INTERFERON-ALPHA AND INTERFERON-GAMMA DIFFERENTIALLY AFFECT PANCREATIC BETA-CELL PHENOTYPE AND FUNCTION

To better clarify individual roles of interferon (IFN)-alpha and IFN-g amma in beta-cell pathology during the onset of type 1 diabetes mellit us, we compared the effects of these cytokines on insulin production a nd major histocompatibility complex (MHC) gene expression in pancreati c beta-cell lines. IFN-gamma but not IFN-alpha decreased secreted and intracellular insulin concentrations in beta TC6-F7 and beta TC3 cells . Likewise, IFN-gamma but not IFN-alpha treatment of beta-cells upregu lated mRNA expression of MHC class I-A antigen-processing genes and su rface expression of class I-A molecules. Alternatively, class I-A MHC expression was upregulated by IFN-gamma and IFN-alpha in the P388D(1) macrophage cell line. The observation of constitutive Ifn-alpha 6 mRNA expression by a differentiated beta-cell line substantiates previous indications that local expression of IFN-alpha in islets may trigger i nsulitis. Evidence that IFN- gamma, a product of infiltrating leukocyt es, directly decreases beta-cell glucose sensitivity and increases M.H C class I-A cell surface expression supports the postulate that IFN-ga mma magnifies the insulitic process.