ACTIVATED MACROPHAGES KILL PANCREATIC SYNGENEIC ISLET CELLS VIA ARGININE-DEPENDENT NITRIC-OXIDE GENERATION

IL-1 and TNFα are assumed to be major mediators of islet cell destruction during the pathogenesis of type 1 diabetes. Here we show by neutralization of the two cytokines with excess antibody that IL-1 and TNFα do not contribute to the cytotoxic activity of activated macrophages towards isolated islet cells. However, islet cells can be protected from lysis by depleting the culture medium of L-arginine or by adding the antagonist NG-monomethyl-L-arginine, both of which inhibit the generation of nitric oxide by activated macrophages. These results indicate a role of nitric oxide or its equivalent, the endothelium-derived relaxing factor in the development of type 1 diabetes. This is the first report showing that nitric oxide may damage normal cells and thus may be a hitherto unrecognized pathogenetic factor in tissue inflammation and autoimmune disence. © 1991.