A potential role of YC-1 on the inhibition of cytokine release in peripheral blood mononuclear leukocytes and endotoxemic mouse models

Summary

To evaluate the anti-sepsis potential of YC-1, we have examined the effect of YC-1 on the regulation of cytokine production in human leukocytes and endotoxemic mice. The data demonstrated that YC-1 showed a preferential inhibition on proinflammatory cytokine production without inhibition of cell growth or induction of cytotoxicity in human leukocytes. On the other hand, in the septic mouse model, treatment with an intraperitoneal application of LPS caused a cumulative death within 27 hours. The post-treatment administration of YC-1 significantly increased the survival rate in endotoxemic mice. Furthermore, several mediators were detected and the data showed that YC-1 profoundly blocked LPS-induced NO as well as TNF-α production, and prevented lung damage by histological examination. Samples from the animal model showed that LPS-induced NF-κB/DNA binding activity and consequent up-regulation of iNOS expression in tissues were abolished by post-administration of YC-1. Furthermore, YC-1, by itself, did not modify cGMP content while significantly inhibit LPS-induced cGMP formation, suggesting that YC-1-mediated effect was not through a cGMP-elevating pathway. Taken together, it is evident that the post-treatment administration of YC-1 after LPS application significantly inhibits NF-κB activation, iNOS expression, NO over-production, and cytokine release reaction resulting in an improved survival rate in endotoxemic mice. It is suggested that YC-1 may be a potential agent for the therapeutic treatment of sepsis.

Keywords

YC-1 - lipopolysaccharide - nuclear factor-κB

• References

• 1 Stone R. Search for sepsis drugs goes on despite past failures. Science 1994; 264: 365-7.
• 2 Karima R, Matsumoto S, Higashi H. et al. The molecular pathogenesis of endotoxic shock and organ failure. Mol Med Today 1999; 5: 123-32.
• 3 Ortolani O, Conti A, De Gaudio AR. et al. The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock. Am J Respir Crit Care Med 2000; 161: 1907-11.
• 4 Kox WJ, Volk T, Kox SN. et al. Immunomodulatory therapies in sepsis. Intensive Care Med 2000; 26: S124-8.
• 5 Boyle WA, 3^rd Parvathaneni LS, Bourlier V. et al. iNOS gene expression modulates microvascular responsiveness in endotoxin-challenged mice. Circ Res 2000; 87: E18-24.
• 6 Glauser MP. Pathophysiologic basis of sepsis: considerations for future strategies of intervention. Crit Care Med 2000; 28: S4-8.
• 7 Ochoa JB, Udekwu AO, Billiar TR. et al. Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 1991; 214: 621-6.
• 8 Nakayama DK, Geller DA, Lowenstein CJ. et al. Cytokines and lipopolysaccharide induce nitric oxide synthase in cultured rat pulmonary artery smooth muscle. Am J Respir Cell Mol Biol 1992; 7: 471-6.
• 9 Rees DD. Role of nitric oxide in the vascular dysfunction of septic shock. Biochem Soc Trans 1995; 23: 1025-9.
• 10 Szabo C. The role of peroxynitrite in the pathophysiology of shock, inflammation and ischemia-reperfusion injury. Shock 1996; 6: 79-88.
• 11 Berner R, Niemeyer CM, Leititis JU. et al. Plasma levels and gene expression of granulocyte colonystimulating factor, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis. Pediatr Res 1999; 44: 469-7.
• 12 Hack CE, Aarden LA, Thijs LG. Role of cytokines in sepsis. Adv Immunol 1997; 66: 101-95.
• 13 Oberholzer A, Oberholzer C, Moldawer LL. Interleukin-10 a complex role in the pathogenesis of sepsis syndromes and its potential as an anti-inflammatory drug. Crit Care Med 2002; 30: S58-63.
• 14 Dinarello CA. Anti-cytokine therapies in response to systemic infection. J Investig Dermatol Symp Proc 2001; 6: 244-50.
• 15 Blackwell TS, Christman JW. The role of nuclear factor- κBin cytokine gene regulation. Am J Respir Cell Mol Biol 1997; 17: 3-9.
• 16 Ko FN, Wu CC, Kuo SC. et al. YC-1, a novel activator of platelet guanylate cyclase. Blood 1994; 84: 4226-33.
• 17 Friebe A, Schultz G, Koesling D. Sensitizing soluble guanylyl cyclase to become a highly CO-sensitive enzyme. EMBO J 1996; 15: 6863-8.
• 18 Pan SL, Guh JH, Huang YW. et al. Inhibition of rasmediated cell proliferation by benzyloxybenzaldehyde. J Biomed Sci 2002; 9: 622-30.
• 19 Hanada T, Yoshimura A.. Regulationof cytokine signalling and inflammation. Cytokine Growth Factor Rev 2002; 13: 413-21.
• 20 Taniguchi T, Koido Y, Aiboshi J. et al. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome. Crit Care Med 1999; 27: 1262-4.
• 21 Kasai T, Inada K, Takakuwa T. et al. Anti-inflammatory cytokine levels in patients with septic shock. Mol Pathol Pharmacol 1997; 98: 34-42.
• 22 Furie MB, Randolph GJ. Chemokines and tissue injury. Am J Pathol 1995; 146: 1287-301.
• 23 Ng PC, Li K, Wong RP. et al. Proinflammatory and anti-inflammatory cytokine responses in preterm infants with systemic infections. Arch Dis Child Fetal Neonatal Ed 2003; 88: F209-13.
• 24 Taniguchi T, Koido Y, Aiboshi J. et al. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome. Crit Care Med 1999; 27: 1262-4.
• 25 Marshall JC. Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov 2003; 2: 391-405.
• 26 Rothermund L, Friebe A, Paul M. et al. Acute blood pressure effects of YC-1-induced activation of soluble guanylyl cyclase in normotensive and hypertensive rats. Br J Pharmacol 2000; 130: 205-8.
• 27 Conkling PR, Greenberg CS, Weinberg JB. Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes. Blood 1998; 72: 128-33.
• 28 Bevilacqua MP, Pober JS, Majeau GR. et al. Recombinant tumor necrosis induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 1986; 12: 4533-7.
• 29 Gregory SA, Morrissey JH, Edgington TS. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol Cell Biol 1989; 9: 2752-5.
• 30 Teng CM, Wu CC, Ko FN. et al. YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice. Eur J Pharmacol 1995; 320: 161-6.
• 31 Cauwels A, Van Molle W, Janssen B. et al. Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible nitric oxide synthase. Immunity 2000; 13: 223-31.
• 32 Wang JP, Chang LC, Raung SL. et al. Inhibition of superoxide anion generation by YC-1 in rat neutrophils through cyclic GMP-dependent and -independent mechanisms. Biochem Pharmacol 2002; 63: 577-85.