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.