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Interferon-γ independently activates the MHC class I antigen processing pathway and diminishes glucose responsiveness in pancreatic β-cell lines

Abstract:

The mouse pancreatic βTC3 and βTC6-F7 cell lines were used to characterize the effects of interferon-γ (IFN-γ) on β-cell phenotype and function. Initially, intracellular and secreted insulin were compared in glucose-stimulated cells over time. A significant reduction in insulin content and secretion was observed on a per-cell basis in glucose-stimulated βTC3 and βTC6-F7 cells after 12 h of exposure to IFN-γ. The steady-state level of pre-proinsulin mRNA expression was not affected by IFN-γ. Thus, we postulate that IFN-γ's inhibitory actions occur after transcription of preproinsulin genes. Time-course analysis of IFN-γ-regulated mRNA expression of the two intra-MHC-encoded subunits of the proteasome (low-molecular-mass polypeptide [Lmp]-2 and Lmp-7) revealed a correlation between their induction and the inhibitory effects of IFN-γ on glucose-stimulated insulin production. Increased expression of Lmp-2 and Lmp-7 mRNA was accompanied by a corresponding induction of LMP2 and LMP7 protein expression. Subsequently, major histocompatibility complex (MHC) class I cell-surface expression was significantly increased in IFN-γ-treated βTC3 and βTC6-F7 cells. Exposure of IFN-γ-treated β-cells to a peptide aldehyde inhibitor of the proteasome (MG132) significantly attenuated MHC class I cell-surface expression but did not prevent the negative effects of IFN-γ on glucose responsiveness. Enhanced expression of the MHC class I antigen processing and presentation pathway and diminished insulin production appear to be distinct pathological alterations in β-cells exposed to the insulitic cytokine IFN-γ.