Regulation of MHC protein expression in pancreatic beta-cells by interferon-gamma and tumor necrosis factor-alpha.
Isolated human and mouse pancreatic islet cells and the rat insulinoma cell line RIN-m5F were used to examine the ability of recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) to regulate the expression of the class I and class II major histocompatibility (MHC) surface proteins and mRNA in beta-cells. Each cytokine increased significantly the expression of class I MHC proteins as determined by double indirect immunofluorescence microscopy and flow cytofluorimetric analysis. In the RIN-m5F cells, this increase in surface expressed class I MHC proteins was mirrored by an increase in the level of class I MHC mRNA. The order of potency of the cytokines on class I MHC expression was TNF-alpha plus IFN-gamma greater than or equal to IFN-gamma greater than or equal to TNF-alpha. While IFN-gamma or TNF-alpha alone were without effect, in combination they were found to induce class II MHC proteins on 30-40% of human or murine beta-cells. In contrast, IFN-gamma plus TNF-alpha did not induce detectable class II MHC proteins or mRNA in the RIN-m5F cells. These findings indicate that 1) TNF-alpha, in addition to IFN-gamma, upregulates the expression of beta-cell class I MHC proteins and mRNA, and 2) more than one signal is required for the induction of class II MHC proteins on beta-cells. The ability of IFN-gamma plus TNF-alpha to induce class II MHC proteins on only a fraction of the normal beta-cell population and not on RIN-m5F cells suggests that this response is related to the differentiation state of the beta-cell.
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007340:Insulinoma / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008285:Major Histocompatibility Complex; D051379:Mice; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma