A metabolic pathway of activated macrophages (M phi) involving oxidation of the guanido nitrogens of L-arginine is required for inhibition of growth and respiration of some target cells. The goal of this study was to identify the M phi metabolite(s) that induce these injuries. The stable products of the L-arginine pathway, NO2- and NO3-, were incapable of causing cytostasis under coculture conditions. However, NO2- became cytostatic upon mild acidification, which favors its transformation into nitrogen oxides of greater reactivity. This suggested that NO. (and/or NO2), recently identified as an M phi metabolite of L-arginine, could be a mediator. Authentic NO. caused cytostasis and respiratory inhibition in L1210 cells in a dose-dependent manner. The mitochondrial lesions caused by NO. were confined to complex 1 and 2, a pattern of injury identical to that seen after coculture with activated M phi. Inclusion of NO. scavenger systems prevented cytostasis from developing in M phi-L1210 cocultures. Thus, M phi-generated NO. can account for L-arginine-dependent cytostasis and respiratory inhibition.
Article|
May 01 1989
Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells.
D J Stuehr,
D J Stuehr
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
Search for other works by this author on:
C F Nathan
C F Nathan
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
Search for other works by this author on:
D J Stuehr
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
C F Nathan
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1989) 169 (5): 1543–1555.
Citation
D J Stuehr, C F Nathan; Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells.. J Exp Med 1 May 1989; 169 (5): 1543–1555. doi: https://doi.org/10.1084/jem.169.5.1543
Download citation file: