To better clarify individual roles of interferon (IFN)- and IFN- in -cell pathology during the onset of type 1 diabetes mellitus, we compared the effects of these cytokines on insulin production and major histocompatibility complex (MHC) gene expression in pancreatic -cell lines. IFN- but not IFN- decreased secreted and intracellular insulin concentrations in TC6-F7 and TC3 cells. Likewise, IFN- but not IFN- treatment of -cells upregulated mRNA expression of MHC class I_A antigen-processing genes and surface expression of class I_A molecules. Alternatively, class I_A MHC expression was upregulated by IFN- and IFN- in the P388D₁ macrophage cell line. The observation of constitutive Ifn-6 mRNA expression by a differentiated -cell line substantiates previous indications that local expression of IFN- in islets may trigger insulitis. Evidence that IFN-, a product of infiltrating leukocytes, directly decreases -cell glucose sensitivity and increases MHC class I_A cell surface expression supports the postulate that IFN- magnifies the insulitic process.