title: Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin.
abstract: Nitric oxide (NO) is a short-lived biologic mediator that is shown to be induced in various cell types and to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of the inducible type of the NO synthase (NOS). However, there is limited evidence for the existence of such inducible NOS in a human cell type. We show here the induction of NO biosynthesis in freshly isolated human hepatocytes (HC) after stimulation with interleukin 1, tumor necrosis factor (TNF), IFN-gamma, and endotoxin. Increased levels of nitrite (NO2-) and nitrate (NO3-) in culture supernatants were associated with NADPH-dependent NOS activity in the cell lysates. The production of NO2- and NO3- was inhibited by NG-monomethyl L-arginine and was associated with an increase in cyclic guanylate monophosphate release. The data presented here provide evidence for the existence of typical inducible NO biosynthesis in a human cell type.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania 15261.
authors.forename: A K
authors.initials: AK
authors.lastname: Nussler
authors.forename: M
authors.initials: M
authors.lastname: Di Silvio
authors.forename: T R
authors.initials: TR
authors.lastname: Billiar
authors.forename: R A
authors.initials: RA
authors.lastname: Hoffman
authors.forename: D A
authors.initials: DA
authors.lastname: Geller
authors.forename: R
authors.initials: R
authors.lastname: Selby
authors.forename: J
authors.initials: J
authors.lastname: Madariaga
authors.forename: R L
authors.initials: RL
authors.lastname: Simmons
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D016207:Cytokines / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D019323:omega-N-Methylarginine
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006152:Cyclic GMP