Interleukin-1β Secretion Is Impaired by Inhibitors of the Atp Binding Cassette Transporter, ABC1

Abstract

The production of interleukin-1β (IL-1β), a powerful mediator of inflammation, is tightly regulated at several levels. However, in some pathologic conditions, a pharmacologic treatment is required to control the toxicity of excessive extracellular IL-1β. Because of the heavy side effects of most therapies used in IL-1β–mediated pathologies, a goal of pharmacologic research is the development of selective anti–IL-1β drugs. We show here that the sulfonylurea glyburide, currently used in the oral therapy of noninsulin dependent diabetes, is an inhibitor of IL-1β secretion from human monocytes and mouse macrophages. Glyburide reduces dramatically the recovery of extracellular 17-kD IL-1β in the absence of toxic effects on the cells and without affecting the synthesis or processing of the IL-1β precursor. IL-1β belongs to the family of leaderless secretory proteins released from the cell by a nonclassical secretory route. In bacteria and yeast Atp binding cassette (ABC) transporters are involved in the secretion of leaderless secretory proteins. Interestingly, glyburide blocks the anion exchanger function of ABC1, a mammalian member of the family of ABC transporters. We thus investigated the involvement of ABC1 in IL-1β secretion, through the analysis of the effects of drugs known to inhibit IL-1β secretion, on the activity of ABC1 and in turn the ability of known inhibitors of ABC1 of blocking IL-1β secretion. Our data show that IL-1β secretion and the function of ABC1 as an anion exchanger are sensitive to the same drugs, therefore suggesting an involvement of the ABC1 transporter in the secretion of leaderless proteins in mammals.

The mystery of nonclassical protein secretion

“…These observations are consistent with the fact that IL-1b secretion is sensitive to methylamine [6], a drug that disturbs endocytosis [26]. Based on pharmacological studies employing the sulfonylurea glyburide (10 lM) along with expression-inhibition studies employing antisense techniques, an ABC transporter, ABC1, has been implicated in the overall process of IL-1b secretion [27,28] and therefore might mediate IL-1b translocation from the cytoplasm to the lumen of the endolysosomal compartment. Interestingly, glyburide also appears to inhibit nonclassical secretion of macrophage migration inhibitory factor (J. Bernhagen, RWTH Aachen, Germany, personal communication), an inflammatory cytokine mediating a number of immune and inflammatory diseases, e.g.…”

Two non-vesicular ATP release pathways in the mouse erythrocyte membrane

“…Recently it has been found that glyburide also affects innate immunity by inhibiting the inflammasome in various settings [34][35][36][37]. Typically, this is taken as evidence, that a key step in inflammasome activation is a potassium efflux [38][39][40].…”

14‐3‐3 epsilon modulates the stimulated secretion of endopeptidase 24.15

“…The mechanism of their release is still unclear, although FGF-1 can be released in response to heat shock (Jackson et al 1992), and FGF-2 may be released through exocytosis, as shown by the fact that depleting cells of ATP inhibits the release of this factor (Miyakawa and Imamura 2003). In contrast, although they lack conventional secretion signal sequences, FGF-9, -16, and -20 contain a bipartite, non-cleavable signal peptide sequence for entry into the conventional secretory pathway (Hamon et al 1997).…”