Download PDF
Thromb Haemost 2009; 102(02): 215-222
DOI: 10.1160/TH09-05-0297
Theme Issue Article
Schattauer GmbH

How much is too much? Interleukin-6 and its signalling in atherosclerosis

Harald Schuett
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Maren Luchtefeld
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Christina Grothusen
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Karsten Grote
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Bernhard Schieffer
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
› Author Affiliations
Further Information

Publication History

Received: 11 May 2009

Accepted after major revision: 02 July 2009

Publication Date:
22 November 2017 (online)

    Permissions and Reprints

Summary

The importance of inflammation as a driver of pathology is no longer confined to autoimmune and infectious diseases. In line with convincing experimental data as well as abundant clinical findings the current view of atherosclerosis points to inflammation as a critical regulator of atherosclerotic plaque formation and progression leading to the fatal clinical endpoints myocardial infarction, stroke or sudden cardiac death. The underlying mechanisms have been a matter of intense research during the last decades. In this regard, the interleukin-6 (IL-6) cytokines and their signalling events have been shown to contribute to both, atherosclerotic plaque development and plaque destabilisation via a variety of mechanisms. These involve the release of other pro-inflammatory cytokines, oxidation of lipoproteins by phospholipases, stimulation of acute phase protein secretion, the release of prothrombotic mediators, and the activation of matrix metalloproteinases. Moreover, the formation of reactive oxygen species generated by vascular enzyme systems may play a critical role in the regulation of IL-6 indicating a cross talk between vasoactive substances i.e. angiotensin II or adrenalin and pro-inflammatory cytokines such as IL-6. In this review we will summarise and discuss the underlying molecular and cellular mechanisms how IL-6 as an early and central regulator of inflammation contributes to atherosclerosis and how this knowledge can be integrated into the clinical context.

Keywords

Cytokines - atherosclerosis - inflammation - signal transduction
 

  • References

  • 1 Hansson GK, Robertson AK, Soderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Pathol 2006; 01: 297-329.
    CrossrefPubMedGoogle Scholar
  • 2 Bonomini F, Tengattini S, Fabiano A. et al. Atherosclerosis and oxidative stress. Histol Histopathol 2008; 23: 381-390.
    PubMedGoogle Scholar
  • 3 Osborn EA, Jaffer FA. Advances in molecular imaging of atherosclerotic vascular disease. Curr Opin Cardiol 2008; 23: 620-628.
    CrossrefPubMedGoogle Scholar
  • 4 Davies JR, Rudd JH, Weissberg PL. Molecular and metabolic imaging of atherosclerosis. J Nucl Med 2004; 45: 1898-1907.
    PubMedGoogle Scholar
  • 5 Ibanez B, Badimon JJ, Garcia MJ. Diagnosis of atherosclerosis by imaging. Am J Med 2009; 122 (Suppl. 01) S15-25.
    CrossrefPubMedGoogle Scholar
  • 6 Yudkin JS, Kumari M, Humphries SE. et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis 2000; 148: 209-214.
    CrossrefPubMedGoogle Scholar
  • 7 Wang Z, Castresana MR, Newman WH. Reactive oxygen and NF-kappaB in VEGF-induced migration of human vascular smooth muscle cells. Biochem Biophys Res Commun 2001; 285: 669-674.
    CrossrefPubMedGoogle Scholar
  • 8 Luchtefeld M, Drexler H, Schieffer B. 5-Lipoxygenase is involved in the angiotensin II-induced NAD(P)H-oxidase activation. Biochem Biophys Res Commun 2003; 308: 668-672.
    CrossrefPubMedGoogle Scholar
  • 9 Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 1997; 15: 797-819.
    CrossrefPubMedGoogle Scholar
  • 10 Taga T, Kishimoto T. Signalling mechanisms through cytokine receptors that share signal transducing receptor components. Curr Opin Immunol 1995; 07: 17-23.
    CrossrefPubMedGoogle Scholar
  • 11 Mullberg J, Oberthur W, Lottspeich F. et al. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J Immunol 1994; 152: 4958-4968.
    PubMedGoogle Scholar
  • 12 Matthews V, Schuster B, Schutze S. et al. Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem 2003; 278: 38829-38839.
    CrossrefPubMedGoogle Scholar
  • 13 Horiuchi S, Koyanagi Y, Zhou Y. et al. Soluble interleukin-6 receptors released from T cell or granulocyte/ macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism. Eur J Immunol 1994; 24: 1945-1948.
    CrossrefPubMedGoogle Scholar
  • 14 Jones SA, Richards PJ, Scheller J. et al. IL-6 transsignalling: the in vivo consequences. J Interferon Cytokine Res 2005; 25: 241-253.
    CrossrefPubMedGoogle Scholar
  • 15 Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol 1998; 16: 249-284.
    CrossrefPubMedGoogle Scholar
  • 16 Hirano T, Nakajima K, Hibi M. Signalling mechanisms through gp130: a model of the cytokine system. Cytokine Growth Factor Rev 1997; 08: 241-252.
    CrossrefPubMedGoogle Scholar
  • 17 Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 2007; 07: 454-465.
    CrossrefPubMedGoogle Scholar
  • 18 Takahashi-Tezuka M, Hibi M, Fujitani Y. et al. Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK. Oncogene 1997; 14: 2273-2282.
    CrossrefPubMedGoogle Scholar
  • 19 Ito H. Anti-interleukin-6 therapy for Crohn’s disease. Curr Pharm Des 2003; 09: 295-305.
    CrossrefPubMedGoogle Scholar
  • 20 Dendorfer U, Oettgen P, Libermann TA. Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol Cell Biol 1994; 14: 4443-4454.
    CrossrefPubMedGoogle Scholar
  • 21 Sehgal PB. Regulation of IL6 gene expression. Res Immunol 1992; 143: 724-734.
    CrossrefPubMedGoogle Scholar
  • 22 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: 1185-1195.
    CrossrefPubMedGoogle Scholar
  • 23 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 06: 772-783.
    CrossrefPubMedGoogle Scholar
  • 24 Ogawa W, Kasuga M. Cell signalling. Fat stress and liver resistance. Science 2008; 322: 1483-1484.
    CrossrefPubMedGoogle Scholar
  • 25 Sabio G, Das M, Mora A. et al. A stress signalling pathway in adipose tissue regulates hepatic insulin resistance. Science 2008; 322: 1539-1543.
    CrossrefPubMedGoogle Scholar
  • 26 Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008; 88: 1379-1406.
    CrossrefPubMedGoogle Scholar
  • 27 Mathur N, Pedersen BK. Exercise as a mean to control low-grade systemic inflammation. Mediators Inflamm 2008; 2008: 109502.
    PubMedGoogle Scholar
  • 28 Miyaura C, Onozaki K, Akiyama Y. et al. Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1). FEBS Lett 1988; 234: 17-21.
    CrossrefPubMedGoogle Scholar
  • 29 Ishibashi T, Kimura H, Uchida T. et al. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA 1989; 86: 5953-5957.
    CrossrefPubMedGoogle Scholar
  • 30 Satoh T, Nakamura S, Taga T. et al. Induction of neuronal differentiation in PC12 cells by B-cell stimulatory factor 2/interleukin 6. Mol Cell Biol 1988; 08: 3546-3549.
    CrossrefPubMedGoogle Scholar
  • 31 Ishimi Y, Miyaura C, Jin CH. et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 1990; 145: 3297-3303.
    CrossrefPubMedGoogle Scholar
  • 32 Jilka RL, Hangoc G, Girasole G. et al. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 1992; 257: 88-91.
    CrossrefPubMedGoogle Scholar
  • 33 Van Damme J, Opdenakker G, Simpson RJ. et al. Identification of the human 26-kD protein, interferon beta 2 (IFN-beta 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med 1987; 165: 914-919.
    CrossrefPubMedGoogle Scholar
  • 34 Kawano M, Hirano T, Matsuda T. et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988; 332: 83-85.
    CrossrefPubMedGoogle Scholar
  • 35 Yoshizaki K, Nishimoto N, Matsumoto K. et al. Interleukin 6 and expression of its receptor on epidermal keratinocytes. Cytokine 1990; 02: 381-387.
    CrossrefPubMedGoogle Scholar
  • 36 Turksen K, Kupper T, Degenstein L. et al. Interleukin 6: insights to its function in skin by overexpression in transgenic mice. Proc Natl Acad Sci USA 1992; 89: 5068-5072.
    CrossrefPubMedGoogle Scholar
  • 37 Horii Y, Muraguchi A, Iwano M. et al. Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol 1989; 143: 3949-3955.
    PubMedGoogle Scholar
  • 38 Miki S, Iwano M, Miki Y. et al. Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett 1989; 250: 607-610.
    CrossrefPubMedGoogle Scholar
  • 39 Miles SA, Rezai AR, Salazar-Gonzalez JF. et al. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci USA 1990; 87: 4068-4072.
    CrossrefPubMedGoogle Scholar
  • 40 Ikebuchi K, Wong GG, Clark SC. et al. Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci USA 1987; 84: 9035-9039.
    CrossrefPubMedGoogle Scholar
  • 41 Koike K, Nakahata T, Takagi M. et al. Synergism of BSF-2/interleukin 6 and interleukin 3 on development of multipotential hemopoietic progenitors in serumfree culture. J Exp Med 1988; 168: 879-890.
    CrossrefPubMedGoogle Scholar
  • 42 Badache A, Hynes NE. Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res 2001; 61: 383-391.
    PubMedGoogle Scholar
  • 43 Hoffman-Liebermann B, Liebermann DA. Interleukin-6– and leukemia inhibitory factor-induced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constitutive c-myc. Mol Cell Biol 1991; 11: 2375-2381.
    CrossrefPubMedGoogle Scholar
  • 44 Gauldie J, Richards C, Harnish D. et al. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA 1987; 84: 7251-7255.
    CrossrefPubMedGoogle Scholar
  • 45 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; 06: 315-325.
    CrossrefPubMedGoogle Scholar
  • 46 Wisithphrom K, Murray PE, Windsor LJ. Interleukin-1 alpha alters the expression of matrix metalloproteinases and collagen degradation by pulp fibroblasts. J Endod 2006; 32: 186-192.
    CrossrefPubMedGoogle Scholar
  • 47 Dasu MR, Barrow RE, Spies M. et al. Matrix metalloproteinase expression in cytokine stimulated human dermal fibroblasts. Burns 2003; 29: 527-531.
    CrossrefPubMedGoogle Scholar
  • 48 Hurst SM, Wilkinson TS, McLoughlin RM. et al. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 2001; 14: 705-714.
    CrossrefPubMedGoogle Scholar
  • 49 Fujihashi K, Kono Y, Kiyono H. Effects of IL6 on B cells in mucosal immune response and inflammation. Res Immunol 1992; 143: 744-749.
    CrossrefPubMedGoogle Scholar
  • 50 Rochman I, Paul WE, Ben-Sasson SZ. IL-6 increases primed cell expansion and survival. J Immunol 2005; 174: 4761-4767.
    CrossrefPubMedGoogle Scholar
  • 51 Sepulveda H, Cerwenka A, Morgan T. et al. CD28, IL-2-independent costimulatory pathways for CD8 T lymphocyte activation. J Immunol 1999; 163: 1133-1142.
    PubMedGoogle Scholar
  • 52 McLoughlin RM, Jenkins BJ, Grail D. et al. IL-6 trans-signalling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci USA 2005; 102: 9589-9594.
    CrossrefPubMedGoogle Scholar
  • 53 Clark SC. Interleukin-6. Multiple activities in regulation of the hematopoietic and immune systems. Ann N Y Acad Sci 1989; 557: 438-443.
    PubMedGoogle Scholar
  • 54 Bettelli E, Carrier Y, Gao W. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235-238.
    CrossrefPubMedGoogle Scholar
  • 55 Fan Y, Ye J, Shen F. et al. Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro. J Cereb Blood Flow Metab 2008; 28: 90-98.
    CrossrefPubMedGoogle Scholar
  • 56 Wang Z, Castresana MR, Newman WH. NF-kappaB is required for TNF-alpha-directed smooth muscle cell migration. FEBS Lett 2001; 508: 360-364.
    CrossrefPubMedGoogle Scholar
  • 57 Wang D, Liu Z, Li Q. et al. An essential role for gp130 in neointima formation following arterial injury. Circ Res 2007; 100: 807-816.
    CrossrefPubMedGoogle Scholar
  • 58 Ikeda U, Ikeda M, Oohara T. et al. Interleukin 6 stimulates growth of vascular smooth muscle cells in a PDGF-dependent manner. Am J Physiol 1991; 260: H1713-1717.
    PubMedGoogle Scholar
  • 59 Nabata T, Morimoto S, Koh E. et al. Interleukin-6 stimulates c-myc expression and proliferation of cultured vascular smooth muscle cells. Biochem Int 1990; 20: 445-453.
    PubMedGoogle Scholar
  • 60 Klouche M, Rose-John S, Schmiedt W. et al. Enzymatically degraded, nonoxidized LDL induces human vascular smooth muscle cell activation, foam cell transformation, and proliferation. Circulation 2000; 101: 1799-1805.
    CrossrefPubMedGoogle Scholar
  • 61 Goldblatt H. Experimental renal hypertension; mechanism of production and maintenance. Circulation 1958; 17: 642-647.
    CrossrefPubMedGoogle Scholar
  • 62 Harris PJ, Navar LG. Tubular transport responses to angiotensin. Am J Physiol 1985; 248: F621-630.
    PubMedGoogle Scholar
  • 63 Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002; 89: 3A-9A discussion 10A.
    PubMedGoogle Scholar
  • 64 Lerman LO, Nath KA, Rodriguez-Porcel M. et al. Increased oxidative stress in experimental renovascular hypertension. Hypertension 2001; 37: 541-546.
    CrossrefPubMedGoogle Scholar
  • 65 Higashi Y, Sasaki S, Nakagawa K. et al. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 2002; 346: 1954-1962.
    CrossrefPubMedGoogle Scholar
  • 66 de Champlain J, Wu R, Girouard H. et al. Oxidative stress in hypertension. Clin Exp Hypertens 2004; 26: 593-601.
    CrossrefPubMedGoogle Scholar
  • 67 Hernandez-Presa M, Bustos C, Ortego M. et al. Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 1997; 95: 1532-1541.
    CrossrefPubMedGoogle Scholar
  • 68 Kranzhofer R, Schmidt J, Pfeiffer CA. et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999; 19: 1623-1629.
    CrossrefPubMedGoogle Scholar
  • 69 Schieffer B, Luchtefeld M, Braun S. et al. Role of NAD(P)H oxidase in angiotensin II-induced JAK/ STAT signalling and cytokine induction. Circ Res 2000; 87: 1195-1201.
    CrossrefPubMedGoogle Scholar
  • 70 Naftilan AJ, Pratt RE, Dzau VJ. Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1419-1424.
    CrossrefPubMedGoogle Scholar
  • 71 Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest 1992; 90: 456-461.
    CrossrefPubMedGoogle Scholar
  • 72 Itoh H, Mukoyama M, Pratt RE. et al. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest 1993; 91: 2268-2274.
    CrossrefPubMedGoogle Scholar
  • 73 Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995; 96: 2515-2520.
    CrossrefPubMedGoogle Scholar
  • 74 Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995; 95: 995-1001.
    CrossrefPubMedGoogle Scholar
  • 75 Luchtefeld M, Grote K, Grothusen C. et al. Angiotensin II induces MMP-2 in a p47phox-dependent manner. Biochem Biophys Res Commun 2005; 328: 183-188.
    CrossrefPubMedGoogle Scholar
  • 76 Guo RW, Yang LX, Wang H. et al. Angiotensin II induces matrix metalloproteinase-9 expression via a nuclear factor-kappaB-dependent pathway in vascular smooth muscle cells. Regul Pept 2008; 147: 37-44.
    CrossrefPubMedGoogle Scholar
  • 77 Sano M, Fukuda K, Sato T. et al. ERK and p38 MAPK, but not NF-kappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. Circ Res 2001; 89: 661-669.
    CrossrefPubMedGoogle Scholar
  • 78 Wassmann S, Stumpf M, Strehlow K. et al. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res 2004; 94: 534-541.
    CrossrefPubMedGoogle Scholar
  • 79 Schrader LI, Kinzenbaw DA, Johnson AW. et al. IL-6 deficiency protects against angiotensin II induced endothelial dysfunction and hypertrophy. Arterioscler Thromb Vasc Biol 2007; 27: 2576-2581.
    CrossrefPubMedGoogle Scholar
  • 80 Coles B, Fielding CA, Rose-John S. et al. Classic interleukin-6 receptor signalling and interleukin-6 trans-signalling differentially control angiotensin IIdependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy in vivo. Am J Pathol 2007; 171: 315-325.
    CrossrefPubMedGoogle Scholar
  • 81 Trautwein C, Boker K, Manns MP. Hepatocyte and immune system: acute phase reaction as a contribution to early defence mechanisms. Gut 1994; 35: 1163-1166.
    CrossrefPubMedGoogle Scholar
  • 82 Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265: 621-636.
    CrossrefPubMedGoogle Scholar
  • 83 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.
    CrossrefPubMedGoogle Scholar
  • 84 Le JM, Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 1989; 61: 588-602.
    PubMedGoogle Scholar
  • 85 Gruys E, Toussaint MJ, Niewold TA. et al. Acute phase reaction and acute phase proteins. J Zhejiang Univ Sci B 2005; 06: 1045-1056.
    PubMedGoogle Scholar
  • 86 Ridker PM, Hennekens CH, Buring JE. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-843.
    CrossrefPubMedGoogle Scholar
  • 87 Paoletti R, Gotto Jr. AM, Hajjar DP. Inflammation in atherosclerosis and implications for therapy. Circulation 2004; 109 (23 Suppl 1): III20-26.
    CrossrefPubMedGoogle Scholar
  • 88 Uhlar CM, Whitehead AS. Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 1999; 265: 501-523.
    CrossrefPubMedGoogle Scholar
  • 89 Wool GD, Reardon CA. The influence of acute phase proteins on murine atherosclerosis. Curr Drug Targets 2007; 08: 1203-1214.
    CrossrefPubMedGoogle Scholar
  • 90 Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000; 102: 2165-2168.
    CrossrefPubMedGoogle Scholar
  • 91 Venugopal SK, Devaraj S, Yuhanna I. et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 2002; 106: 1439-1441.
    CrossrefPubMedGoogle Scholar
  • 92 Luchtefeld M, Schunkert H, Stoll M. et al. Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man. J Exp Med 2007; 204: 1935-1944.
    CrossrefPubMedGoogle Scholar
  • 93 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
    CrossrefPubMedGoogle Scholar
  • 94 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-126.
    CrossrefPubMedGoogle Scholar
  • 95 Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 2008; 08: 802-815.
    CrossrefPubMedGoogle Scholar
  • 96 Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-1143.
    CrossrefPubMedGoogle Scholar
  • 97 Zhou X, Hansson GK. Detection of B cells and proinflammatory cytokines in atherosclerotic plaques of hypercholesterolaemic apolipoprotein E knockout mice. Scand J Immunol 1999; 50: 25-30.
    CrossrefPubMedGoogle Scholar
  • 98 Sukovich DA, Kauser K, Shirley FD. et al. Expression of interleukin-6 in atherosclerotic lesions of male ApoE-knockout mice: inhibition by 17beta-estradiol. Arterioscler Thromb Vasc Biol 1998; 18: 1498-1505.
    CrossrefPubMedGoogle Scholar
  • 99 Recinos 3rd A, LeJeune WS, Sun H. et al. Angiotensin II induces IL-6 expression and the Jak-STAT3 pathway in aortic adventitia of LDL receptor-deficient mice. Atherosclerosis 2007; 194: 125-133.
    CrossrefPubMedGoogle Scholar
  • 100 Keidar S, Heinrich R, Kaplan M. et al. Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6. Arterioscler Thromb Vasc Biol 2001; 21: 1464-1469.
    CrossrefPubMedGoogle Scholar
  • 101 Takeda N, Manabe I, Shindo T. et al. Synthetic retinoid Am80 reduces scavenger receptor expression and atherosclerosis in mice by inhibiting IL-6. Arterioscler Thromb Vasc Biol 2006; 26: 1177-1183.
    CrossrefPubMedGoogle Scholar
  • 102 Grote K, Luchtefeld M, Schieffer B. JANUS under stress--role of JAK/STAT signalling pathway in vascular diseases. Vascul Pharmacol 2005; 43: 357-363.
    CrossrefPubMedGoogle Scholar
  • 103 Huber SA, Sakkinen P, Conze D. et al. Interleukin-6 exacerbates early atherosclerosis in mice. Arteriosclerosis Thromb Vasc Biol 1999; 19: 2364-2367.
    CrossrefPubMedGoogle Scholar
  • 104 Schieffer B, Selle T, Hilfiker A. et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation 2004; 110: 3493-3500.
    CrossrefPubMedGoogle Scholar
  • 105 Elhage R, Clamens S, Besnard S. et al. Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak formation by 17beta-estradiol in apolipoprotein E-deficient mice. Atherosclerosis 2001; 156: 315-320.
    CrossrefPubMedGoogle Scholar
  • 106 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.
    CrossrefPubMedGoogle Scholar
  • 107 Wallenius V, Wallenius K, Ahren B. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002; 08: 75-79.
    CrossrefPubMedGoogle Scholar
  • 108 Spranger J, Kroke A, Mohlig M. et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52: 812-817.
    CrossrefPubMedGoogle Scholar
  • 109 Vozarova B, Weyer C, Hanson K. et al. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res 2001; 09: 414-417.
    CrossrefPubMedGoogle Scholar
  • 110 Al-Khalili L, Bouzakri K, Glund S. et al. Signalling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. Mol Endocrinol 2006; 20: 3364-3375.
    CrossrefPubMedGoogle Scholar
  • 111 Nishimoto N, Kanakura Y, Aozasa K. et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005; 106: 2627-2632.
    CrossrefPubMedGoogle Scholar
  • 112 Nishimoto N, Yoshizaki K, Miyasaka N. et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, doubleblind, placebo-controlled trial. Arthritis Rheum 2004; 50: 1761-1769.
    CrossrefPubMedGoogle Scholar
  • 113 Genovese MC, McKay JD, Nasonov EL. et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008; 58: 2968-2980.
    CrossrefPubMedGoogle Scholar
  • 114 Tsigos C, Papanicolaou DA, Kyrou I. et al. Dosedependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab 1997; 82: 4167-4170.
    CrossrefPubMedGoogle Scholar
  • 115 Kallen KJ. The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochim Biophys Acta 2002; 1592: 323-343.
    PubMedGoogle Scholar
  • 116 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-1772.
    CrossrefPubMedGoogle Scholar
  • 117 Lindmark E, Diderholm E, Wallentin L. et al. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. J Am Med Assoc 2001; 286: 2107-2113.
    CrossrefPubMedGoogle Scholar
  • 118 Gibson CM, Karmpaliotis D, Kosmidou I. et al. Comparison of effects of bare metal versus drug-eluting stent implantation on biomarker levels following percutaneous coronary intervention for non-ST-elevation acute coronary syndrome. Am J Cardiol 2006; 97: 1473-1477.
    CrossrefPubMedGoogle Scholar
  • 119 Hedman A, Larsson PT, Alam M. et al. CRP, IL-6 and endothelin-1 levels in patients undergoing coronary artery bypass grafting. Do preoperative inflammatory parameters predict early graft occlusion and late cardiovascular events?. Int J Cardiol 2007; 120: 108-114.
    CrossrefPubMedGoogle Scholar
  • 120 Sattar N, Murray HM, Welsh P. et al. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?. PLoS Med 2009; 06: e1000099.
    CrossrefPubMedGoogle Scholar
  • 121 Stork S, Feelders RA, van den Beld AW. et al. Prediction of mortality risk in the elderly. Am J Med 2006; 119: 519-525.
    CrossrefPubMedGoogle Scholar
  • 122 Pradhan AD, Manson JE, Rossouw JE. et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. J Am Med Assoc 2002; 288: 980-987.
    CrossrefPubMedGoogle Scholar
  • 123 Ascer E, Bertolami MC, Venturinelli ML. et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis 2004; 177: 161-166.
    CrossrefPubMedGoogle Scholar
  • 124 Schieffer B, Bunte C, Witte J. et al. Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease. J Am Coll Cardiol 2004; 44: 362-368.
    CrossrefPubMedGoogle Scholar
  • 125 Trevelyan J, Brull DJ, Needham EW. et al. Effect of enalapril and losartan on cytokines in patients with stable angina pectoris awaiting coronary artery bypass grafting and their interaction with polymorphisms in the interleukin-6 gene. Am J Cardiol 2004; 94: 564-569.
    CrossrefPubMedGoogle Scholar
  • 126 Maini RN, Taylor PC, Szechinski J. et al. Doubleblind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006; 54: 2817-2829.
    CrossrefPubMedGoogle Scholar
  • 127 Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation 1999; 100: 2124-2126.
    CrossrefPubMedGoogle Scholar