ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock

Gantsetseg Tumurkhuu, Naoki Koide, Takaki Hiwasa, Motohiro Ookoshi, Jargalsaikhan Dagvadorj, Shadat Mohammod Noman Abu Shadat Mohammod Noman, Imtiaz Iftakhar-E-Khuda, Yoshikazu Naiki, Takayuki Komatsu, Tomoaki Yoshida, Takashi Yokochi

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6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)97-105
Number of pages9
JournalInnate Immunity
Volume17
Issue number1
DOIs
Publication statusPublished - 02-2010

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Molecular Biology
  • Cell Biology
  • Infectious Diseases

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  • Cite this

    Tumurkhuu, G., Koide, N., Hiwasa, T., Ookoshi, M., Dagvadorj, J., Abu Shadat Mohammod Noman, S. M. N., Iftakhar-E-Khuda, I., Naiki, Y., Komatsu, T., Yoshida, T., & Yokochi, T. (2010). ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production and protects mice from lethal endotoxic shock. Innate Immunity, 17(1), 97-105. https://doi.org/10.1177/1753425909353641