Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules

Several death-signaling or death-inducing molecules have been implicated in beta cell destruction, including Fas, perforin, and TNFR-1, In this study, we examined the role of each death-signaling molecule in the IL-10-acceler ated diabetes of nonobese diabetic (NOD) mice, Groups of IL-10-NOD mice, ea ch deficient in either Fas, perforin, or TNFR-1 molecules, readily develope d insulitis, and subsequently succumbed to diabetes with an accelerated kin etics and incidence similar to that observed in their wild-type or heterozy gous IL-10-NOD littermates. Similarly, a TNFR-2 deficiency did not block ac celerated diabetes in IL-10-NOD mice and spontaneous diabetes In NOD mice. These results demonstrate that pancreatic IL-10 promotes diabetes independe nt of Fas, perforin, TNFR-1, and TNFR-2 molecules. Subsequently, when cyclo phosphamide, a diabetes-inducing agent, was injected into insulitis-free NO D..lpr/lpr mice, none of these mice developed insulitis or diabetes. Our da ta suggest that cyclophosphamide-but not IL-10-induced diabetes is Fas depe ndent, Overall, these findings provide evidence that pancreatic expression of IL-10 promotes diabetes independent of the major death pathways and prov ide impetus for identification of novel death pathways precipitating autoim mune destruction of insulin-producing beta cells.