Inhibitory action of daunorubicin on lipopolysaccharide-stimulated inducible-type nitric oxide synthase induction in alveolar macrophages.
The purpose of this study was to investigate the effects of daunorubicin on lipopolysaccharide (LPS)-stimulated inducible-type nitric oxide synthase (iNOS) expression in macrophages. LPS-stimulated iNOS expression and NO production were significantly inhibited in alveolar macrophages from rats administrated daunorubicin (4 mg/kg body weight per day) for 5 consecutive days. Incubation of macrophages with daunorubicin at 1 muM but not at 0.1 and 0.5 muM significantly inhibited LPS-stimulated NO production and iNOS induction. Activation of extracellular regulated kinase (ERK) by LPS was markedly attenuated in both macrophages isolated from in vivo daunorubicin-treated rats and those incubated in vitro with daunorubicin at 1 microM. ERK activation, iNOS induction, and NO production following LPS stimulation were all markedly inhibited in the presence of U0126, an ERK inhibitor. The viability of macrophages was decreased by incubation with daunorubicin at 0.5 and 1 microM, while treatment of rats with daunorubicin did not affect viability of macrophages isolated from the rats. These results suggest that in vivo treatment of rats with daunorubicin attenuates LPS-induced iNOS expression of macrophages through inhibition of ERK activation, while inhibition of iNOS induction by in vitro incubation with daunorubicin may be mainly due to its cytotoxicity.
Saito
Fumiaki
F
Department of Hygiene and Preventive Medicine, Yamagata University School of Medicine, Japan.
Matsusaka
Satoshi
S
Kato
Hirohisa
H
Wakabayashi
Ichiro
I
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001772:Blood Cell Count; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000302:isolation & purification; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D000900:Anti-Bacterial Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009570:Nitriles; C113580:U 0126; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D003630:Daunorubicin