Roles of IL-6-gp130 Signaling in Vascular Inflammation

Tieying Hou, Brian C Tieu, Sutapa Ray, Adrian Recinos Iii, Ruwen Cui, Ronald G Tilton, Allan R Brasier, Tieying Hou, Brian C Tieu, Sutapa Ray, Adrian Recinos Iii, Ruwen Cui, Ronald G Tilton, Allan R Brasier

Abstract

Interleukin-6 (IL-6) is a well-established, independent indicator of multiple distinct types of cardiovascular disease and all-cause mortality. In this review, we present current understanding of the multiple roles that IL-6 and its signaling pathways through glycoprotein 130 (gp130) play in cardiovascular homeostasis. IL-6 is highly inducible in vascular tissues through the actions of the angiotensin II (Ang II) peptide, where it acts in a paracrine manner to signal through two distinct mechanisms, the first being a classic membrane receptor initiated pathway and the second, a trans-signaling pathway, being able to induce responses even in tissues lacking the IL-6 receptor. Recent advances and new concepts in how its intracellular signaling pathways operate via the Janus kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) are described. IL-6 has diverse actions in multiple cell types of cardiovascular importance, including endothelial cells, monocytes, platelets, hepatocytes and adipocytes. We discuss central roles of IL-6 in endothelial dysfunction, cellular inflammation by affecting monocyte activation/differentiation, cellular cytoprotective functions from reactive oxygen species (ROS) stress, modulation of pro-coagulant state, myocardial growth control, and its implications in metabolic control and insulin resistance. These multiple actions indicate that IL-6 is not merely a passive biomarker, but actively modulates adaptive and pathological responses to cardiovascular stress.

Summary: IL-6 is a multifunctional cytokine whose presence in the circulation is linked with diverse types of cardiovascular disease and is an independent risk factor for atherosclerosis. In this review, we examine the mechanisms by which IL-6 signals and its myriad effects in cardiovascular tissues that modulate the manifestations of vascular inflammation.

Keywords: IL-6/ gp-130/ angiotensin II/ STAT3/ vascular inflammation..

Figures

Fig. (1).
Fig. (1).
IL-6 induced classical and trans-signaling pathways. Shown is a schematic view of classical IL-6 signaling via the IL-6Rα receptor and gp130 for a representative hepatocyte. IL-6Rα bound to the IL-6 ligand results in complex formation with gp130, activating tyrosine kinase activity, including and culminating in tyrosine phosphorylation of STAT3. The IL-6 trans-signaling pathway is diagrammed at top, using a representative endothelial cell. Circulating IL-6∙IL-6Rα engages with gp130 expressed on cells, enabling activation of the IL-6 signaling pathway in cells lacking IL-6Rα. See text for further details.
Fig. (2).
Fig. (2).
Discrete mechanisms for IL-6 induction of target genes. Top, coactivator recruitment mechanism. Tyrosine phosphorylated STAT3 binds to p300/CBP, resulting in STAT3 acetylation (Ac) on its NH2 terminus, and stabilization of the STAT3-p300/CBP complex. The acetylated-phosphorylated STAT3-p300/CBP complex then binds to high affinity IL-6 response elements in the promoters of target genes. This complex induces nucleosomal reorganization via the p300 histone acetylase activity, pre-initiation complex formation, recruiting TATA box binding protein, and enhanced RNA polymerase II activity. Bottom, transcriptional elongation. In a subset of IL-6 responsive promoters, RNA polymerase (Pol) II is engaged with the promoter producing incomplete transcripts. During the process of activation, tyrosine phosphorylated STAT3 complexes with the positive transcriptional elongation factor (PTEF-b), a complex containing CDK9. CDK9 phosphorylates the COOH terminal domain of RNA polymerase II, enabling it to enter productive elongation mode, producing full length RNA transcripts.
Fig. (3).
Fig. (3).
Negative regulation of the JAK-STAT pathway. Shown are the major negative autoregulatory pathways of IL-6 induced STAT3 signaling. IL-6 activated STAT3 both engages the suppressor of cytokine signaling (SOCS3) gene, inducing its expression and recruits SOC3 to gp130 where it subsequently terminates STAT3 activation via JAK1 inactivation. SHP2 phosphatase activity also inactivates gp130 and JAKs.

References

    1. Brasier AR, Recinos A III, Eledrisi MS. Vascular inflammation and the renin-angiotensin system. Arterioscler Thromb Vasc Biol. 2002;22(8):1257–66.
    1. Recinos III 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(1):125–33.
    1. Han Y, Runge MS, Brasier AR. Angiotensin II induces interleukin-6 transcription in vascular smooth muscle cells through pleiotropic activation of nuclear factor-kappa B transcription factors. Circ Res. 1999;84(6):695–703.
    1. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction Among Apparently Healthy Men. Circulation. 2000;101(15):1767–72.
    1. Biasucci LM, Liuzzo G, Fantuzzi G, et al. Increasing Levels of Interleukin (IL)-1Ra and IL-6 During the First 2 Days of Hospitalization in Unstable Angina Are Associated With Increased Risk of In-Hospital Coronary Events. Circulation. 1999;99(16):2079–84.
    1. Chae CU, Lee RT, Rifai N, Ridker PM. Blood Pressure and Inflammation in Apparently Healthy Men. Hypertension. 2001;38(3):399–403.
    1. Tsutamoto T, Hisanaga T, Wada A, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol. 1998;31(2):391–8.
    1. Roig E, Orus J, Pare C, et al. Serum Interleukin-6 in congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol. 1998;82(5):688–+.
    1. Blake GJ, Ridker PM. Inflammatory bio-markers and cardiovascular risk prediction. J Intern Med. 2002;252(4):283–94.
    1. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab. 1997;82(5):1313–6.
    1. Fernandez-Real JM, Vayreda M, Richart C, et al. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab. 2001;86(3):1154–9.
    1. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus. JAMA. 2001;286(3):327–34.
    1. Cui R, Tieu B, Recinos A, Tilton RG, Brasier AR. RhoA mediates angiotensin II-induced phospho-Ser536 nuclear factor kappaB/RelA subunit exchange on the interleukin-6 promoter in VSMCs. Circ Res. 2006;99(7):723–30.
    1. Akira S, Kishimoto T. IL-6 and NF-IL6 in acute-phase response and viral infection. Immunol Rev. 1992;127:25–50.
    1. Brasier AR. The NF-kB regulatory network. Cardiovasc Toxicol. 2006;6:111–30.
    1. Choudhary S, Lu M, Cui R, Brasier AR. Involvement of a novel Rac/RhoA guanosine triphosphatase-nuclear factor-{kappa}B inducing kinase signaling pathway mediating angiotensin II-Induced RelA transactivation. Mol Endocrinol. 2007;21(9):2203–17.
    1. McAllister-Lucas LM, Ruland J, Siu K, et al. CARMA3/Bcl10/ MALT1-dependent NF-{kappa}B activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells. Proc Natl Acad Sci USA. 2007;104(1):139–44.
    1. Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques: potential implications for inflammation and plaque instability. Circulation. 2000;101(12):1372–8.
    1. Ernst M, Jenkins BJ. Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet. 2004;20(1):23–32.
    1. Murakami M, Kamimura D, Hirano T. New IL-6 (gp130) family cytokine members, CLC/NNT1/BSF3 and IL-27. Growth Factors. 2004;22(2):75–7.
    1. Kurdi M, Booz GW. Can the protective actions of JAK-STAT in the heart be exploited therapeutically? Parsing the regulation of lnterleukin-6-type cytokine signaling. J Cardiovasc Pharmacol. 2007;50(2):126–41.
    1. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621–36.
    1. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. [Review] [44 refs] Atherosclerosis. 2000;148(2):209–14.
    1. Hojo Y, Ikeda U, Takahashi M, Shimada K. Increased levels of monocyte-related cytokines in patients with unstable angina. Atherosclerosis. 2002;161(2):403–8.
    1. Marrone D, Pertosa G, Simone S, et al. Local activation of interleukin 6 signaling is associated with arteriovenous fistula stenosis in hemodialysis patients. Am J Kidney Dis. 2007;49(5):664–73.
    1. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J. 2001;15(1):43–58.
    1. Boulanger MJ. Hexameric Structure and Assembly of the Interleukin-6/IL-6 [alpha]-Receptor/gp130 Complex.[Report] Science. 2003;300(5628):2101–4.
    1. 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.
    1. Vardam TD, Zhou L, Appenheimer MM, et al. Regulation of a lymphocyte-endothelial-IL-6 trans-signaling axis by fever-range thermal stress: hot spot of immune surveillance. [Review] [151 refs] Cytokine. 2007;39(1):84–96.
    1. Nakaoka Y, Nishida K, Fujio Y, et al. Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ Res. 2003;93(3):221–9.
    1. Scheller J, Rose-John S. Updating interleukin-6 classic- and transsignaling. Signal Transduct. 2006;6:240–59.
    1. Sun W, Snyder M, Levy DE, Zhang JJ. Regulation of Stat3 transcriptional activity by the conserved LPMSP motif for OSM and IL-6 signaling. FEBS Lett. 2006;580(25):5880–4.
    1. Bhattacharya S, Eckner R, Grossman S, et al. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-α. Nature. 1996;383:344–7.
    1. Pfitzner E, Jahne R, Wissler M, Stoecklin E, Groner B. p300/CREB-binding protein enhances the prolactin-mediated transriptional induction through direct interaction with the transactivation domain of STAT5, but does not participate in the Stat5-mediated suppression of the glucorticoid response. Mol Endocrinol. 1998;12(10):1582–93.
    1. Ray S, Sherman CT, Lu M, Brasier AR. Angiotensinogen gene expression is dependent on signal transducer and activator of transcription 3-mediated p300/cAMP response element binding protein-binding protein coactivator recruitment and histone acetyl-transferase activity. Mol Endocrinol. 2002;16:824–36.
    1. Yuan ZL, Guan YJ, Chatterjee D, Chin YE. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science. 2005;307(5707):269–73.
    1. Ray S, Boldogh I, Brasier AR. STAT3 NH2-terminal acetylation is activated by the hepatic acute-phase response and required for IL-6 induction of angiotensinogen. Gastroenterology. 2005;129:1616–32.
    1. Hou T, Ray S, Brasier AR. The functional role of an interleukin 6-inducible CDK9.STAT3 complex in human gamma-fibrinogen gene expression. J Biol Chem. 2007;282(51):37091–102.
    1. Giraud S, Hurlstone A, Avril S, Coqueret O. Implication of BRG1 and cdk9 in the STAT3-mediated activation of the p21waf1 gene. Oncogene. 2004;23(44):7391–8.
    1. Lust JA, Donovan KA, Kline MP, et al. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine. 1992;4(2):96–100.
    1. Chalaris A, Rabe B, Paliga K, et al. Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory transsignaling function of neutrophils. Blood. 2007;110(6):1748–55.
    1. Coles B, Fielding CA, Rose-John S, et al. Classic interleukin-6 receptor signaling and interleukin-6 trans-signaling differentially control angiotensin II-dependent hypertension, cardiac signal transducer and activator of transcription-3 activation, and vascular hypertrophy In vivo. Am J Pathol. 2007;171(1):315–25.
    1. Rabe B, Chalaris A, May U, et al. Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood. 2008;111(3):1021–8.
    1. Kile BT, Alexander WS. The suppressors of cytokine signalling (SOCS) Cell Mol Life Sci. 2001;58(11):1627–35.
    1. Krebs DL, Hilton DJ. SOCS proteins: Negative regulators of cytokine signaling. Stem Cells. 2001;19(5):378–87.
    1. Lehmann U, Schmitz J, Weissenbach M, et al. SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130. J Biol Chem. 2003;278(1):661–71.
    1. Mueller CF, Laude K, McNally JS, Harrison DG. ATVB in focus: redox mechanisms in blood vessels. Arterioscler Thromb Vasc Biol. 2005;25:274–8.
    1. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia Increases Endothelial Superoxide Anion Production. J Clin Invest. 1993;91(6):2546–51.
    1. Rajagopalan S, Kurz S, Munzel T, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation - Contribution to alterations of vasomotor tone. J Clin Invest. 1996;97(8):1916–23.
    1. Kawasaki H, Abe K, Kanno M, Hattori Y. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol. 1991;261:1086–94.
    1. van der Loo B, Labugger R, Skepper JN, et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000;192:1731–44.
    1. Laurindo FRM, de Souza HP, Pedro MD, Janiszewski M. Redox aspects of vascular response to injury. Redox Cell Biol Genet, Part A. 2002;352:432–54.
    1. Touyz RM. Reactive oxygen species and angiotensin II signaling in vascular cells -- implications in cardiovascular disease. Related Articles, Links Touyz RM. Braz J Med Biol Res. 2004;37:1263–73.
    1. Swindle EJ, Metcalfe DD. The role of reactive oxygen species and nitric oxide in mast cell-dependent inflammatory processes. Immunol Rev. 2007;217:186–205.
    1. Faraci FM. Oxidative stress: the curse that underlies cerebral vascular dysfunction? Stroke. 2005;36:186–8.
    1. Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25:29–38.
    1. Griendling KK, Harrison DG. Dual role of reactive oxygen species in vascular growth. Circ Res. 1999;85(6):562–3.
    1. Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. [Review] [132 refs] Arterioscler Thromb Vasc Biol. 2000;20(10):2175–83.
    1. Harrison D, Griendling KK, Landmesser U, Hornig B, Drexler H. Role of oxidative stress in atherosclerosis. Am J Cardiol. 2003;91(3):7A–11A.
    1. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest. 1997;100(9):2153–7.
    1. 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(4):534–41.
    1. Schrader LI, Kinzenbaw DA, Johnson AW, Faraci FM, Didion SP. IL-6 deficiency protects against angiotensin II - Induced endothelial dysfunction and hypertrophy. Arterioscler Thromb Vasc Biol. 2007;27(12):2576–81.
    1. Didion SP, Kinzenbaw DA, Faraci FM. Critical role for CuZn-superoxide dismutase in preventing angiotensin II-induced endothelial dysfunction. Hypertension. 2005;46:1147–53.
    1. Sironi M, Breviario F, Proserpio P, et al. IL-1 stimulates IL-6 production in endothelial cells. J Immunol. 1989;142(2):549–53.
    1. Verhamme P, Hoylaerts MF. The pivotal role of the endothelium in haemostasis and thrombosis. Acta Clin Belg. 2006;61(5):213–9.
    1. Gross PL, Aird WC. The endothelium and thrombosis. Semin Thromb Hemost. 2000;26(5):463–78.
    1. Bierhaus A, Chen J, Liliensiek B, Nawroth PP. LPS and cytokine-activated endothelium. Semin Thromb Hemost. 2000;26(5):571–87.
    1. Modat G, Dornand J, Bernad N, et al. LPS-stimulated bovine aortic endothelial cells produce IL-1 and IL-6 like activities. Agents Actions. 1990;30(3-4):403–11.
    1. Pober JS. Effects of tumour necrosis factor and related cytokines on vascular endothelial cells. Ciba Found Symp. 1987;131:170–84.
    1. Howells G, Pham P, Taylor D, Foxwell B, Feldmann M. Interleukin 4 induces interleukin 6 production by endothelial cells: synergy with interferon-gamma. Eur J Immunol. 1991;21(1):97–101.
    1. Colotta F, Sironi M, Borre A, et al. Interleukin 4 amplifies monocyte chemotactic protein and interleukin 6 production by endothelial cells. Cytokine. 1992;4(1):24–8.
    1. 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(3):315–25.
    1. Shabo Y, Lotem J, Rubinstein M, et al. The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood. 1988;72(6):2070–3.
    1. Oritani K, Kaisho T, Nakajima K, Hirano T. Retinoic acid inhibits interleukin-6-induced macrophage differentiation and apoptosis in a murine hematopoietic cell line, Y6. Blood. 1992;80(9):2298–305.
    1. Matas D, Milyavsky M Shats I, et al. p53 is a regulator of macrophage differentiation. Cell Death Differ. 2004;11(4):458–67.
    1. Tanaka H, Matsumura I, Nakajima K, et al. GATA-1 blocks IL-6-induced macrophage differentiation and apoptosis through the sustained expression of cyclin D1 and bcl-2 in a murine myeloid cell line M1. Blood. 2000;95(4):1264–73.
    1. Krishnaraju K, Hoffman B, Liebermann DA. The zinc finger transcription factor Egr-1 activates macrophage differentiation in M1 myeloblastic leukemia cells. Blood. 1998;92(6):1957–66.
    1. Minami M, Inoue M, Wei S, et al. STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line. Proc Natl Acad Sci USA. 1996;93(9):3963–6.
    1. Yamanaka Y, Nakajima K, Fukada T, Hibi M, Hirano T. Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation. EMBO J. 1996;15(7):1557–65.
    1. 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(1):17–21.
    1. Chiu CP, Lee F. IL-6 is a differentiation factor for M1 and WEHI-3B myeloid leukemic cells. J Immunol. 1989;142(6):1909–15.
    1. Haviernik P, Lahoda C, Bradley HL, et al. Tissue inhibitor of matrix metalloproteinase-1 overexpression in M1 myeloblasts impairs IL-6-induced differentiation. Oncogene. 2004;23(57):9212–9.
    1. Chomarat P, Banchereau J, Davoust J, Palucka AK. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol. 2000;1(6):510–4.
    1. Keidar S, Heinrich R, Kaplan M, Hayek T, Aviram M. Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized ldl: a possible role for interleukin-6. Arterioscler Thromb Vasc Biol. 2001;21(9):1464–9.
    1. Oritani K, Tomiyama Y, Kincade PW, et al. Both Stat3-activation and Stat3-independent BCL2 downregulation are important for interleukin-6-induced apoptosis of 1A9-M cells. Blood. 1999;93(4):1346–54.
    1. Goralski KB, Sinal CJ. Type 2 diabetes and cardiovascular disease: getting to the fat of the matter. Can J Physiol Pharmacol. 2007;85(1):113–32.
    1. Biswas P, Delfanti F, Bernasconi S, et al. Interleukin-6 induces monocyte chemotactic protein-1 in peripheral blood mononuclear cells and in the U937 cell line. Blood. 1998;91(1):258–65.
    1. Mitani H, Katayama N, Araki H, et al. Activity of interleukin 6 in the differentiation of monocytes to macrophages and dendritic cells. Br J Haematol. 2000;109(2):288–95.
    1. Jansen JH, Kluin-Nelemans JC, Van Damme J, et al. Interleukin 6 is a permissive factor for monocytic colony formation by human hematopoietic progenitor cells. J Exp Med. 1992;175(4):1151–4.
    1. Nakajima K, Yamanaka Y, Nakae K, et al. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J. 1996;15(14):3651–8.
    1. Mangan JK, Rane SG, Kang AD, et al. Mechanisms associated with IL-6-induced up-regulation of Jak3 and its role in monocytic differentiation. Blood. 2004;103(11):4093–101.
    1. Yamaguchi Y, Zon LI, Ackerman SJ, Yamamoto M, Suda T. Forced GATA-1 expression in the murine myeloid cell line M1: induction of c-Mpl expression and megakaryocytic/erythroid differentiation. Blood. 1998;91(2):450–7.
    1. Nguyen HQ, Hoffman-Liebermann B, Liebermann DA. The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage. Cell. 1993;72(2):197–209.
    1. Lee SL, Wang Y, Milbrandt J. Unimpaired macrophage differentiation and activation in mice lacking the zinc finger transplantation factor NGFI-A (EGR1) Mol Cell Biol. 1996;16(8):4566–72.
    1. Dalrymple SA, Lucian LA, Slattery R, et al. Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia. Infect Immun. 1995;63(6):2262–8.
    1. Kopf M, Baumann H, Freer G, et al. Impaired immune and acutephase responses in interleukin-6-deficient mice. Nature. 1994;368(6469):339–42.
    1. Akira S, Kishimoto T. Role of interleukin-6 in macrophage function. Curr Opin Hematol. 1996;3(1):87–93.
    1. Bluethmann H, Rothe J, Schultze N, Tkachuk M, Koebel P. Establishment of the role of IL-6 and TNF receptor 1 using gene knockout mice. J Leukoc Biol. 1994 Nov;56(5):565–70.
    1. Tanaka T, Akira S, Yoshida K, et al. Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages. Cell. 1995;80(2):353–61.
    1. Bernad A, Kopf M, Kulbacki R, et al. Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hemaopoietic system. Immunity. 1994;1:725–31.
    1. Daugherty A, Manning MW, Cassis LA. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest. 2000;105(11):1605–12.
    1. Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev. 2007;21(2):99–111.
    1. 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(15):5953–7.
    1. Kimura H, Ishibashi T, Uchida T, et al. Interleukin 6 is a differentiation factor for human megakaryocytes in vitro. Eur J Immunol. 1990;20(9):1927–31.
    1. Bruno E, Cooper RJ, Briddell RA, Hoffman R. Further examination of the effects of recombinant cytokines on the proliferation of human megakaryocyte progenitor cells. Blood. 1991;77(11):2339–46.
    1. Asano S, Okano A, Ozawa K, et al. In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood. 1990;75(8):1602–5.
    1. Metcalf D, Nicola NA, Gearing DP. Effects of injected leukemia inhibitory factor on hematopoietic and other tissues in mice. Blood. 1990;76(1):50–6.
    1. Neben TY, Loebelenz J, Hayes L, et al. Recombinant human interleukin-11 stimulates megakaryocytopoiesis and increases peripheral platelets in normal and splenectomized mice. Blood. 1993;81(4):901–8.
    1. Wallace PM, MacMaster JF, Rillema JR, et al. Thrombocytopoietic properties of oncostatin M. Blood. 1995;86(4):1310–5.
    1. Hollen CW, Henthorn J, Koziol JA, Burstein SA. Elevated serum interleukin-6 levels in patients with reactive thrombocytosis. Br J Haematol. 1991;79(2):286–90.
    1. Peng J, Friese P, George JN, Dale GL, Burstein SA. Alteration of platelet function in dogs mediated by interleukin-6. Blood. 1994;83(2):398–403.
    1. Burstein SA, Peng J, Friese P, et al. Cytokine-induced alteration of platelet and hemostatic function. Stem Cells. 1996;14(Suppl 1):154–62.
    1. Oleksowicz L, Mrowiec Z, Zuckerman D, et al. Platelet activation induced by interleukin-6: evidence for a mechanism involving arachidonic acid metabolism. Thromb Haemost. 1994;72(2):302–8.
    1. Oleksowicz L, Puszkin E, Mrowiec Z, Isaacs R, Dutcher JP. Alterations in platelet function in patients receiving interleukin-6 as cytokine therapy. Cancer Invest. 1996;14(4):307–16.
    1. Hirota H, Yoshida K, Kishimoto T, Taga T. Continuous Activation of gp130, a Signal-Transducing Receptor Component for Interleukin 6-Related Cytokines, Causes Myocardial Hypertrophy in Mice. Proceedings of the National Academy of Sciences. 1995;92(11):4862–6.
    1. Hirota H, Chen J, Betz UAK, et al. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1998;97:189–98.
    1. Negoro S, Kunisada K, Tone E, et al. Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc Res. 2000;47(4):797–805.
    1. Cressman DE, Diamond RH, Taub R. Rapid Activation of the Stat3 Transcription Complex in Liver-Regeneration. Hepatology. 1995;21(5):1443–9.
    1. Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274(5291):1379–83.
    1. Kushner I. The acute phase response: an overview. Methods Enzymol. 1988;163:373–83.
    1. Haga S, Terui K, Zhang HQ, et al. Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms. J Clin Invest. 2003;112(7):989–98.
    1. Grosch S, Fritz G, Kaina B. Apurinic endonuclease (Ref-l) is induced in mammalian cells by oxidative stress and involved in clastogenic adaptation. Cancer Research. 1998;58(19):4410–6.
    1. Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Annu Rev Immunol. 1997;15:351–69.
    1. Kovalovich K, Li W, DeAngelis R, et al. Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J Biol Chem. 2001;276:26605–13.
    1. Williams JL. Cross talk between the inflammation and coagulation systems. Clin Lab Sci. 2007;20(4):224–9.
    1. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005;131(4):417–30.
    1. Levi M, van der PT. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med. 2005;15(7):254–9.
    1. Amrani DL. Regulation of fibrinogen biosynthesis: glucocorticoid and interleukin-6 control. Blood Coagul Fibrinolysis. 1990;1(4-5):443–6.
    1. Cermak J, Key NS, Bach RR, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993;82(2):513–20.
    1. Stirling D, Hannant WA, Ludlam CA. Transcriptional activation of the factor VIII gene in liver cell lines by interleukin-6. Thromb Haemost. 1998;79(1):74–8.
    1. Niessen RW, Lamping RJ, Jansen PM, et al. Antithrombin acts as a negative acute phase protein as established with studies on HepG2 cells and in baboons. Thromb Haemost. 1997;78(3):1088–92.
    1. Hooper WC, Phillips DJ, Evatt BL. Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor. Thromb Haemost. 1997;77(5):1014–9.
    1. Burstein SA. Cytokines, platelet production and hemostasis. Platelets. 1997;8(2-3):93–104.
    1. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993;118(12):956–63.
    1. Rooney MM, Parise LV, Lord ST. Dissecting clot retraction and platelet aggregation. Clot retraction does not require an intact fibrinogen gamma chain C terminus. J Biol Chem. 1996;271(15):8553–5.
    1. Hu CH, Harris JE, Davie EW, Chung DW. Characterization of the 5'-flanking region of the gene for the alpha chain of human fibrinogen. J Biol Chem. 1995;270(47):28342–9.
    1. Mizuguchi J, Hu CH, Cao Z, et al. Characterization of the 5'-flanking region of the gene for the gamma chain of human fibrinogen. J Biol Chem. 1995;270(47):28350–6.
    1. Anderson GM, Shaw AR, Shafer JA. Functional characterization of promoter elements involved in regulation of human B beta-fibrinogen expression. Evidence for binding of novel activator and repressor proteins. J Biol Chem. 1993;268(30):22650–5.
    1. Gervois P, Vu-Dac. N, Kleemann R, et al. Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta. J Biol Chem. 2001;276(36):33471–7.
    1. Dalmon J, Laurent M, Courtois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. Mol Cell Biol. 1993;13(2):1183–93.
    1. Hawiger J. Adhesive ends of fibrinogen and its antiadhesive peptides: the end of a sage? Semin Hematol. 1995;32(2):99–109.
    1. Ugarova TP, Lishko VK, Podolnikova NP, et al. Sequence gamma 377-395(P2), but not gamma 190-202(P1), is the binding site for the alpha MI-domain of integrin alpha M beta 2 in the gamma C-domain of fibrinogen. Biochemistry. 2003;42(31):9365–73.
    1. Sahni A, Altland OD, Francis CW. FGF-2 but not FGF-1 binds fibrin and supports prolonged endothelial cell growth. J Thromb Haemost. 2003;1(6):1304–10.
    1. Sahni A, Guo M, Sahni SK, Francis CW. Interleukin-1beta but not IL-1alpha binds to fibrinogen and fibrin and has enhanced activity in the bound form. Blood. 2004;104(2):409–14.
    1. Sahni A, Francis CW. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation. Blood. 2000;96(12):3772–8.
    1. Zhang Z, Fuentes NL, Fuller GM. Characterization of the IL-6 responsive elements in the gamma fibrinogen gene promoter. J Biol Chem. 1995;270(41):24287–91.
    1. Duan HO, Simpson-Haidaris PJ. Functional analysis of interleukin 6 response elements (IL-6REs) on the human gamma-fibrinogen promoter: binding of hepatic Stat3 correlates negatively with transactivation potential of type II IL-6REs. J Biol Chem. 2003;278(42):41270–81.
    1. Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA. 1977;74(12):5260–4.
    1. Chin BS, Blann AD, Gibbs CR, et al. Prognostic value of interleukin-6, plasma viscosity, fibrinogen, von Willebrand factor, tissue factor and vascular endothelial growth factor levels in congestive heart failure. Eur J Clin Invest. 2003;33(11):941–8.
    1. Neumann FJ, Ott I, Marx N, et al. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol. 1997;17(12):3399–405.
    1. Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol. 2004;43(11):2075–82.
    1. Dong J, Fuji S, Goto D, et al. Increased expression of plasminogen activator inhibitor-1 by mediators of the acute phase response: a potential progenitor of vasculopathy in hypertensives. Hypertension Research. 2003;26(9):723–9.
    1. Healy AM, Gelehrter TD. Induction of Plasminogen-Activator Inhibitor-1 in Hepg2 Human Hepatoma-Cells by Mediators of the Acute-Phase Response. J Biol Chem. 1994;269(29):19095–100.
    1. Dong J, Fujii S, Li HM, et al. Interleukin-6 and mevastatin regulate plasminogen activator inhibitor-1 through CCAAT/enhancer-binding protein-delta. Arterioscler Thromb Vasc Biol. 2005;25(5):1078–84.
    1. Dong J, Fujii S, Kaneko T, et al. IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBP delta. Circulation. 2006;114(18):116.
    1. Dahlback B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system. Thromb Haemost. 1991;66(1):49–61.
    1. Ritchie SA, Connell JM. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr Metab Cardiovasc Dis. 2007;17(4):319–26.
    1. Trayhurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans. 2005;33(Pt 5):1078–81.
    1. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol. 2005;115(5):911–9.
    1. Bastard JP, Maachi M, Van Nhieu JT, et al. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab. 2002;87(5):2084–9.
    1. Havel PJ. Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes. 2004;53(Suppl 1):S143–S151.
    1. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83(3):847–50.
    1. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004;145(5):2273–82.
    1. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003;107(3):363–9.
    1. Kralisch S, Bluher M, Paschke R, Stumvoll M, Fasshauer M. Adipokines and adipocyte targets in the future management of obesity and the metabolic syndrome. Mini Rev Med Chem. 2007;7(1):39–45.
    1. Mohamed-Ali V, Goodrick S, Rawesh A, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82(12):4196–200.
    1. Sjoholm A, Nystrom T. Inflammation and the etiology of type 2 diabetes. Diabetes Metab Res Rev. 2006;22(1):4–10.
    1. Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes. 2004;53(3):693–700.
    1. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327–34.
    1. Kristiansen OP, Mandrup-Poulsen T. Interleukin-6 and diabetes: the good, the bad, or the indifferent? Diabetes. 2005;54(Suppl 2):S114–S124.
    1. Burstein SA, Peng J, Friese P, et al. Cytokine-induced alteration of platelet and hemostatic function. Stem Cells. 1996;14(Suppl 1):154–62.
    1. Orban Z, Remaley AT, Sampson M, Trajanoski Z, Chrousos GP. The differential effect of food intake and beta-adrenergic stimulation on adipose-derived hormones and cytokines in man. J Clin Endocrinol Metab. 1999;84(6):2126–33.
    1. Carey AL, Febbraio MA. Interleukin-6 and insulin sensitivity: friend or foe? Diabetologia. 2004;47(7):1135–42.
    1. Bastard JP, Jardel C, Bruckert E, et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab. 2000;85(9):3338–42.
    1. Mooney RA, Senn J, Cameron S, et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J Biol Chem. 2001;276(28):25889–93.
    1. Lagathu C, Bastard JP, Auclair M, et al. Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun. 2003;311(2):372–9.
    1. Grimble RF. Inflammatory status and insulin resistance. Curr Opin Clin Nutr Metab Care. 2002;5(5):551–9.
    1. Gollasch M, Dubrovska G. Paracrine role for periadventitial adipose tissue in the regulation of arterial tone. Trends Pharmacol Sci. 2004;25(12):647–53.
    1. Gao YJ. Dual modulation of vascular function by perivascular adipose tissue and its potential correlation with adiposity/lipoatrophy-related vascular dysfunction. Curr Pharm Des. 2007;13(21):2185–92.
    1. Galvez B, de CJ, Herold D, et al. Perivascular adipose tissue and mesenteric vascular function in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 2006;26(6):1297–302.
    1. Guzik TJ, Marvar PJ, Czesnikiewicz-Guzik M, Korbut R. Perivascular adipose tissue as a messenger of the brain-vessel axis: role in vascular inflammation and dysfunction. J Physiol Pharmacol. 2007 Dec;58(4):591–610.
    1. Soltis EE, Cassis LA. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin Exp Hypertens A. 1991;13(2):277–96.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera