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. Its mechanism of action is, however, largely unknown. In the present study rat pancreatic beta-cells, INS-1, were incubated with rat interferon-gamma (rIRN-gamma) for 24 h. rIFN-gamma at 1-1000 U/ml caused a dose-dependent inhibition of insulin release and cell metabolism with maximal inhibition being observed at 100 U/ml (insulin release: 51.2%, cell 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 nitric oxide synthase and NO production. Similarly, beta-cell dysfunction and death were not prevented by coincubation of the INS-1 cells with the poly(ADP-ribose) polymerase inhibitors benzamide, 3-aminobenzamide, and 4-aminobenzamide, the oxygen free radical scavenger Trolox, and the antioxidant N-acetylcysteine, indicating that NO, poly(ADP-ribose) polymerase, and oxygen free radicals are not involved in IFN-gamma induced beta-cell dysfunction and death.
Laffranchi
R
R
Department of Internal Medicine, University Hospital, Zürich, Switzerland.
Spinas
G A
GA
D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D009569:Nitric Oxide / Q000096:biosynthesis*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology; D062366:para-Aminobenzoates
D000975:Antioxidants; D001549:Benzamides; D002839:Chromans; D016166:Free Radical Scavengers; D007328:Insulin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; D062366:para-Aminobenzoates; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C037689:benzamide; C041338:4-aminobenzamide; D007371:Interferon-gamma; C025160:3-aminobenzamide; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D010129:4-Aminobenzoic Acid; D000111:Acetylcysteine