Interferon-γ: pleiotropic effects on a rat pancreatic beta cell line

We have recently shown that interferon-y (IFN-y) markedly upregulates the expression of the class I major histocompatibility proteins on pancreatic beta cells and have therefore postulated that interferon-y may enhance cytotoxic lymphocyte-mediated beta cell damage in insulin-dependent diabetes mellitus. To further explore the interaction between interferon-γ and the pancreatic beta cell we have used the RIN-m5F insulinoma line to define the effects of interferon-γ on major histocompatibility protein expression, (pro)insulin and protein synthesis and cell growth. Interferon-γ induced a dose-dependent increase in the expression of the class I major histocompatibility proteins on the RIN-m5F cells, the maximal increase (10-fold) being seen at an interferon-γ concentration of 1 U/ml. The induction of class I proteins by interferon-γ was nearly completely abolished by cycloheximide. Expression of class II (la) proteins was not detected either in the presence or absence of interferon-y. (Pro)insulin and protein synthesis were decreased by 60% and 40%, respectively, in RIN-m5F cells cultured with interferon-γ (10 U/ml). Furthermore, the growth of RIN-m5F cells was significantly inhibited, and corresponding changes in cell morphology were evident, after 3 days of exposure to interferon-y (10 U/ml). These findings indicate that, in addition to its potential role in amplifying cytotoxic T cell activity against the pancreatic beta cell, IFN-y may also directly inhibit beta cell function and growth. Several mechanisms could therefore account for an ability of IFN-γ to compromise beta cell function and contribute to the pathogenesis of insulin-dependent diabetes.