Human pancreatic islet beta-cell destruction by cytokines is independent of nitric oxide production.
The inflammatory cytokines, interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma are cytotoxic to human islet beta-cells in vitro. To determine the possible role of nitric oxide (NO) as a mediator of cytokine-induced islet beta-cell destruction, we studied the relationships between NO production and destruction of human pancreatic islet cells incubated with cytokines in vitro. 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 a significant increase in NO production and significant decreases in DNA and insulin contents of the islet cell cultures after a 48-h incubation. L-NG-Monomethyl arginine, an inhibitor of NO synthase, completely prevented cytokine-induced NO production during incubations of 18, 36, 60, and 84 h. Cytokine-induced decreases in DNA and insulin contents of the islet cell cultures, however, were unaffected by the NO synthase inhibitor. Conversely, nicotinamide prevented cytokine-induced islet beta-cell destruction without inhibiting NO production. We conclude that cytokine-induced NO production in human islet cells may be neither necessary nor sufficient to destroy the islet beta-cells and that cytotoxic mechanisms, independent of NO, exist and can be inhibited by nicotinamide.
Rabinovitch
A
A
Department of Medicine, University of Alberta, Edmonton, Canada.
Suarez-Pinzon
W L
WL
Strynadka
K
K
Schulz
R
R
Lakey
J R
JR
Warnock
G L
GL
Rajotte
R V
RV
D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019323:omega-N-Methylarginine
D016207:Cytokines; D007328:Insulin; D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D004247:DNA; D001120:Arginine