Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line. Implications for regulation of nitric oxide production.
In macrophages and other cell types, bacterial lipopolysaccharide and certain cytokines stimulate nitric oxide (NO) production via expression of the inducible isoform of nitric oxide synthase (NOS). Citrulline, which is the coproduct of NOS-catalyzed metabolism of arginine, can be recycled to arginine by the action of argininosuccinate synthetase and argininosuccinate lyase, which are present at high levels in hepatocytes and renal tubular cells but normally at very low levels in other cell types such as macrophages. The present study demonstrates that lipopolysaccharide and interferon-gamma, which induce NOS in the murine macrophage cell line RAW 264.7, also coinduce activity and mRNA for argininosuccinate synthetase, which is limiting for arginine synthesis. Argininosuccinate lyase activity and mRNA abundance are unaffected. Induction of argininosuccinate synthetase is not blocked by NG-monomethyl-L-arginine, a potent inhibitor of NOS, indicating that argininosuccinate synthetase induction is not the consequence of depleting cellular arginine levels by NOS. Because plasma levels of arginine are limiting for NO synthesis, enhanced cellular capacity to regenerate arginine from citrulline could play a significant role in regulating NO production, especially under conditions where the inducible isoform of NOS is expressed.
Nussler
A K
AK
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Billiar
T R
TR
Liu
Z Z
ZZ
Morris
S M
SM
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D001123:Argininosuccinate Lyase / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000096:biosynthesis*; D002460:Cell Line; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase