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Essential Role for Membrane Lipid Rafts in Interleukin-1ß–Induced Nitric Oxide Release From Insulin-Secreting Cells

Potential Regulation by Caveolin-1⁺

¹ Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan
² Department of Internal Medicine, Wayne State University, Detroit, Michigan
³ ß Cell Biochemistry Research Laboratory, John D. Dingell VA Medical Center, Detroit, Michigan
⁴ Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana
⁵ National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland

We recently reported that the activation of H-Ras represents one of the signaling steps underlying the interleukin-1ß (IL-1ß)–mediated metabolic dysfunction of the islet ß-cell. In the present study, we examined potential contributory roles of membrane-associated, cholesterol-enriched lipid rafts/caveolae and their constituent proteins (e.g., caveolin-1 [Cav-1]) as potential sites for IL-1ß–induced nitric oxide (NO) release in the isolated ß-cell. Disruption of lipid rafts (e.g., with cyclodextrin) markedly reduced IL-1ß–induced gene expression of inducible NO synthase (iNOS) and NO release from ß-cells. Immunologic and confocal microscopic evidence also suggested a transient but significant stimulation of tyrosine phosphorylation of Cav-1 in ß-cells briefly (for 15 min) exposed to IL-1ß that was markedly attenuated by three structurally distinct inhibitors of protein tyrosine phosphorylation. Overexpression of an inactive mutant of Cav-1 lacking the tyrosine phosphorylation site (Y14F) or an siRNA-mediated Cav-1 knock down also resulted in marked attenuation of IL-1ß–induced iNOS gene expression and NO release from these cells, thus further implicating Cav-1 in this signaling cascade. IL-1ß treatment also increased (within 20 min) the translocation of H-Ras into lipid rafts. Here we provide the first evidence to suggest that tyrosine phosphorylation of Cav-1 and subsequent interaction among members of the Ras signaling pathway within the membrane lipid microdomains represent early signaling mechanisms of IL-1ß in ß-cells.

Abbreviations: Cav-1, caveolin-1; FITC, fluorescein isothiocyanate; ß-Gal, ß-galactosidase; IL-1ß, interleukin-1ß; iNOS, inducible nitric oxide synthase; MCD, methyl-ß-cyclodextrin; Mes, morpholine-ethanesulfonic acid

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