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REVIEW PAPER
Interleukin 6 – biological activities and role in rheumatoid arthritis pathogenesis
Online publication date: 2009-04-01
Reumatologia 2009;47(1):24-33
KEYWORDS
ABSTRACT
Interleukin 6 (IL-6) is a pleiotropic cytokine exerting multidirectional effects on the cells of both innate and acquired immune systems. This cytokine is recognized as a key factor regulating the defence mechanisms of organisms. Its ability to initiate and regulate acute inflammation as well as to facilitate and direct an acquired immune response are the major functions of this cytokine. Interleukin 6 also exerts systemic effects. Overproduction of IL-6 mediates a shift from acute to chronic inflammation and is critical for the development of some diseases. The structure of IL-6 and its receptors, the signal transduction pathways and biological activities, as well as the implications of this cytokine in animal models of both arthritis and rheumatoid arthritis (RA) are reviewed. Currently available data show that IL-6 blockade will be a useful therapeutic strategy for RA patients and has scientific support.
REFERENCES (57)
1.
Kontny E, Masliński W. Zburzenia immunologiczne w patogenezie chorób reumatycznych. W: Reumatologia kliniczna. Zimmermann-Górska I (red.). Wydawnictwo Lekarskie PZWL, Warszawa 2008; 101-131.
2.
Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008; 118: 3537-3545. .
3.
Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res 2002; 4 (Suppl 3): S233-S242.
4.
Shabo Y, Lotem J, Rubinstein M, et al. The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood 1988; 72: 2070-2073.
5.
Nishimoto N, Kishimoto T. Interleukin 6: from bench to bedside. Natl Clin Pract Rheumatol 2006; 11: 619-626. .
6.
Tamura T, Udagawa N, Takahashi N, et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A 1993; 90: 11924-11928.
7.
Romano M, Sironi M, Toniatti C, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997; 6: 315-325.
8.
Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002; 13: 357-368.
9.
Akira S, Isshiki H, Nakajima T, et al. Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL-6. Ciba Found Symp 1992; 167: 47-62.
10.
Vanden Berghe W, Vermeulen L, De Wilde G, et al. Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. Biochem Pharmacol 2000; 60: 1185-1189.
11.
Xiao W, Hodge DR, Wang L, et al. NF-kappaB activates IL-6 expression through cooperation with c-Jun and IL-6-AP1 site, but is independent of its IL-6-NFkappaB regulatory site in autocrine human multiple myeloma cells. Cancer Biol Ther 2004; 3: 1007-1017. .
12.
Pritts T, Hungness E, Wang Q, et al. Mucosal and enterocyte IL-6 production during sepsis and endotoxemia – role of transcription factors and regulation by the stress response. Am J Surg 2002; 183: 372-383. 13. Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65 (Suppl 1): S4-S10.
13.
Heinrich PC, Behrmann I, Müller-Newen G, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334: 297-314. 15. Rose-John S, Waetzig GH, Scheller J, et al. The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets 2007; 11: 613-624.
14.
Grotzinger J. Molecular mechanisms of cytokine receptor activation. Biochim Biophys Acta 2002; 1592: 215-223.
15.
Müllberg J, Schooltnik H, Stoyan T, et al. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 1993; 23: 473-480. .
16.
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 2007; 178: 2623-2629.
17.
Heinrich PC, Behrmann I, Haan S, et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003; 374: 1-20.
18.
Ohtani T, Ishihara K, Atsumi T, et al. Dissection of signaling cascades through gp130 in vivo: reciprocal roles of STAT3- and SHP2-mediated signals in immune responses. Immunity 2000; 12: 95-105.
19.
Kaplanski G, Marin V, Montero-Julian F, et al. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol 2003; 24: 25-29.
20.
McLoughlin RM, Hurst SM, Nowell MA, et al. Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms. J Immunol 2004; 172: 5676-5683.
21.
Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 2005; 175: 3463-3468.
22.
Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther 2006; 8 (Suppl 2): S2-S8.
23.
Fielding CA, McLoughlin RM, McLeod L, et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol 2008; 181: 2189-2195.
24.
Xing Z, Gauldie J, Cox G, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998; 101: 311-320.
25.
Choy E. Interleukin 6 receptor as a target for the treatment of rheumatoid arthritis. Ann Rheum Dis 2003; 62 (Suppl II): ii68-ii69.
26.
Cronstein BN. Interleukin-6. A key mediator of systemic and local symptoms in rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65 (Suppl 1): S11-S15.
27.
Streetz KL, Wüdstefeld T, Klein C, et al. Mediators of inflammation and acute phase response in the liver. Cell Mol Biol (Noisy-le-grand) 2002; 47: 661-673.
28.
Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113: 1271-1276.
29.
Verga Falzacappa MV, Vujic Spasic M, Kessler R, et al. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 2007; 109: 353-358.
30.
Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest 2004; 113: 1251-1253.
31.
Pedersen BK. IL-6 signalling in exercise and disease. Biochem Soc Trans 2007; 35: 1295-1297.
32.
Ohsugi Y. Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, tocilizumab (recombinant humanized anti-human interleukin-6 receptor antibody), unveils the mysterious etiology of immune- mediated inflammatory diseases. Biol Pharm Bull 2007; 30: 2001-2006.
33.
Andersen K, Pedersen BK. The role of inflammation in vascular insulin resistance with focus on IL-6. Horm Metab Res 2008; 40: 635-639.
34.
Tuchocka A, Puszczewicz M. Rola tocilizumabu w leczeniu reumatoidalnego zapalenia stawów na tle znaczenia patogenetycznego interleukiny 6 w rozwoju choroby. Reumatologia 2008; 46: 140-150.
35.
Biffl WL, Moore EE, Moore FA, et al. Interleukin-6 delays neutrophil apoptosis. Arch Surg 1996; 131: 24-30.
36.
Lally F, Smith E, Filer A, et al. A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. Arthritis Rheum 2005; 52: 3460-3469. .
37.
Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 2006; 80: 227-236.
38.
Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 2000; 51: 245-270.
39.
Evans SS, Fisher DT, Skitzki JJ, Chen Q. Targeted regulation of a lymphocyte-endothelial-interleukin-6 axis by thermal stress. Int J Hyperthermia 2008; 24: 67-78.
40.
Mills KH. Induction, function and regulation of IL-17-producting T cells. Eur J Immunol 2008; 38: 2636-2649.
41.
Nishihara M, Ogura H, Ueda N, et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol 2007; 19: 695-702.
42.
Dominitzki S, Fantini MC, Neufert C, et al. Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25- T cells. J Immunol 2007; 179: 2041-2045.
43.
Wan S, Xia Ch, Morel L. IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions. J Immunol 2007; 178: 271-279.
44.
Pillemer BB, Xu H, Oriss TB, et al. Deficient SOCS3 expression in CD4+CD25+FoxP+ regulatory T cells and SOCS3-mediated suppression of Treg function. Eur J Immunol 2007; 37: 2082-2089.
45.
Jego G, Pascual V, Palucka AK, Banchereau J. Dendritic cells control B cell growth and differentiation. Curr Dir Autoimmun 2005; 8: 124-139.
46.
Hillion S, Youinou P, Jamin C. Peripheral expression of RAG in human B lymphocytes in normal and pathological conditions is dependent on interleukin-6. Autoimmun Rev 2007; 6: 415-420.
47.
Koga T, Torigoshi T, Motokawa S, et al. Serum amyloid A-induced IL-6 production by rheumatoid synoviocytes. FEBS Lett 2008; 582: 579-585.
48.
Lipsky PE. Interleukin-6 and rheumatic diseases. Arthritis Res Ther 2006; 8 (Suppl 2): S4-S8.
49.
Scheller J, Ohnesorge N, Rose-John S. Interleukin-6 trans-signalling in chronic inflammation and cancer. Scand J Immunol 2006; 63: 321-329.
50.
Jones SA, Richards PJ, Scheller J, Rose-John S. IL-6 transsignalling: the in vivo consequences. J Interferon Cytokine Res 2005; 25: 241-253.
51.
Hashizume M, Hayakawa N, Mihara M. IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-αlpha and IL-17. Rheumatology (Oxford) 2008; 47: 1635-1640.
52.
Kudo O, Sabokbar A, Pocock A, et al. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 2003; 32: 1-7.
53.
Klimiuk PA, Sierakowski S, Gińdzieńska-Sieśkiewicz, et al. Przydatność oznaczania w surowicy krwi stężeń interleukiny 6 (IL-6), metaloproteinaz i ich tkankowych inhibitorów w ocenie aktywności reumatoidalnego zapalenia stawów. Reumatologia 2005; 43: 239-242.
54.
Jikko A, Wakisaka T, Iwamoto M, et al. Effects of interleukin-6 on proliferation and proteoglycan metabolism in articular chondrocyte cultures. Cel Biol Int 1998; 22: 615-621.
55.
De Benedetti F, Rucci N, Del Fattore A, et al. Impaired skeletal development in interleukin-6-transgenic mice. A model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum 2006; 54: 3551-3563.
56.
Voulgari PV, Kolios G, Papadopoulos GK, et al. Role of cytokines in the pathogenesis of anemia of chronic disease in rheumatoid arthritis. Clin Immunol 1999; 92: 153-160.
57.
Atsumi T, Ishikara K, Kamimura D, et al. A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J Exp Med 2002; 196: 979-990.
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