INTERFERON-GAMMA INHIBITS INSULIN RELEASE AND INDUCES CELL-DEATH IN THE PANCREATIC BETA-CELL LINE INS-1 INDEPENDENTLY OF NITRIC-OXIDE PRODUCTION

Interferon-gamma is among the cytokines which have been implicated as effector molecules of beta-cell destruction in autoimmune diabetes. It s mechanism of action is, however, largely unknown, In the present stu dy rat pancreatic beta-cells, INS-1, were incubated with rat interfero n-gamma (rIRN-gamma) for 24 h. rIFN-gamma at 1 - 1000 U/ml caused a do se-dependent inhibition of insulin release and cell metabolism with ma ximal inhibition being observed at 100 U/ml (insulin release: 51.2%, c ell metabolism: 43.3% of control, respectively). In addition, 100 U/ml rIFN-gamma induced a 4- and 8.3-fold increase in apoptotic cell death after 24 and 48 h of incubation, respectively. These effects were not mediated by nitric oxide (NO), since IFN-gamma failed to induce nitri c oxide synthase and NO production. Similarly, beta-cell dysfunction a nd death were not prevented by coincubation of the INS-1 cells with th e poly(ADP-ribose) polymerase inhibitors benzamide, 3-aminobenzamide, and 4-aminobenzamide, the oxygen free radical scavenger Trolox, and th e antioxidant N-acetylcysteine, indicating that NO, poly(ADP-ribose) p olymerase, and oxygen free radicals are not involved in IFN-gamma indu ced beta-cell dysfunction and death. (C) 1997 Academic Press.