Effects of anti-interleukin 6 on inflammatory responses during murine septic peritonitis

Abstract

Interleukin (IL)-6 has a limited role in the pathogenesis of the acute systemic inflammatory response syndrome elicited by bolus administration of bacteria or bacterial products. We sought to determine the role of IL-6 in septic peritonitis induced by cecal ligation and puncture (CLP). CLP led to a rapid and sustained induction of IL-6 in plasma and organ homogenates. Pretreatment (-2 h) with an anti-IL-6 mAb (1 mg) resulted in higher plasma and hepatic levels of tumor necrosis factor (TNF), as well as higher plasma concentrations of soluble TNF receptors and IL-10, while attenuating the acute phase protein response. Administration of anti-IL-6 did not influence survival. These results suggest that IL-6 production during septic peritonitis serves to inhibit the appearance of both agonist and antagonist members of the cytokine network. The importance of IL-6 in mediating the cytokine response to infection may be underestimated in more acute sepsis models.

Get full access to this article

View all access options for this article.

References

Bone R.C. The pathogenesis of sepsis. Ann Intern Med 1991; 115: 457-469.

Tracey K.J. , Fong Y. , Hesse D.G. et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330: 662-664.

Bagby G.J. , Plessala K.J. , Wilson L.A. , Thompson J.J. , Nelson S. Divergent efficacy of antibody to tumor necrosis factor-α in intravascular and peritonitis model of sepsis. J Infect Dis 1991; 163:83-88.

Ohlsson K. , Björk P. , Bergenfeldt M. , Hageman R. , Thompson R.C. Interleukin 1 receptor antagonist reduces mortality from endotoxin shock. Nature 1990; 348: 550-552.

Fischer E. , Marano M.A. , van Zee K.J. et al. Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 1992 ; 89: 1551-1557.

Lowry S.F. , Calvano S.E. , van der Poll T. Measurement of inflammatory mediators in clinical sepsis. In: Sibbald W.J. , Vincent J.L. (Eds) Clinical Trials for the Treatment of Sepsis. Berlin: Springer, 1995; 86-105.

Z van der Poll T. , Lowry S.F. Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense? Shock 1995 ; 3: 1-12.

Fisher Jr CJ , Dhainaut J.F.A. , Opal S.M. et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. JAMA 1994; 271: 1836-1843.

Fink M.P. , Heard S.O. Laboratory models of sepsis and septic shock. J Surg Res 1990; 49: 186-196.

10.

Hyde S.R. , Stith R.D. , McCallum R.E. Mortality and bacteriology of sepsis following cecal ligation and puncture in mice. Infect Immun 1990; 58: 619-624.

11.

Evans G.F. , Snyder Y.M. , Butler L.D. , Zuckerman S.H. Differential expression of interleukin-1 and tumor necrosis factor in murine septic shock models. Circ Shock 1989; 29: 279-290.

12.

McMasters K.M. , Peyton J.C. , Hadjiminas D.J. , Cheadle W.G. Endotoxin and tumour necrosis factor do not cause mortality from caecal ligation and puncture . Cytokine 1994; 6: 530-536.

13.

Alexander H.R. , Sheppard B.C. , Jensen J.C. et al. Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension and hypothermia of gram-negative sepsis. J Clin Invest 1991; 88: 34-39.

14.

van der Poll T. , Marchant A. , Buurman W.A. et al. Endogenous interleukin 10 protects mice from death during septic peritonitis. J Immunol 1995; 155: 5397-5401.

15.

Eskandari M.K. , Bolgos G. , Miller C. , Nguyen D.T. , DeForge L.E. , Remick D.G. Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia . J Immunol 1992; 148: 2724-2730.

16.

Echtenacher B. , Falk W. , Mannel D.N. , Krammer P.H. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 1990; 145:3762-3766.

17.

Van Snick J. Interleukin-6: an overview. Annu Rev Immunol 1990; 8:253-278.

18.

van der Poll T. , Levi M. , Hack C.E. et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179: 1253-1259.

19.

Stouthard J.M.L. , Levi M. , Hack C.E. et al. Interleukin 6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemostas 1996; In press.

20.

Tilg H. , Trehu E. , Atkins M.B. , Dinarello C.A. , Mier J.W. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 1994; 83: 113-118.

21.

Aderka D. , Le J. , Vilcek J. IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells and mice. J Immunol 1989; 143: 3517-3523.

22.

Schindler R. , Mancilla J. , Endres S. , Ghorbani R. , Clark S.C. , Dinarello C.A. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1 and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 1990; 75: 40-47.

23.

Heremans H. , Dillen C. , Put W. , van Damme J. , Billiau A. Protective effect of anti-interleukin (IL)-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels . Eur J Immunol 1992 ; 22: 2395-2401.

24.

Libert C. , Vink P. , Coulie P. et al. Limited involvement of interleukin-6 in the pathogenesis of lethal septic shock as revealed by the effect of monoclonal antibodies against interleukin-6 or its receptor in various murine models. Eur J Immunol 1992; 22: 2625-2630.

25.

Barton B.E. , Jackson J.V. Protective role of interleukin 6 in the lipopolysaccharide-galactosamine septic shock model. Infect Immun 1993; 61: 1496-1499.

26.

Matthys P. , Mitera T. , Heremans H. , Van Damme J. , Billiau A. Anti-gamma interferon and anti-interleukin-6 antibodies affect staphyloccoccal enterotoxin B-induced weight loss, hypoglycemia, and cytokine release in D-galactosamine-sensitized and unsensitized mice. Infect Immun 1995; 63: 1158-1164.

27.

Strassmann G. , Fong M. , Kenney J.S. , Jacob C.O. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 1992; 89: 1681-1684.

28.

Oldenburg H.S.A. , Rogy M.A. , Lazarus D.D. et al. Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6. Eur J Immunol 1993; 23: 1889-1894.

29.

Havell E.A. , Moldawer L.L. , Helfgott D. , Kilian P.L. , Sehgal P.B. Type I IL-1 receptor blockade exacerbates murine listeriosis. J Immunol 1992; 148:1486-1492.

30.

Helle M. , Boeije L. , Aarden L.A. Functional discrimination between interleukin 6 and interleukin 1 . Eur J Immunol 1988; 18:1535-1540.

31.

Mosmann T. Rapid colorimetric assay for cellular growth and cytotoxicity assays . J Immunol Methods 1983; 65: 55-60.

32.

Espevik T. , Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods 1986; 95: 99-105.

33.

Van Zee K.J. , Kohno T. , Fischer E. , Rock S.C. , Moldawer L.L. , Lowry S.F. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor α in vitro and in vivo. Proc Natl Acad Sci USA 1992; 89: 4845-4849.

34.

Bemelmans M.H.A. , Gouma D.J. , Buurman W.A. Tissue distribution and clearance of soluble murine TNF receptors in mice. Cytokine 1994 ; 6: 608-615.

35.

Bucklin S.E. , Silverstein R. , Morrison D.C. An interleukin-6-induced acute phase protein response does not confer protection against lipopolysaccharide lethality. Infect Immun 1993; 61:3184-3189.

36.

Mancuso G. , Tomasello F. , Migliardo M. et al. Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease. Infect Immun 1994; 62: 4997-5002.

37.

Gennari R. , Alexander J.W. , Pyles T. , Hartmann S. , Ogle C.K. Effects of antimurine interleukin-6 on bacterial translocation during gut-derived sepsis. Arch Surg 1994; 129: 1191-1197.

38.

Kopf M. , Baumann H. , Freer G. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 1994;368:339-342.

39.

Fattori E. , Cappelletti M. , Costa P. et al. Defective inflammatory response in interleukin-6-deficient mice . J Exp Med 1994; 180: 1243-1250.

40.

Dalrymple S.A. , Lucian L.A. , Slattery R. et al. Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia. Infect Immun 1995; 63:2262-2268.

41.

Martens E. , Dillen C. , Put W. et al. Increased circulating interleukin-6 (IL-6) activity in endotoxin-challenged mice pretreated with an anti-IL-6 antibody is due to IL-6 accumulated in antigen-antibody complexes. Eur J Immunol 1993; 23: 2026-2029.

42.

Klein B. , Wijdenes J. , Zhang X.G. et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 1991 ; 48: 1198-1204.

43.

van der Poll T. , Jansen J. , van Leenen D. et al. Release of soluble receptors for tumor necrosis factor in clinical sepsis and experimental endotoxemia. J Infect Dis 1993; 168: 955-960.

44.

Moore K.W. , O'Garra A. , de Waal Malefyt R. , Vieira P. , Mosmann T.R. Interleukin-10. Annu Rev Immunol 1993 ; 11: 165-190.

45.

Dalrymple S.A. , Slattery R. , Aud D.M. , Krishna M. , Lucian L.A. , Murray R. Interleukin-6 is required for a protective immune response to systemic Escherichia coli infection. Infect Immun 1996; 64:3231-3235.

46.

Jansen J. , van der Poll T. , Levi M. et al. Inhibition of the release of soluble tumour necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor-α antibody . J Clin Immunol 1995; 15:45-50.

47.

Z van der Poll T. , Jansen J. , Levi M. , ten Cate H. , ten Cate J.W. , van Deventer S.J.H. Regulation of interleukin 10 release by tumor necrosis factor in humans and chimpanzees . J Exp Med 1994; 180:1985-1988.

48.

van der Poll T. , Jansen J. , Levi M. et al. Interleukin 10 release during endotoxaemia in chimpanzees: role of platelet activating factor and interleukin 6. Scand J Immunol 1996; 43: 122-125.

49.

Kato T. , Murata A. , Toda H. et al. Interleukin 10 reduces mortality from severe peritonitis in mice . Antimicrob Agents Chemother 1995; 39: 1336-1340.