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

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.

Keywords

ONO 3403 synthetic serine protease inhibitor LPS TNF-α NO endotoxic shock

References

Turk B. Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov 2006; 5: 785-799.

Tamura Y. , Hirado M. , Okamura K. et al. Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r, and C1 esterase. Biochim Biophys Acta 1997; 484: 417-422.

Griscavage JM , Wilk S. , Ignarro LJ Serine and cysteine proteinase inhibitors prevent nitric oxide production by activated macrophages by interfering with transcription of the inducible NO synthase gene. Biochem Biophys Res Commun 1995; 215: 721-729.

Aosasa S. , Ono S. , Mochizuki H. , Tsujimoto H. , Ueno C. , Matsumoto A. Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes. Shock 2001; 15: 101-105.

Kanoh M. , Ibata H. , Miyagawa M. et al. Clinical effects of camostat in chronic pancreatitis. Biomed Res 1989; 10: 145-150.

Hsu JT , Chen HM , Chiu DF et al. Efficacy of gabexate mesilate on disseminated intravascular coagulation as a complication of infection developing after abdominal surgery. J Formos Med Assoc 2004; 103: 678-684.

Ohkoshi M. , Sasaki Y. Antimetastatic activity of a synthetic serine protease inhibitor, FOY-305 (Foypan). In Vivo 2005; 19: 133-136.

Ikeda T. , Murakami K. , Hayakawa Y. et al. Anti-invasive activity of synthetic serine protease inhibitors and its combined effect with a matrix metalloproteinase inhibitor. Anticancer Res 1998; 18: 4259-4265.

Senokuchi K. , Nakai H. , Nakayama Y. et al. New orally active serine protease inhibitors . J Med Chem 1995; 38: 2521-2523.

10.

Ohkoshi M. , Denda T. , Hiwasa T. Growth-suppressive activity of a serine protease inhibitors, FOY 305, ONO-3403 and FO-349 toward human carcinoma cells. Oncol Rep 1997; 4: 521-523.

11.

Pålsson-McDermott EM , O’Neill LA Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 2004; 113: 153-162.

12.

Freudenberg MA , Tchaptchet S. , Keck S. et al. Lipopolysaccharide sensing an important factor in the innate immune response to Gram-negative bacterial infections: benefits and hazards of LPS hypersensitivity. Immunobiology 2008; 213: 193-203.

13.

Lin WJ , Yeh WC Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock. Shock 2005; 24: 206-229.

14.

Takeda K. , Kaisho T. , Akira S. Toll-like receptors. Annu Rev Immunol 2003 ; 21: 335-376.

15.

Akira S. , Takeda K. Toll-like receptor signaling. Nat Rev Immunol 2004; 4: 499-511.

16.

Murakami K. , Okajima K. , Uchiba M. , Okabe K. , Takatsuki K. Gabexate mesilate, a synthetic protease inhibitor, attenuates endotoxin-induced pulmonary vascular injury by inhibiting tumor necrosis factor production by monocytes. Crit Care Med 1996; 24: 1047-1053.

17.

Inoue K. , Takano H. , Shimada A. et al. Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide. Mol Pharmacol 2005; 67: 673-680.

18.

Takano H. , Inoue K. , Shimada A. , Sato H. , Yanagisawa R. , Yoshikawa T. Urinary trypsin inhibitor protects against liver injury and coagulation pathway dysregulation induced by lipopolysaccharide/D-galactosamine in mice. Lab Invest 2009; 89: 833-839.

19.

Yuksel M. , Okajima K. , Uchiba M. et al. Gabexate mesilate, a synthetic protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α production by inhibiting activation of both nuclear factor-κB and activator protein-1 in human monocytes. J Pharmacol Exp Ther 2003; 305: 298-305.

20.

Iwadou H. , Morimoto Y. , Iwagaki H. et al. Differential cytokine response in host defence mechanisms triggered by Gram-negative and Gram-positive bacteria, and the roles of gabexate mesilate, a synthetic protease inhibitor. J Int Med Res 2002; 30: 99-108.

21.

Nakamura A. , Mori Y. , Hagiwara K. et al. Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice . J Exp Med 2003; 197: 669-674.

22.

Green LC , Wagner DA , Glowgowski J. , Skepper PL , Wishnok JS , Tannenbaum SR Analysis of nitrate, nitrite and 15 N nitrate in biological fluids. Anal Biochem 1982; 126: 131-138.

23.

Lu YC , Yeh WC , Ohashi PS LPS/TLR4 signal transduction pathway. Cytokine 2008; 42: 145-151.

24.

Beutler B. Inferences, questions and possibilities in Toll-like receptor signaling. Nature 2004; 430: 257-263.

25.

Mansell A. , Reinicke A. , Worrall DM , O’Neill LA The serine protease inhibitor antithrombin III inhibits LPS-mediated NF-kappaB activation by TLR-4. FEBS Lett 2001; 508: 313-317.

26.

Lakhani SA , Bogue CW Toll-like receptor signaling in sepsis. Curr Opin Pediatr 2003; 15: 278-282.

27.

Lin WJ , Yeh WC Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock. Shock 2005; 24: 206-209.

28.

Hiwasa T. , Shimada H. , Ochiai T. et al. Decrease in growth factor receptors after treatment with serine protease inhibitor ONO-3403. Int J Oncol 2002 ; 20: 797-802.

29.

Hiwasa T. Induction of apoptosis by a calpain stimulator, ONO 3403. Apoptosis 1996; 1: 75-80.

30.

Yuksel M. , Okajima K. , Uchiba M. , Okabe H. Gabexate mesilate, a synthetic protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappaB and activator protein-1 in human monocytes. J Pharmacol Exp Ther 2003; 305: 298-305.

31.

Dowling D. , Hamilton CM , O’Neill SM A comparative analysis of cytokine responses, cell surface marker expression and MAPKs in DCs matured with LPS compared with a panel of TLR ligands. Cytokine 2008; 41: 254-262.

32.

Morikawa A. , Kato Y. , Sugiyama T. et al. Role of nitric oxide in lipopolysaccharide-induced hepatic injury in D-galactosamine sensitized mice as an experimental endotoxic shock model . Infect Immun 1999; 67: 1018-1024.

33.

Hayakawa M. , Sawamura A. , Yanagida Y. , Sugano M. , Hoshino H. , Gando S. The response of antithrombin III activity after supplementation decreases in proportion to the severity of sepsis and liver dysfunction. Shock 2008; 30: 649-652.

34.

Novelli GP , Innocenti P. , Livi P. Gabexate mesilate (FOY), a new synthetic protease inhibitor, in the treatment of shock. An Italian multicenter study. Minerva Anesthesiol 1993; 59: 247-253.

35.

Vanaman TC , Bradshaw RA Proteases in cellular regulation. J Biol Chem 1999; 274: 20047-20048.

36.

Ward JR , Dower SK , Whyte MK , Buttle DJ , Sabroe I. Potentiation of TLR4 signaling by plasmin activity. Biochem Biophys Res Commun 2006; 341: 299-303.

37.

Triantafilou M. , Triantafilou K. The dynamics of LPS recognition: complex orchestration of multiple receptors. J Endotoxin Res 2005 ; 11: 5-11.

38.

Morisato D. , Anderson KV The Spatzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo. Cell 1994; 76: 677-688.

39.

Schneider DS , Jin Y., Morisato D. , Anderson KV A processed form of the Spatzle protein defines dorsal ventral polarity in the Drosophila embryo. Development 1994; 120: 1243-1250.

40.

Imler JL , Hoffmann JA Toll and Toll-like proteins: an ancient family of receptors signaling infection . Rev Immunogenet 1990; 2: 294-304.