Macrophages and nitric oxide: A deadly combination

Mixed signals? The immunology field got a hint that NO might be a host product in 1985, when Michael Marletta and his graduate student Dennis Stuehr at the Massachusetts Institute of Technology found an ex cess of nitrate in the urine of bacterially infected mice (1). To find its source, the researchers focused on macrophages, immune cells that help defend against infections. Meanwhile, at the University of Utah, John Hibbs Jr. was also studying macrophages. He wanted to identify the ingredients in a cell culture medium that macrophages needed to kill tumor cells. The key ingredient was the amino acid arginine. When arginine was present, the activated macrophages removed its guanidino group, producing nitrite. An arginine analogue that could not be catabolized prevented tumor cell killing (2). But exposing tumor cells to nitrite alone did not kill them. Hibbs concluded that macrophages must be converting arginine into a reactive nitrogen intermediate (RNI), which then decomposed into nontoxic nitrite.