Dominant negative MyD88 proteins inhibit interleukin-1 beta/interferon-gamma-mediated induction of nuclear factor kappa B-dependent nitrite production and apoptosis in beta cells
P. Dupraz et al., Dominant negative MyD88 proteins inhibit interleukin-1 beta/interferon-gamma-mediated induction of nuclear factor kappa B-dependent nitrite production and apoptosis in beta cells, J BIOL CHEM, 275(48), 2000, pp. 37672-37678
Insulin-dependent diabetes mellitus is an autoimmune disease in which pancr
eatic islet beta cells are destroyed by a combination of immunological and
inflammatory mechanisms. In particular, cytokine-induced production of nitr
ic oxide has been shown to correlate with beta cell apoptosis and/or inhibi
tion of insulin secretion. In the present study, we investigated whether th
e interleukin (IL)-1 beta intracellular signal transduction pathway could b
e 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 1pr mutant of MyD88 in beta Tc-Tet cells decreased nuclear factor ka
ppaB (NF-kappaB) activation upon IL-1 beta and IL-1 beta /interferon (IFN)-
gamma stimulation, Inducible nitric oxide synthase mRNA accumulation and ni
trite production, which required the simultaneous presence of IL-1 beta and
IFN-gamma, were also suppressed by similar to 70%, and these cells were mo
re resistant to cytokine-induced apoptosis as compared with parental cells.
The decrease in glucose-stimulated insulin secretion induced by IL-1 beta
and IFN-gamma was however not prevented. This was because these dysfunction
s were induced by IFN-gamma alone, which decreased cellular insulin content
and stimulated insulin exocytosis, These results demonstrate that IL-1 bet
a is involved in inducible nitric oxide synthase gene expression and induct
ion of apoptosis in mouse beta cells but does not contribute to impaired gl
ucose stimulated insulin secretion. Furthermore, our data show that IL-1 be
ta cellular actions can be blocked by expression of MyD88 dominant negative
proteins and, finally, that cytokine-induced beta cell secretory dysfuncti
ons are due to the action of IFN-gamma.