INTERFERON STIMULATES THE EXPRESSION OF 2',5'-OLIGOADENYLATE SYNTHETASE AND MHC CLASS-I ANTIGENS IN INSULIN-PRODUCING CELLS

The pathogenesis of type 1 diabetes involves autoimmune processes directed against the pancreatic-beta-cells. The etiology is not known, but circumstantial evidence suggests a connection between virus infection and development of the disease. Therefore, because the interferon-(IFN) dependent 2',5'-oligoadenylate (2-5A) synthetase system constitutes an important part of the nonspecific immune defense against viral infections, the activity of the enzyme was examined in islets of Langerhans, RIN cells, and GH3 cells. First, the 2-5A synthetase was expressed constitutively in all cell types and, second, all cells were sensitive to stimulation with IFN-alpha. The 2-5A synthetase activity induced by 1,000 U/ml of IFN-alpha increased by 400% in pancreatic islets and by more than 1000% in GH3 and RIN cells. However, the IFN-alpha concentration needed to induce half-maximal 2-5A synthetase activity was nearly the same in the three cell types (i.e., ranging from 59 to 66 U/ml IFN-alpha). The 2-5A synthetase present in islets and RIN cells was highly sensitive to poly (I:C). In pancreatic islets and RIN cells, the 2-5A synthetase enzyme generated dimers and trimers of 2',5'-oligoadenylates. Furthermore, exposure of RIN cells to IFN-alpha showed an increase in MHC class I expression already at 5 U/ml and maximal expression at about 200 U/ml IFN-alpha. The examined endocrine cells express the 2-5A synthetase enzyme as well as MHC class I antigen constitutively, but also by stimulation with IFN in vitro. This part of the immune defense system, therefore, is active in the basal state and is readily activated in the presence of IFN in endocrine cells.