Abstract
Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide–dependent manner.
Highlights
Autoimmune diabetes is characterized by selective destruction of insulin-secreting b-cells found in pancreatic islets [1]
INOS expression in murine b-cells requires a combination of IL-1 and IFN-g [35], and IFN-g is known to have antiviral activities that could mask the antiviral actions of nitric oxide
It has long been known that inhibitory actions of cytokines on insulin secretion are mediated by b-cell production of nitric oxide [15,16,17,18]
Summary
Autoimmune diabetes is characterized by selective destruction of insulin-secreting b-cells found in pancreatic islets [1]. We and others have shown that treating islets with IL-1 or activating resident macrophages to release IL-1 locally in islets results in an inhibition of mitochondrial oxidative metabolism and insulin secretion that is mediated by iNOS expression and the production of micromolar levels of nitric oxide in b-cells [15,16,17,18,19]. We have shown that EMCV replication is elevated in mice lacking the chemokine receptor CCR5, a cell surface receptor required for EMCV to induce inflammatory gene expression in macrophages, such as iNOS [14] These findings suggest that nitric oxide may function in a protective role within the context of viral infection. These findings support the inhibition of mitochondrial oxidative metabolism as a novel mechanism by which nitric oxide attenuates EMCV replication and protects b-cells from viral lysis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
