Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 14, Pages 11151-11158Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M009159200
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Funding
- NIAID NIH HHS [AI44458] Funding Source: Medline
- NIDDK NIH HHS [DK-52194] Funding Source: Medline
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Viral infection is one environmental factor that may initiate beta -cell damage during the development of autoimmune diabetes. Formed during viral replication, double-stranded RNA (dsRNA) activates the antiviral response in infected cells. In combination, synthetic dsRNA (polyinosinic-polycytidylic acid, poly(I-C)) and interferon (IFN)-gamma stimulate inducible nitric-oxide synthase (iNOS) expression, inhibit insulin secretion, and induce islet degeneration. Interleukin-1 (IL-1) appears to mediate dsRNA + IFN-gamma -induced islet damage in a nitric oxide-dependent manner, as the interleukin-l receptor antagonist protein prevents dsRNA + IFN-gamma -induced iNOS expression, 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 stimulate IL-1 beta expression and ICE activation in primary beta -cells, respectively. Selective ICE inhibition attenuates dsRNA + IFN-gamma -induced iNOS expression by primary beta -cells. In addition, poly(I-C) + IFN-gamma -induced iNOS expression and nitric oxide production by human islets are prevented by interleukin-1 receptor antagonist protein, indicating that human islets respond to dsRNA and IFN-gamma in a manner similar to rat islets, These studies provide biochemical evidence for a novel mechanism by which viral infection may initiate beta -cell damage during the development of autoimmune diabetes. The viral replicative intermediate dsRNA stimulates beta -cell production of pro-IL-1 beta, and following cleavage to its mature form by IFN-beta -activated ICE, IL-1 then initiates beta -cell damage in a nitric oxide-dependent fashion.
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