Subscribe to RSS
IL-33 stimulates the release of procoagulant microvesicles from human monocytes and differentially increases tissue factor in human monocyte subsetsFinancial Support: The research was funded by the “Young Thrombosis Researcher Exchange Grant” of the Working Group on Thrombosis of European Society of Cardiology to Stefan Stojkovic; by a special programme grant of the FWF to Johann Wojta, grant number SFB54 “Cellular mediators linking inflammation and thrombosis”. Furthermore, the work was supported by the Association for the Promotion of Research in Arteriosclerosis, Thrombosis and Vascular Biology, the Swedish Research Council, grant number 2012–2579 to Agneta Siegbahn, and local funds at Uppsala University and SciLifeLab, Uppsala University, Uppsala, Sweden.
14 October 2016
Accepted after major revision: 05 April 2017
11 November 2017 (online)
Monocytes and monocyte-derived microvesicles (MVs) are the main source of circulating tissue factor (TF). Increased monocyte TF expression and increased circulating levels of procoagulant MVs contribute to the formation of a prothrombotic state in patients with cardiovascular disease. Interleukin (IL)-33 is a pro-inflammatory cytokine involved in atherosclerosis and other inflammatory diseases, but its role in regulating thrombosis is still unclear. The aim of the present study was to investigate the effects of IL-33 on the procoagulant properties of human monocytes and monocyte-derived MVs. IL-33 induced a time- and concentration-dependent increase of monocyte TF mRNA and protein levels via binding to the ST2-receptor and activation of the NFκB-pathway. The IL-33 treated monocytes also released CD14+TF+ MVs and IL-33 was found to increase the TF activity of both the isolated monocytes and monocyte-derived MVs. The monocytes were classified into subsets according to their CD14 and CD16 expression. Intermediate monocytes (IM) showed the highest ST2 receptor expression, followed by non-classical monocytes (NCM), and classical monocytes (CM). IL-33 induced a significant increase of TF only in the IM (p<0.01), with a tendency in NCM (p=0.06), but no increase was observed in CM. Finally, plasma levels of IL–33 were positively correlated with CD14+TF+ MVs in patients undergoing carotid endarterectomy (r=0.480; p=0.032; n=20). We hereby provide novel evidence that the proinflammatory cytokine IL-33 induces differential TF expression and activity in monocyte subsets, as well as the release of procoagulant MVs. In this manner, IL-33 may contribute to the formation of a prothrombotic state characteristic for cardiovascular disease.
Supplementary Material to this article is available online at www.thrombosis-online.com.
- 1 Aberg M, Eriksson O, Siegbahn A. Tissue Factor Noncoagulant Signaling: Mechanisms and Implications for Cell Migration and Apoptosis. Semin Thromb Hemost 2015; 41: 691-699.
- 2 Wilcox JN, Smith KM, Schwartz SM. et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-2843.
- 3 Giesen PL, Rauch U, Bohrmann B. et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999; 96: 2311-2315.
- 4 Brambilla M, Facchinetti L, Canzano P. et al. Human megakaryocytes confer tissue factor to a subset of shed platelets to stimulate thrombin generation. Thromb Haemost 2015; 114: 579-592.
- 5 Ernofsson M, Siegbahn A. Platelet-derived growth factor-BB and monocyte chemotactic protein-1 induce human peripheral blood monocytes to express tissue factor. Thromb Res 1996; 83: 307-320.
- 6 Lindmark E, Tenno T, Siegbahn A. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol 2000; 20: 2322-2328.
- 7 Mackman N. Regulation of the tissue factor gene. FASEB J 1995; 9: 883-889.
- 8 Breitenstein A, Tanner FC, Luscher TF. Tissue factor and cardiovascular disease: quo vadis?. Circ J 2010; 74: 3-12.
- 9 Hron G, Kollars M, Weber H. et al. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 2007; 97: 119-123.
- 10 Leatham EW, Bath PM, Tooze JA. et al. Increased monocyte tissue factor expression in coronary disease. Br Heart J 1995; 73: 10-13.
- 11 Kakkar AK, DeRuvo N, Chinswangwatanakul V. et al. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995; 346: 1004-1005.
- 12 Holschermann H, Haberbosch W, Terhalle HM. et al. Increased monocyte tissue factor activity in women following cerebral venous thrombosis. J Neurol 2003; 250: 631-632.
- 13 Matsumoto N, Nomura S, Kamihata H. et al. Increased level of oxidized LDL-dependent monocyte-derived microparticles in acute coronary syndrome. Thromb Haemost 2004; 91: 146-154.
- 14 Khorana AA, Francis CW, Menzies KE. et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost 2008; 6: 1983-1985.
- 15 Geddings JE, Mackman N. New players in haemostasis and thrombosis. Thromb Haemost 2014; 111: 570-574.
- 16 Pawlinski R, Mackman N. Cellular sources of tissue factor in endotoxemia and sepsis. Thromb Res 2010; 125 (Suppl. 01) S70-S73.
- 17 Ruf W. Tissue factor and cancer. Thromb Res 2012; 130 (Suppl. 01) S84-S87.
- 18 Ziegler-Heitbrock L, Ancuta P, Crowe S. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116: e74-e80.
- 19 Weber C, Shantsila E, Hristov M. et al. Role and analysis of monocyte subsets in cardiovascular disease. Joint consensus document of the European Society of Cardiology (ESC) Working Groups “Atherosclerosis & Vascular Biology„ and “Thrombosis„. Thromb Haemost 2016; 116: 626-637.
- 20 Wong KL, Tai JJ, Wong WC. et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 2011; 118: e16-e31.
- 21 Cros J, Cagnard N, Woollard K. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 2010; 33: 375-386.
- 22 Mukherjee R, Kanti Barman P, Kumar Thatoi P. et al. Non-Classical monocytes display inflammatory features: Validation in Sepsis and Systemic Lupus Erythematous. Sci Rep 2015; 5: 13886.
- 23 Leers MP, Keuren JF, Frissen ME. et al. The pro- and anticoagulant role of blood-borne phagocytes in patients with acute coronary syndrome. Thromb Haemost 2013; 110: 101-109.
- 24 Schmitz J, Owyang A, Oldham E. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005; 23: 479-490.
- 25 Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol 2010; 10: 103-110.
- 26 Kakkar R, Hei H, Dobner S. et al. Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J Biol Chem 2012; 287: 6941-6948.
- 27 Miller AM. Role of IL-33 in inflammation and disease. J Inflamm 2011; 8: 22.
- 28 Stojkovic S, Kaun C, Heinz M. et al. Interleukin-33 induces urokinase in human endothelial cells-possible impact on angiogenesis. J Thromb Haemost 2014; 12: 948-957.
- 29 Demyanets S, Konya V, Kastl SP. et al. Interleukin-33 induces expression of adhesion molecules and inflammatory activation in human endothelial cells and in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2011; 31: 2080-2089.
- 30 Stojkovic S, Kaun C, Basilio J. et al. Tissue factor is induced by interleukin-33 in human endothelial cells: a new link between coagulation and inflammation. Sci Rep 2016; 6: 25171.
- 31 Aoki S, Hayakawa M, Ozaki H. et al. ST2 gene expression is proliferation-dependent and its ligand, IL-33, induces inflammatory reaction in endothelial cells. Mol Cell Biochem 2010; 335: 75-81.
- 32 Montanari E, Stojkovic S, Kaun C. et al. Interleukin-33 stimulates GM-CSF and M-CSF production by human endothelial cells. Thromb Haemost 2016; 116: 317-327.
- 33 Choi YS, Choi HJ, Min JK. et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood 2009; 114: 3117-3126.
- 34 Demyanets S, Speidl WS, Tentzeris I. et al. Soluble ST2 and interleukin-33 levels in coronary artery disease: relation to disease activity and adverse outcome. PLoS One 2014; 9: e95055.
- 35 Dhillon OS, Narayan HK, Khan SQ. et al. Pre-discharge risk stratification in unselected STEMI: is there a role for ST2 or its natural ligand IL-33 when compared with contemporary risk markers?. Int J Cardiol 2013; 167: 2182-2188.
- 36 Demyanets S, Kaun C, Pentz R. et al. Components of the interleukin-33/ST2 system are differentially expressed and regulated in human cardiac cells and in cells of the cardiac vasculature. J Mol Cell Cardiol 2013; 60: 16-26.
- 37 Abeles RD, McPhail MJ, Sowter D. et al. CD14, CD16 and HLA-DR reliably identifies human monocytes and their subsets in the context of pathologically reduced HLA-DR expression by CD14(hi) /CD16(neg) monocytes: Expansion of CD14(hi) /CD16(pos) and contraction of CD14(lo) /CD16(pos) monocytes in acute liver failure. Cytometry A 2012; 81: 823-834.
- 38 North American Symptomatic Carotid Endarterectomy Trial. Methods, patient characteristics, and progress. Stroke 1991; 22: 711-720.
- 39 Christersson C, Johnell M, Siegbahn A. Evaluation of microparticles in whole blood by multicolour flow cytometry assay. Scand J Clin Lab Invest 2013; 73: 229-239.
- 40 Mun SH, Ko NY, Kim HS. et al. Interleukin-33 stimulates formation of functional osteoclasts from human CD14(+) monocytes. Cell Mol Life Sci 2010; 67: 3883-392.
- 41 Ghattas A, Griffiths HR, Devitt A. et al. Monocytes in coronary artery disease and atherosclerosis: where are we now?. J Am Coll Cardiol 2013; 62: 1541-1551.
- 42 Krychtiuk KA, Kastl SP, Speidl WS. et al. Inflammation and coagulation in atherosclerosis. Hamostaseologie 2013; 33: 269-282.
- 43 Mallat Z, Benamer H, Hugel B. et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000; 101: 841-843.
- 44 Schlitt A, Heine GH, Blankenberg S. et al. CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-alpha levels. Thromb Haemost 2004; 92: 419-424.
- 45 Rogacev KS, Cremers B, Zawada AM. et al. CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography. J Am Coll Cardiol 2012; 60: 1512-1520.
- 46 Guha M, O’Connell MA, Pawlinski R. et al. Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression. Blood 2001; 98: 1429-1439.
- 47 Koga H, Sugiyama S, Kugiyama K. et al. Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2005; 45: 1622-1630.
- 48 Leroyer AS, Isobe H, Leseche G. et al. Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. J Am Coll Cardiol 2007; 49: 772-777.
- 49 Miller AM, Xu D, Asquith DL. et al. IL-33 reduces the development of atherosclerosis. J Exp Med 2008; 205: 339-346.
- 50 Martin P, Palmer G, Rodriguez E. et al. Atherosclerosis severity is not affected by a deficiency in IL-33/ST2 signaling. Immun Inflamm Dis 2015; 3: 239-246.