cromakalim, pinacidil, or diazoxide. Although Scatchard analysis of [3H]glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor (SUR1) is not 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 eosinophils with combinations of glyburide, lidocaine, and dexamethasone resulted in synergistic inhibition of cytokine-mediated eosinophil survival and superoxide production. These results have intriguing clinical implications for the treatment of eosinophil-associated diseases.
Bankers-Fulbright
J L
JL
Department of Immunology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Kephart
G M
GM
Loegering
D A
DA
Bradford
A L
AL
Okada
S
S
Kita
H
H
Gleich
G J
GJ
D018528:ATP-Binding Cassette Transporters; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D019806:Cromakalim / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology; D015221:Potassium Channels / Q000096:biosynthesis; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000096:biosynthesis; D013453:Sulfonylurea Compounds / Q000378:metabolism / Q000494:pharmacology*; D064233:Sulfonylurea Receptors; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D016207:Cytokines; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D019806:Cromakalim; D013481:Superoxides; D019789:Tetraethylammonium; D003907:Dexamethasone; D008012:Lidocaine; D005905:Glyburide