RRC ID 17699
著者 Tumurkhuu G, Koide N, Hiwasa T, Ookoshi M, Dagvadorj J, Abu Shadat Mohammod Noman, Iftakhar-E-Khuda I, Naiki Y, Komatsu T, Yoshida T, Yokochi T.
タイトル ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-{alpha} and nitric oxide production and protects mice from lethal endotoxic shock.
ジャーナル Innate Immun
Abstract ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-α production at a lower concentration than camostat mesilate. It also inhibited LPS-induced NO production. Their inhibition was responsible for the reduced mRNA expression of TNF-α and inducible NO synthase. In LPS-stimulated cells, ONO 3403 prevented the augmentation of MyD88 expression and inhibited the phosphorylation of IκB-α, stress-activated protein kinase (SAPK) and IRF-3, and the production of interferon-β. ONO 3403 abolished the elevation of the extracellular serine protease activity in response to LPS. Further, it reduced the circulating TNF-α level, hepatic injury and mortality in mice receiving an injection of D-galactosamine and LPS. ONO 3403 was suggested to inhibit LPS-induced inflammatory responses via inactivation of MyD88-dependent and independent pathways.
巻・号 17(1)
ページ 97-105
公開日 2011-2-1
DOI 10.1177/1753425909353641
PII 1753425909353641
PMID 20023007
MeSH Allylglycine / analogs & derivatives* Allylglycine / pharmacology Allylglycine / therapeutic use Animals Benzamidines / pharmacology* Benzamidines / therapeutic use* Cell Line, Tumor Culture Media, Conditioned / metabolism Esters Female Gabexate / analogs & derivatives Gabexate / pharmacology Gene Expression / drug effects Gene Expression / genetics Guanidines I-kappa B Proteins / metabolism Interferon Regulatory Factor-3 / metabolism Interferon-gamma / blood Interleukin-6 / metabolism JNK Mitogen-Activated Protein Kinases / metabolism Lipopolysaccharides / pharmacology* Liver / drug effects Liver / pathology Macrophages / drug effects Macrophages / metabolism* Macrophages, Peritoneal / drug effects Macrophages, Peritoneal / metabolism Mice Mice, Inbred BALB C Myeloid Differentiation Factor 88 / metabolism NF-KappaB Inhibitor alpha Nitric Oxide / metabolism* Nitric Oxide Synthase Type II / genetics Nitric Oxide Synthase Type II / metabolism Phosphorylation / drug effects Serine Proteases / metabolism Serine Proteinase Inhibitors / pharmacology Serine Proteinase Inhibitors / therapeutic use Shock, Septic / blood Shock, Septic / pathology Shock, Septic / prevention & control* Signal Transduction / drug effects Toll-Like Receptor 4 / metabolism Tumor Necrosis Factor-alpha / blood Tumor Necrosis Factor-alpha / genetics Tumor Necrosis Factor-alpha / metabolism*
IF 2.298
引用数 6
WOS 分野 MEDICINE, RESEARCH & EXPERIMENTAL MICROBIOLOGY IMMUNOLOGY BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 RAW 264(RCB0535)