Mechanisms of nitric oxide -dependent beta-cell damage in response to double -stranded RNA.

摘要

Autoimmune diabetes is characterized by a local inflammatory reaction in and around the pancreatic islets of Langerhans, followed by the selective destruction of insulin-secreting beta-cells. Viral infection has been implicated as one environmental factor that may trigger the initial destruction of beta-cells during the development of diabetes. Analysis of animal models suggests that inflammatory cytokines and the cytotoxic molecule nitric oxide may participate in the development of viral-induced diabetes. Double-stranded (ds)RNA is one active component of a viral infection that stimulates host cell antiviral responses. Studies have shown that dsRNA, in combination IFN-gamma, stimulates islet damage by a mechanism that is dependent on nitric oxide production by beta-cells. We hypothesize that signaling factors activated during the antiviral response may participate in dsRNA + IFN-gamma-induced nitric oxide production by islets.;In this study, we examine four signaling molecules that are activated in response to dsRNA in islets: the transcription factors NF-kappaB and IRF-1, the kinase PKR, and the cytokine IL-1. We show that NF-kappaB, but not PKR, is required for dsRNA + IFN-gamma-induced iNOS expression and nitric oxide production by islets. Interestingly, IRF-1 is also not required for dsRNA + IFN-gamma-induced iNOS expression by islets, but is required for dsRNA + IFN-gamma-induced iNOS expression by peritoneal macrophages. Importantly, we show that dsRNA + IFN-gamma-induced iNOS expression by islets is mediated by beta-cell IL-1 release and by an unknown macrophage-derived factor, suggesting that the effects of dsRNA + IFN-gamma on iNOS expression and nitric oxide production by islets are indirect. These results indicate that factors activated during the antiviral response are required for iNOS expression and nitric oxide-dependent islet damage in response to dsRNA + IFN-gamma.