Augmentation of nitric oxide production by gamma interferon in a mouse vascular endothelial cell line and its modulation by tumor necrosis factor alpha and lipopolysaccharide.
The effect of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and lipopolysaccharide (LPS) on nitric oxide (NO) production in the mouse vascular aortic endothelial cell line END-D was examined. LPS, TNF-alpha, and a low concentration of IFN-gamma inhibited NO production in END-D cells, while a high concentration of IFN-gamma definitely enhanced it. The NO production induced by a high concentration of IFN-gamma was further augmented by using IFN-gamma in combination with LPS or TNF-alpha. In sequential incubations of LPS and IFN-gamma, the enhancement of NO production required prior treatment with IFN-gamma. Stimulation of END-D cells with a high concentration of IFN-gamma led to the expression of inducible NO synthase (iNOS). The augmentation of NO production by IFN-gamma alone or in combination with LPS or TNF-alpha was completely blocked by several inhibitors of iNOS. It was strongly suggested that a high concentration of IFN-gamma itself enhanced NO production in END-D cells through inducing the expression of iNOS. LPS and TNF-alpha exclusively modulated the activity of iNOS once its expression was triggered by IFN-gamma. On the other hand, a low concentration of IFN-gamma, LPS, and TNF-alpha reduced NO production through down-regulating constitutive NOS (cNOS). The differential regulation of cNOS- and iNOS-mediated NO production by IFN-gamma, TNF-alpha, and LPS is discussed.
Morikawa
A
A
Department of Microbiology and Immunology, Research Center for Infectious Diseases, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
Koide
N
N
Kato
Y
Y
Sugiyama
T
T
Chakravortty
D
D
Yoshida
T
T
Yokochi
T
T
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D006854:Hydrocortisone / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011725:Pyridines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D006854:Hydrocortisone