Oxygen free radical scavengers protect rat islet cells from damage by cytokines

Abstract

Summary. A possible role for oxygen free radicals in mediating the cytotoxic effects of cytokines in islets was sought by the use of agents that scavenge free radicals. Rat islet cell monolayer cultures were incubated for 6 days with t-butylhydroperoxide, alloxan, streptozotocin, or the cytokines, interleukin 1, tumour necrosis factor, and interferon gamma, without and together with the oxygen free radical scavenger combination of dimethylthiourea and citiolone, and islet cell lysis was measured in a Slchromium cytotoxicity assay. The free radical scavengers significantly inhibited the islet cell cytotoxic effects of t-butylhydroperoxide and alloxan, but not streptozotocin. Similarly, the cytotoxic effects of the cytokine combinations of interleukin 1 plus tumour necrosis factor, interferon gamma plus tumour necrosis factor, and interferon gamma plus interleukin 1 were significantly inhibited by the free radical scavenger combination of dimethylthiourea and citiolone. These results suggest that the cytokine products of macrophages and lymphocytes infiltrating islets in Type 1 (insulin-dependent) diabetes may contribute to B-cell damage by inducing the production of oxygen free radicals in the islet cells.

Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets

“…The role of oxygen free radicals in beta-cell destruction is also supported by studies of the protective effects of antioxidants against cytokine-or ROS-mediated beta-cell destruction [13]. These studies were conducted mostly in vitro and usually did not use genetic approaches, with the exception of the report of transgenic expression of CuZn superoxide dismutase in mice that enhanced the tolerance of pancreatic beta cells to two models of oxidative stress-induced diabetogenesis, alloxan-and streptozotocin-induced diabetes [14].…”

Cytokines and autoimmunity

“…The eflects described appear to be mediated by the binding of IL-1 to specific receptors [66] which has been demonstrated on both fi islet cells and thyrocytes [67,68], and seems to involve the generation of oxygen free radicals [69,70]. Thus, islet cell cytotoxicity mediated by IL-1 and other cytokines was prevented by oxygen free radical scavengers in vitro [69]. The toxic eflects are potentiated by several cytokines in a synergistic manner, i.e.…”

“…Thus, acute exposure to IL-l/3 produced a stimulation of fi islet cell function with increased insulin production, whilst long-term exposure suppressed insulin production and release, ultimately leading to fi islet cell death [61,65]. The eflects described appear to be mediated by the binding of IL-1 to specific receptors [66] which has been demonstrated on both fi islet cells and thyrocytes [67,68], and seems to involve the generation of oxygen free radicals [69,70]. Thus, islet cell cytotoxicity mediated by IL-1 and other cytokines was prevented by oxygen free radical scavengers in vitro [69].…”

IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

“…Free radicals are normally scavenged by protective proteins [e.g. haeme oxygenases and manganese superoxide dismutase (MnSOD)] [5,6]. Many IL-1β effects are mediated by inducing the inducible nitric oxide syntase (iNOS) and its product, nitric oxide [7]; however, NO-independent mechanisms also occur [8,9,10].…”