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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allylglycine / analogs & derivatives*
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Allylglycine / pharmacology
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Allylglycine / therapeutic use
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Animals
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Benzamidines / pharmacology*
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Benzamidines / therapeutic use*
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Cell Line, Tumor
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Culture Media, Conditioned / metabolism
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Esters
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Female
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Gabexate / analogs & derivatives
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Gabexate / pharmacology
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Gene Expression / drug effects
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Gene Expression / genetics
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Guanidines
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I-kappa B Proteins / metabolism
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Interferon Regulatory Factor-3 / metabolism
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Interferon-gamma / blood
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Interleukin-6 / metabolism
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipopolysaccharides / pharmacology*
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Liver / drug effects
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Liver / pathology
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Macrophages / drug effects
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Macrophages / metabolism*
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred BALB C
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Myeloid Differentiation Factor 88 / metabolism
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NF-KappaB Inhibitor alpha
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Phosphorylation / drug effects
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Serine Proteases / metabolism
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Serine Proteinase Inhibitors / pharmacology
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Serine Proteinase Inhibitors / therapeutic use
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Shock, Septic / blood
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Shock, Septic / pathology
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Shock, Septic / prevention & control*
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Signal Transduction / drug effects
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / blood
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Benzamidines
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Culture Media, Conditioned
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Esters
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Guanidines
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I-kappa B Proteins
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Interferon Regulatory Factor-3
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Interleukin-6
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Irf3 protein, mouse
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Lipopolysaccharides
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Nfkbia protein, mouse
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Serine Proteinase Inhibitors
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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ethyl N-allyl-N-(2-methyl-3-(4-(4-amidinophenoxycarbonyl)phenyl)propenoyl)aminoacetate methanesulfonate
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camostat
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Allylglycine
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NF-KappaB Inhibitor alpha
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Nitric Oxide
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Gabexate
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Interferon-gamma
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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JNK Mitogen-Activated Protein Kinases
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Serine Proteases