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(Journal Article): Dominant negative MyD88 proteins inhibit interleukin-1beta /interferon-gamma-mediated induction of nuclear factor kappa B-dependent nitrite production and apoptosis in beta cells.
Dupraz P, Cottet S, Hamburger F, Dolci W, Felley-Bosco E, Thorens B (Institute of Pharmacology and Toxicology, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland.)
IN:
J Biol Chem
2000; 275(48):37672–37678.-
Impact Factor(s) of J Biol Chem: 6.355 (2004), 6.482 (2003), 7.258 (2001)
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ABSTRACT: Insulin-dependent diabetes mellitus is an autoimmune disease in which pancreatic islet beta cells are destroyed by a combination of immunological and inflammatory mechanisms. In particular, cytokine-induced production of nitric oxide has been shown to correlate with beta cell apoptosis and/or inhibition of insulin secretion. In the present study, we investigated whether the interleukin (IL)-1beta intracellular signal transduction pathway could be blocked by overexpression of dominant negative forms of the IL-1 receptor interacting protein MyD88. We show that overexpression of the Toll domain or the lpr mutant of MyD88 in betaTc-Tet cells decreased nuclear factor kappaB (NF-kappaB) activation upon IL-1beta and IL-1beta/interferon (IFN)-gamma stimulation. Inducible nitric oxide synthase mRNA accumulation and nitrite production, which required the simultaneous presence of IL-1beta and IFN-gamma, were also suppressed by approximately 70%, and these cells were more resistant to cytokine-induced apoptosis as compared with parental cells. The decrease in glucose-stimulated insulin secretion induced by IL-1beta and IFN-gamma was however not prevented. This was because these dysfunctions were induced by IFN-gamma alone, which decreased cellular insulin content and stimulated insulin exocytosis. These results demonstrate that IL-1beta is involved in inducible nitric oxide synthase gene expression and induction of apoptosis in mouse beta cells but does not contribute to impaired glucose-stimulated insulin secretion. Furthermore, our data show that IL-1beta cellular actions can be blocked by expression of MyD88 dominant negative proteins and, finally, that cytokine-induced beta cell secretory dysfunctions are due to the action of IFN-gamma.
TYPE OF PUBLICATION: Original article
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