Abstract
Interleukin (IL)-6 is a member of the cytokine network that can not be simply classified as a pro- or an anti-inflammatory cytokine. It was originally described under many different names, including interferon (IFN)-β2, 26K factor, B-cell stimulatory factor, and hybridoma/plasmacytoma growth factor. In 1987, these seemingly unrelated factors turned out to be one and the same protein. In 1989 it was recommended that the provisional names be replaced by the term ‘IL-6’ [1]. It has been recognized for many years that the circulating levels of IL-6 increase in a variety of infectious, and non-infectious, conditions. IL-6 can be detected in the circulation of the vast majority of patients with sepsis, and the extent of IL-6 release during sepsis carries a strong predictive value for a bad prognosis (see below). Nonetheless, the scientific community has long considered IL-6 as ‘an innocent bystander’ rather than a mediator directly involved in pathogenetic mechanisms operative during sepsis. In this chapter we will discuss new evidence that IL-6 should not merely be considered a marker of disease severity, and that this cytokine may play a significant role in the pathogenesis of bacterial infections.
Keywords
- Pneumococcal Pneumonia
- Innocent Bystander
- Essential Mediator
- Acute Phase Protein Response
- Tumor Necrosis Factor Release
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References
Paul WE, Laughlin CA, Johnson MI (1989) Report of nomenclature discussion. Ann NY Acad Sci 557:579.
Van Snick J (1990) Interleukin-6: an overview. Annu Rev Immunol 8:253–278.
Taga T, Kishimoto T (1997) GP130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819.
Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T (1989) The complex pattern of cytokines in serum from patients with meningococcal septic shock. J Exp Med 169:333–338.
Helfgott DC, Tatter SB, Santhanam U, et al (1989) Multiple forms of IFN-β2/IL-6 in serum and body fluids during acute bacterial infection. J Immunol 142:948–953.
Lowry SF, Calvano SE, van der Poll T (1995) Measurement of inflammatory mediators in clinical sepsis. In: Sibbald WJ, Vincent JL (eds) Clinical trials for the treatment of sepsis. Springer-Verlag, Heidelberg, pp 86–105.
Hack CE, de Groot ER, Felt-Bersma RJF, et al (1989) Increased plasma levels of interleukin-6 in sepsis. Blood 74:1704–1710.
Calandra T, Gérain J, Heumann D, et al (1991) High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. Am J Med 91:23–29.
Wortel CH, von der Möhlen MAM, van Deventer SJH, et al (1992) Effectiveness of a human monoclonal anti-endotoxin antibody (HA-1A) in gram-negative sepsis: relation to endotoxin and cytokine levels. J Infect Dis 166:1367–1374.
Fong Y, Moldawer LL, Marano M, et al (1989) Endotoxemia elicits increased circulating β2-IFN/IL-6 in man. J Immunol 142:2321–2324.
Van Deventer SJH, Biiller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A (1990) Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic and complement pathways. Blood 76:2520–2526.
Suffredini AF, Reda D, Banks SM, Tropea M, Agosti JM, Miller R (1995) Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration. J Immunol 155:5038–5045.
Van der Poll T, Coyle SM, Levi M, et al (1997) Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. Blood 89:3727–3734.
Van der Poll T, Levi M, van Deventer SJH, et al (1994) Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood 83:446–451.
Fong Y, Tracey KJ, Moldawer LL, et al (1989) Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia. J Exp Med 170: 1627–1633.
Ulich TR, Guo K, Remick D, del Castillo J, Yin S (1991) Endotoxin-induced cytokine gene expression in vivo. III. IL-6 mRNA and serum protein expression and the in vivo hematologic effects of IL-6. J Immunol 146:2316–2323.
Van der Poll T, van Deventer SJH, Hack CE, et al (1992) Effects on leukocytes following injection of tumor necrosis factor into healthy humans. Blood 79:693–698.
Fischer E, Marano MA, Van Zee KJ, et al (1992) 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 89:1551–1557.
Fischer E, Marano MA, Barber AE, et al (1991) Comparison between effects of interleukin-1α administration and sublethal endotoxemia in primates. Am J Physiol 261: R442–R452.
Ogilvie AC, Hack CE, Wagstaff J, et al (1996) IL-1β does not cause neutrophil degranulation but does lead to IL-6, IL-8, and nitrite/nitrate release when used in patients with cancer. J Immunol 156:389–394.
Granowitz EV, Porat R, Mier JW, et al (1993) Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low dose endotoxemia in healthy humans. Blood 82:2985–2990.
Van Zee KJ, Coyle SM, Calvano SE, et al (1995) Influence of interleukin-1 receptor blockade on the human response to endotoxemia. J Immunol 154:1499–1507.
Dehoux MS, Boutten A, Ostinelli J, et al (1994) Compartmentalized cytokine production within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 150:710–716.
Van Berge Henegouwen MIV, van der Poll T, van Deventer SJH, Gouma DJ (1998) Peritoneal cytokine release after elective gastrointestinal surgery and postoperative complications. Am J Surg 175:311–316.
Ulich TR, Yin S, Remick DG, Russell D, Eisenberg SP, Kohno T (1993) Intratracheal administration of endotoxin and cytokines. IV. The soluble tumor necrosis factor type I inhibits acute inflammation. Am J Pathol 142:1335–1338.
Van der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF (1997) Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis 176: 439–444.
Zanetti G, Heumann D, Gérain J, et al (1992) Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice. Comparative protective efficacy of antibodies to tumor necrosis factor-α and to lipopolysaccharide. J Immunol 148:1890–1897.
Weber J, Yang JC, Topalian SL, et al (1993) Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol 11:499–506.
Van Gameren MM, Willemse PHB, Mulder NH, et al (1994) Effects of recombinant human interleukin-6 in cancer patients: a phase I/II study. Blood 84:1434–1441.
Stouthard JML, Romijn JA, van der Poll T, et al (1995) Endocrine and metabolic effects of interleukin-6 in humans. Am J Physiol 268: E813–E819.
Stouthard JML, Levi M, Hack CE, et al (1996) Interleukin 6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 76:738–742.
Preiser JC, Schmartz D, van der Linden P, et al (1991) Interleukin-6 administration has no acute hemodynamic or hematologic effect in the dog. Cytokine 3:1–4.
Aderka D, Le J, Vilcek J (1989) IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells and mice. J Immunol 143:3517–3523.
Schindler R, Mancilla J, Endres S, Ghorbani R, Clark R, Dinarello CA (1990) 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 75:40–47.
Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW (1994) Interleukin-6 (IL-6) as an antiinflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83:113–118.
Woodroofe C, Muller W, Ruther U (1992) Long-term consequences of interleukin-6 overexpression in transgenic mice. DNA Cell Biol 11:587–592.
Ulich TR, Yin S, Guo K, Yi ES, Remick D, del Castillo J (1991) Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation. Am J Pathol 138:1097–1101.
Castell JV, Gomez-Lechon MJ, Daivid M, Fabra R, Trullenque R, Henrich PC (1990) Acute phase response of human hepatocyte: regulation of acute phase protein synthesis by interleukin-6. Hepatology 12:1179–1186.
Matsuda T, Hirano T, Nagasawa S, Kishimoto T (1989) Identification of (α2-macroglobulin as a carrier protein for IL-6. J Immunol 142:148–152.
Tilg H, Dinarello CA, Mier JW (1997) IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol Today 18:428–432.
Heremans H, Dillen C, Put W, van Damme J, Billiau A (1992) Protective effect of anti-interleukin (IL)-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels. Eur J Immunol 22:2395–2401.
Klein B, Brailly H (1995) Cytokine-binding proteins: stimulating antagonists. Immunol Today 16:216–220.
Kopf M, Baumann H, Freer G, et al (1994) Impaired immune and acute-phase responses in inter-leukin-6-deficient mice. Nature 368:339–342.
Fattori E, Cappelletti M, Costa P, et al (1994) Defective inflammatory response in interleukin-6-deficient mice. J Exp Med 180:1243–1250.
Dalrymple SA, Lucian LA, Slattery R, et al (1995) Interleukin-ö-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia. Infect Immun 63 2262–2268.
Dalrymple SA, Slattery R, Aud DM, Krishna M, Lucian LA, Murray R (1996) Interleukin-6 is required for a protective immune response to systemic Escherichia coli infection. Infect Immun 64:3231–3235.
Xing Z, Gauldie J, Cox G, et al (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101:311–320.
Van der Poll T, Levi M, Hack CE, et al (1994) Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 179:1253–1259.
Levi M, van der Poll T, ten Cate H, et al (1998) Differential effects of anti-cytokine treatment on bronchoalveolar hemostasis in endotoxemic chimpanzees. Am J Respir Crit Care Med 158: 92–98.
Romani L, Mencacci A, Cenci E, et al (1996) Impaired neutrophil response and CD4 + T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans. J Exp Med 183:1345–1355.
Van der Poll T, Keogh CV, Buurman WA, Lowry SF (1997) Passive immunization against tumor necrosis factor a impairs host defense during pneumococcal pneumonia in mice. Am J Respir Crit Care Med 155:603–608.
Echtenacher B, Falk W, Mannel DN, et al (1990) Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 145:3762–3766.
Havell EA (1989) Evidence that tumor necrosis factor has an important role in antibacterial resistance. J Immunol 143:2894–2899.
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Van der Poll, T., Van Deventer, S.J.H. (1999). Interleukin-6 in Bacterial Infection and Sepsis: Innocent Bystander or Essential Mediator?. In: Vincent, JL. (eds) Yearbook of Intensive Care and Emergency Medicine 1999. Yearbook of Intensive Care and Emergency Medicine, vol 1999. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-13453-5_5
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DOI: https://doi.org/10.1007/978-3-662-13453-5_5
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