Atrial natriuretic peptide inhibits tumor necrosis factor-alpha production by interferon-gamma-activated macrophages via suppression of p38 mitogen-activated protein kinase and nuclear factor-kappa B activation.
We investigated whether the atrial natriuretic peptide (ANP) might have an inhibitory effect on inflammatory cells. Treatment of RAW264.7 macrophages with interferon-gamma (IFN- gamma) caused a significant increase in tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production. Activation of p38 mitogen-activated protein (MAP) kinase was observed 30 to 120 min after IFN-gamma, and transcription factor nuclear factor-kappa B (NF-kappaB) was activated about 7 to 9 times of the basal activity. Human ANP(99-126) and a specific p38 MAP kinase inhibitor SB203580 inhibited the IFN-gamma-induced TNF-alpha production in a dose-dependent manner without affecting NO production. ANP inhibited the IFN-gamma-induced p38 MAP kinase activation, and ANP and SB203580 inhibited NF-kappaB activation. To study the involvement of oxidative stress in this system, the effects of allopurinol and acetovanillone, inhibitors of xanthine oxidase and NADPH oxidase, respectively, were studied. Allopurinol or acetovanillone did not inhibit the IFN-gamma-induced production of TNF-alpha or NO, suggesting little involvement of oxidative stress in this system. This is the first evidence in vitro that ANP has an anti-inflammatory activity on IFN-gamma-activated macrophages by suppressing signal transduction pathway leading to p38 MAP kinase and NF-kappaB activation.
First Department of Internal Medicine, Gunma University School of Medicine, 3-39-15 Showa, Gunma, 371-8511, Maebashi, Japan. hideot@showa.gunma-u.ac.jp
H
H
Tsukagoshi
Y
Y
Shimizu
T
T
Kawata
T
T
Hisada
Y
Y
Shimizu
S
S
Iwamae
T
T
Ishizuka
K
K
Iizuka
K
K
Dobashi
M
M
Mori
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D009573:Nitrites; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D009320:Atrial Natriuretic Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580