Pancreatic beta-cell damage mediated by beta-cell production of interleukin-1 - A novel mechanism for virus-induced diabetes

Viral infection is one environmental factor that may initiate beta -cell da mage during the development of autoimmune diabetes. Formed during viral rep lication, double-stranded RNA (dsRNA) activates the antiviral response in i nfected cells. In combination, synthetic dsRNA (polyinosinic-polycytidylic acid, poly(I-C)) and interferon (IFN)-gamma stimulate inducible nitric-oxid e synthase (iNOS) expression, inhibit insulin secretion, and induce islet d egeneration. Interleukin-1 (IL-1) appears to mediate dsRNA + IFN-gamma -ind uced islet damage in a nitric oxide-dependent manner, as the interleukin-l receptor antagonist protein prevents dsRNA + IFN-gamma -induced iNOS expres sion, inhibition of insulin secretion, and islet degeneration. IL-1 beta is synthesized as an inactive precursor protein that requires cleavage by the IL-1 beta -converting enzyme (ICE) for activation. dsRNA and IFN-gamma sti mulate IL-1 beta expression and ICE activation in primary beta -cells, resp ectively. Selective ICE inhibition attenuates dsRNA + IFN-gamma -induced iN OS expression by primary beta -cells. In addition, poly(I-C) + IFN-gamma -i nduced iNOS expression and nitric oxide production by human islets are prev ented by interleukin-1 receptor antagonist protein, indicating that human i slets respond to dsRNA and IFN-gamma in a manner similar to rat islets, The se studies provide biochemical evidence for a novel mechanism by which vira l infection may initiate beta -cell damage during the development of autoim mune diabetes. The viral replicative intermediate dsRNA stimulates beta -ce ll production of pro-IL-1 beta, and following cleavage to its mature form b y IFN-beta -activated ICE, IL-1 then initiates beta -cell damage in a nitri c oxide-dependent fashion.