INTERLEUKIN-1-BETA SECRETION IS IMPAIRED BY INHIBITORS OF THE ATP BINDING CASSETTE TRANSPORTER, ABC1

The production of interleukin-1 beta (IL-1 beta), a powerful mediator of inflammation, is tightly regulated at several levels. However, in s ome pathologic conditions, a pharmacologic treatment is required to co ntrol the toxicity of excessive extracellular IL-1 beta. Because of th e heavy side effects of most therapies used in IL-1 beta-mediated path ologies, a goal of pharmacologic research is the development of select ive anti-IL-1 beta drugs. We show here that the sulfonylurea glyburide , currently used in the oral therapy of noninsulin dependent diabetes, is an inhibitor of IL-1 beta secretion from human monocytes and mouse macrophages. Glyburide reduces dramatically the recovery of extracell ular 17-kD IL-1 beta in the absence of toxic effects on the cells and without affecting the synthesis or processing of the IL-1 beta precurs or. IL-1 beta belongs to the family of leaderless secretory proteins r eleased from the cell by a nonclassical secretory route. In bacteria a nd yeast Atp binding cassette (ABC) transporters are involved in the s ecretion of leaderless secretory proteins. Interestingly, glyburide bl ocks the anion exchanger function of ABC1, a mammalian member of the f amily of ABC transporters, We thus investigated the involvement of ABC 1 in IL-1 beta secretion, through the analysis of the effects of drugs known to inhibit IL-1 beta secretion, on the activity of ABC1 and in turn the ability of known inhibitors of ABC1 of blocking IL-1 beta sec retion. Our data show that IL-1 beta secretion and the function of ABC 1 as an anion exchanger are sensitive to the same drugs, therefore sug gesting an involvement of the ABC1 transporter in the secretion of lea derless proteins in mammals. (C) 1997 by The American Society of Hemat ology.