In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 13 ( 1997-06-24), p. 6954-6958
Abstract:
Superoxide (O 2⨪ ) and nitric oxide (NO) act to kill invading microbes in phagocytes. In macrophages NO is synthesized by inducible nitric oxide synthase (iNOS, NOS 2) from l -arginine ( l -Arg) and oxygen; however, O 2⨪ was thought to be produced mainly by NADPH oxidase. Electron paramagnetic resonance (EPR) spin trapping experiments performed in murine macrophages demonstrate a novel pathway of O 2⨪ generation. It was observed that depletion of cytosolic l -Arg triggers O 2⨪ generation from iNOS. This iNOS-mediated O 2⨪ generation was blocked by the NOS inhibitor N -nitro- l -arginine methyl ester or by l -Arg, but not by the noninhibitory enantiomer N -nitro- d -arginine methyl ester. In l -Arg-depleted macrophages iNOS generates both O 2⨪ and NO that interact to form the potent oxidant peroxynitrite (ONOO − ), which was detected by luminol luminescence and whose formation was blocked by superoxide dismutase, urate, or l -Arg. This iNOS-derived ONOO − resulted in nitrotyrosine formation, and this was inhibited by iNOS blockade. iNOS-mediated O 2⨪ and ONOO − increased the antibacterial activity of macrophages. Thus, with reduced l -Arg availability iNOS produces O 2⨪ and ONOO − that modulate macrophage function. Due to the existence of l -Arg depletion in inflammation, iNOS-mediated O 2⨪ and ONOO − may occur and contribute to cytostatic/cytotoxic actions of macrophages.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.94.13.6954
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1997
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
