Dominant Negative MyD88 Proteins Inhibit Interleukin-1β/Interferon-γ-mediated Induction of Nuclear Factor κB-dependent Nitrite Production and Apoptosis in β Cells

Insulin-dependent diabetes mellitus is an autoimmune disease in which pancreatic islet β 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 β cell apoptosis and/or inhibition of insulin secretion. In the present study, we investigated whether the interleukin (IL)-1β 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 βTc-Tet cells decreased nuclear factor κB (NF-κB) activation upon IL-1β and IL-1β/interferon (IFN)-γ stimulation. Inducible nitric oxide synthase mRNA accumulation and nitrite production, which required the simultaneous presence of IL-1β and IFN-γ, were also suppressed by ∼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-1β and IFN-γ was however not prevented. This was because these dysfunctions were induced by IFN-γ alone, which decreased cellular insulin content and stimulated insulin exocytosis. These results demonstrate that IL-1β is involved in inducible nitric oxide synthase gene expression and induction of apoptosis in mouse β cells but does not contribute to impaired glucose-stimulated insulin secretion. Furthermore, our data show that IL-1β cellular actions can be blocked by expression of MyD88 dominant negative proteins and, finally, that cytokine-induced β cell secretory dysfunctions are due to the action of IFN-γ.