Effect of Interferon-γ and Glucose on Major Histocompatibility Complex Class I and Class II Expression by Pancreatic β- and Non-β-Cells¹

Abstract

Surface major histocompatibility complex (MHC) class I and class II expression by pancreatic islet cells is considered a local initiator or regulator of immune processes that can lead to diabetes. Locally released cytokines, in particular interferon-␥, are known to stimulate MHC antigen expression by islet cells. The present study quantifies MHC expression in cultured pancreatic ␤-and non-␤-cells from both rat and human organs. Interferon-␥ increased MHC class I expression in endocrine ␤-and non-␤-cells as well as in pancreatic ductal cells. The cytokine induced a 6-fold increase in the MHC class I messenger ribonucleic acid levels in pancreatic ␤-cells; this effect was 2-fold amplified in the presence of elevated glucose levels (20 mmol/L instead of 6 mmol/L). No MHC class II expression was observed in endocrine ␤-or non-␤-cells; human, but not rat, ductal cells exhibited MHC class II expression that increased in the presence of interferon-␥.These data indicate that the increase in ␤-cell MHC class I expression described in the pancreata of diabetic patients may result from stimulated transcription after exposure to locally released interferon-␥ and/or to a hyperglycemic state. The association of human islets with ductal cells in which MHC class II expression is stimulated by interferon-␥ makes these cells potential participants in the autoimmune process in diabetes. (J Clin Endocrinol Metab 82: 2329 -2336, 1997) S URFACE expression of major histocompatibility complex (MHC) antigens by nonimmune cells can regulate their interactions with immune cells (1-5). In the endocrine pancreas, hyperexpression of MHC class I antigens and aberrant expression of MHC class II antigens have been suggested to induce lymphocyte infiltrations and subsequent local reactions (6 -13). The products of immune cells, cytokines, were shown to stimulate MHC class I and/or class II expression in the islets of Langerhans (14 -17). Although this general concept has been supported by in vitro and in vivo studies in both rodents and humans, the specific data are sometimes controversial, raising questions about the cell, strain, and species specificity of the observed phenomena (6 -17). The complexity of the studied models in terms of both interactive agents and cell composition makes it difficult to clearly identify the events at the level of the ␤-cells. For these reasons, we have compared MHC class I and class II expression on the surface of pancreatic ␤-and non-␤-cells that were isolated from normal rat or human organs. We choose to examine the effect of interferon-␥ because this cytokine is known for its stimulatory action on MHC expression (14 -17), it has been demonstrated in mononuclear cell infiltrates of diabetic islets (10, 12, 13), and treatment with anti-interferon-␥ antibodies suppresses the inflammatory reactions and the MHC class I hyperexpression in mice (18,19). The cell preparations were studied at basal and high glucose levels because glucose-induced activation of ␤-cells may facilitate antigen expression by these ...

Interferon-γ potentiates endoplasmic reticulum stress-induced death by reducing pancreatic beta cell defence mechanisms

“…Of note, IFN-γ stimulates MHC class I and II expression and induction of transporter associated with antigen processing (TAP) genes in beta cells [12,42]. The MHC class I complex is assembled in the ER, while antigenic peptides generated in the cytosol are transported to the ER via the TAP transporters.…”