INTERFERON-GAMMA INDEPENDENTLY ACTIVATES THE MHC CLASS-I ANTIGEN-PROCESSING PATHWAY AND DIMINISHES GLUCOSE RESPONSIVENESS IN PANCREATIC BETA-CELL LINES

The mouse pancreatic beta TC3 and beta TC6-F7 cell lines were used to characterize the effects of interferon-gamma (IFN-gamma) on beta-cell phenotype and function. Initially, intracellular and secreted insulin mere compared in glucose-stimulated cells over time. A significant red uction in insulin content and secretion was observed on a per-cell bas is in glucose-stimulated beta TC3 and beta TC6-F7 cells after 12 h of exposure to IFN-gamma. The steady-state level of pre-proinsulin mRNA e xpression was not affected by IFN-gamma. Thus, we postulate that IFN-g amma's inhibitory actions occur after transcription of preproinsulin g enes. Time-course analysis of IFN-gamma-regulated mRNA expression of t he two intra-MHC-encoded subunits of the proteasome (low-molecular-mas s polypeptide [Lmp]-2 and Lmp-7) revealed a correlation between their induction and the inhibitory effects of IFN-gamma on glucose-stimulate d insulin production. Increased expression of Lmp-2 and Lmp-7 mRNA was accompanied by a corresponding induction of LMP2 and LMP7 protein exp ression. Subsequently, major histocompatibility complex (MHC) class I cell-surface expression was significantly increased in IFN-gamma-treat ed beta TC3 and beta TC6-F7 cells. Exposure of IFN-gamma-treated beta- cells to a peptide aldehyde inhibitor of the proteasome (MG132) signif icantly attenuated MHC class I cell-surface expression but did not pre vent the negative effects of IFN-gamma on glucose responsiveness. Enha nced expression of the MHC class I antigen processing and presentation pathway and diminished insulin production appear to be distinct patho logical alterations in beta-cells exposed to the insulitic cytokine IF N-gamma.