Human pancreatic islet beta-cell destruction by cytokines involves oxygen free radicals and aldehyde production.
Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. Cytokine-induced islet beta-cell destruction may be mediated by reactive oxygen intermediates. To determine the possible roles of oxygen free radicals and nitric oxide (NO) as mediators of islet beta-cell destruction, we studied the relationships among cytokine-induced beta-cell destruction, production of malondialdehyde (MDA; an end product of lipid peroxidation), and production of nitrite (the stable end product of NO). The cytokine combination of interleukin-1 beta (50 U/mL), tumor necrosis factor-alpha (10(3) U/mL), and interferon-gamma (10(3) U/mL) induced significant increases in MDA and nitrite and significant decreases in insulin and DNA in islets after 60-h incubation. A novel antioxidant (lazaroid U78518E) significantly inhibited both a strong oxidant. t-butylhydroperoxide, and the combination of cytokines from inducing MDA production, but not from increasing nitrite production in the islets. Also, the lazaroid antioxidant significantly reversed the cytokine-induced decreases in insulin and DNA contents of the islet cultures. In contrast, L-NG-monomethyl arginine, an inhibitor of NO synthase, prevented cytokine-induced nitrite production, but did not prevent cytokine-induced increases in MDA and decreases in insulin and DNA in the islet cultures. In addition, the addition of MDA to the islets produced a dose-dependent decrease in their insulin and DNA contents, and this was only partially prevented by the lazaroid antioxidant. These results suggest that cytokines may be toxic to human islet beta-cells by inducing oxygen free radicals, lipid peroxidation, and aldehyde production in the islets, and that MDA is one of the cytotoxic mediators of cytokine-induced beta-cell destruction.
Rabinovitch
A
A
Department of Medicine, University of Alberta, Edmonton, Canada.
Suarez-Pinzon
W L
WL
Strynadka
K
K
Lakey
J R
JR
Rajotte
R V
RV
D000447:Aldehydes / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004247:DNA / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005021:Ethylamines / Q000494:pharmacology; D005609:Free Radicals; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology*; D008315:Malondialdehyde / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019323:omega-N-Methylarginine
D000447:Aldehydes; D000975:Antioxidants; D016207:Cytokines; D004791:Enzyme Inhibitors; D005021:Ethylamines; D005609:Free Radicals; D007328:Insulin; D007375:Interleukin-1; D010879:Piperazines; D011725:Pyridines; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C072017:U 78518F; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D008315:Malondialdehyde; D007371:Interferon-gamma; D004247:DNA; D001120:Arginine; D019001:Nitric Oxide Synthase