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Low IL-10/TNFα Ratio in Patients with Coronary Artery Disease and Reduced Left Ventricular Ejection Fraction with a Poor Prognosis After 10 Years

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Abstract

Monocytes and dendritic cells (DC) produce tumour necrosis factor (TNF)α during inflammatory processes, but secrete interleukin (IL)-10 simultaneously in order to balance the pro-inflammation. In the present study, we investigated the expression of TNFα and IL-10 by monocytes and DC in patients with a poor cardiovascular prognosis after 10 years. Peripheral blood monocytes were isolated from 30 patients with coronary artery disease (CAD) with stable angina pectoris (SAP), or with an acute coronary syndrome (ACS). Monocytes were differentiated over 7 days to DC. Intracellular accumulation of TNFα and IL-10 in monocytes and DC was analysed by flow cytometry and correlated with the heart function, total and cardiovascular (CV) mortality, as well as with cardiovascular event rate over 10 years. We observed a decreased left ventricular function (LV-EF) for both SAP and ACS patients (p < 0.01), as well as a reduced IL-10/TNFα ratio for monocytes (p = 0.01) and DC (p < 0.01) for both patient groups in comparison to age-matched control group. Only the IL-10/TNFα ratio for monocytes correlated with LV-EF (r = 0.4302; p < 0.01). Patients with a low LV-EF as well as patients with a low IL-10/TNFα ratio showed an increased cardiovascular mortality over 10 years (both p < 0.05). The IL-10/TNFα ratio is decreased in patients with low ejection fraction and poor prognosis. The reduced heart function correlates with an increased proinflammatory state (low monocytic IL-10/TNFα ratio) in patients with CAD. This observed imbalance of IL-10 and TNFα in monocytes might explain pathophysiological processes in atherosclerosis and heart failure.

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References

  1. Ross, R. 1999. Atherosclerosis: an inflammatory disease. The New England Journal of Medicine 340: 115–126.

    Article  CAS  PubMed  Google Scholar 

  2. Hansson, G.K. 2001. Regulation of immune mechanisms in atherosclerosis. The Annals of the New York Academy of Sciences 947: 157–165.

    Article  CAS  PubMed  Google Scholar 

  3. Hansson, G.K., P. Libby, U. Schonbeck, and Z.Q. Yan. 2002. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circulation Research 91(4): 281–291.

    Article  CAS  PubMed  Google Scholar 

  4. Lotze, M.T., and A.W. Thomson. 2001. Dendritic cells: biology and clinical applications, 2nd ed. San Diego: Academic.

    Google Scholar 

  5. Galkina, E., and K. Ley. 2009. Immune and inflammatory mechanisms of atherosclerosis (*). Annual Review of Immunology 27: 165–197.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Jovinge, S., M.P.S. Ares, B. Kallin, and J. Nilsson. 1996. Human monocytes/macrophages release TNF-α in response to Ox-LDL. Arteriosclerosis, Thrombosis, and Vascular Biology 16(12): 1573–1579.

    Article  CAS  PubMed  Google Scholar 

  7. Nouri-Shirazi, M., and E. Guinet. 2003. Evidence for the immunosuppressive role of nicotine on human dendritic cell functions. Immunology 109(3): 365–373.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Guinet, E., K. Yoshida, and M. Nouri-Shirazi. 2004. Nicotinic environment affects the differentiation and functional maturation of monocytes derived dendritic cells (DCs). Immunology Letters 95(1): 45–55.

    Article  CAS  PubMed  Google Scholar 

  9. Alderman, C.J.J., R. Bunyarad, B.M. Chain, J.C. Foreman, D.S. Leake, and D.R. Katz. 2002. Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment. Cardiovascular Research 55: 806–819.

    Article  CAS  PubMed  Google Scholar 

  10. Perrin-Cocon, L., F. Coutant, S. Agaugue, S. Deforges, P. Andre, and V. Lotteau. 2001. Oxidized low-density lipoprotein promotes mature dendritic cell transition from differentiating monocyte. Journal of Immunology 167(7): 3785–3791.

    Article  CAS  Google Scholar 

  11. Aicher, A., C. Heeschen, M. Mohaupt, J.P. Cooke, A. Zeiher, and S. Dimmeler. 2003. Nicotine strongly activates dendritic cell-mediated adaptive immunity. Potential role for progression of atherosclerotic lesions. Circulation 107: 604–611.

    Article  CAS  PubMed  Google Scholar 

  12. Cella, M., D. Scheidegger, K. Palmer-Lehmann, P. Lane, A. Lanzavecchia, and G. Alber. 1996. Ligation of CD40 on dendritic cells triggers production of high levels of levels of IL-12 and enhances T-cell stimulatory capacity: T-T help via APC activation. The Journal of Experimental Medicine 184: 747–752.

    Article  CAS  PubMed  Google Scholar 

  13. Woollard, K.J., and F. Geissmann. 2010. Monocytes in atherosclerosis: subsets and functions. Nature Reviews Cardiology 7(2): 77–86.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Niessner, A., and C.M. Weyand. 2010. Dendritic cells in atherosclerotic disease. Clinical Immunology 134(1): 25–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Cesari, M., B.W.J.H. Penninx, A.B.. Newman, S.B. Kritchevsky, B.J. Nicklas, K. Sutton-Tyrrell, S.M. Rubin, J. Ding, E.M. Simonsick, T.B. Harris, and M. Pahor. 2003. Inflammatory markers and onset of cardiovascular events: results from the health ABC study. Circulation 108(19): 2317–2322.

  16. Heeschen, C., S. Dimmeler, C.W. Hamm, S. Fichtlscherer, E. Boersma, M.L. Simoons, A.M. Zeiher, and Investigators ftCS. 2003. Serum level of the antiinflammatory cytokine interleukin-10 is an important prognostic determinant in patients with acute coronary syndromes. Circulation 107(16): 2109–2114.

    Article  CAS  PubMed  Google Scholar 

  17. Blankenberg, S., L. Tiret, C. Bickel, D. Peetz, F. Cambien, J. Meyer, H.J. Rupprecht, and for the AtheroGene investigators. 2002. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106(1): 24–30.

    Article  CAS  PubMed  Google Scholar 

  18. Pickl, W., O. Majdic, P. Kohl, J. Stockl, E. Riedl, C. Scheinecker, C. Bello-Fernandez, and W. Knapp. 1996. Molecular and functional characteristics of dendritic cells generated from highly purified CD14+ peripheral blood monocytes. Journal of Immunology 157(9): 3850–3859.

    CAS  Google Scholar 

  19. Romani, N., D. Reider, M. Heuer, S. Ebner, E. Kampgen, B. Eibl, D. Niederwieser, and G. Schuler. 1996. Generation of mature dendritic cells from human blood: an improved method with special regard to clinical application. Journal of Immunological Methods 196: 137–151.

    Article  CAS  PubMed  Google Scholar 

  20. Sester, M., U. Sester, B. Gartner, G. Heine, M. Girndt, N. Mueller-Lantzsch, A. Meyerhans, and H. Kohler. 2001. Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation1. Transplantation 71(9): 1287–1294.

    Article  CAS  PubMed  Google Scholar 

  21. De Backer, J., R. Mark, D. De Bacquer, L. Van Renterghem, E. Verbraekel, M. Kornitzer, and G. De Backer. 2002. Parameters of inflammation and infection in a community based case-control study of coronary heart disease. Atherosclerosis 160: 457–463.

    Article  PubMed  Google Scholar 

  22. Fernandes, J.L., R.L. Mamoni, J.L. Orford, C. Garcia, A.P. Selwyn, O.R. Coelho, and M.H. Blotta. 2004. Increased Th1 activity in patients with coronary artery disease. Cytokine 26(3): 131–137.

    Article  CAS  PubMed  Google Scholar 

  23. Mizia-Stec, K., T. Mandecki, B. Zahorska-Markiewicz, J. Janowska, A. Szulc, E. Jastrzebska-Maj, and L. Szymanski. 2002. Is there a relationship between left ventricular systolic function and serum cytokines level in patients with coronary artery disease? Medical Science Monitor : International Medical Journal of Experimental and Clinical Research 8(2): CR87–92.

    Google Scholar 

  24. Mizia-Stec, K., Z. Gasior, B. Zahorska-Markiewicz, J. Janowska, A. Szulc, E. Jastrzebska-Maj, and I. Kobielusz-Gembala. 2003. Serum tumour necrosis factor-alpha, interleukin-2 and interleukin-10 activation in stable angina and acute coronary syndromes. Coronary Artery Disease 14(6): 431–438.

    Article  PubMed  Google Scholar 

  25. Schlitt, A., G.H. Heine, S. Blankenberg, C. Espinola-Klein, J.F. Dopheide, C. Bickel, K.J. Lackner, M. Iz, J. Meyer, H. Darius, and H.J. Rupprecht. 2004. CD14+ CD16+ monocytes in coronary artery disease and their relationship to serum TNF-alpha levels. Thrombosis and Haemostasis 92(2): 419–424.

    CAS  PubMed  Google Scholar 

  26. Dopheide, J.F., U. Sester, A. Schlitt, G. Horstick, H.J. Rupprecht, T. Munzel, and S. Blankenberg. 2007. Monocyte-derived dendritic cells of patients with coronary artery disease show an increased expression of costimulatory molecules CD40, CD80 and CD86 in vitro. Coronary Artery Disease 18(7): 523–531.

    Article  PubMed  Google Scholar 

  27. Delirezh, N., and E. Shojaeefar. 2012. Phenotypic and functional comparison between flask adherent and magnetic activated cell sorted monocytes derived dendritic cells. Iranian Journal of Immunology: IJI 9(2): 98–108.

    CAS  PubMed  Google Scholar 

  28. Delirezh, N., E. Shojaeefar, P. Parvin, and B. Asadi. 2013. Comparison the effects of two monocyte isolation methods, plastic adherence and magnetic activated cell sorting methods, on phagocytic activity of generated dendritic cells. Cell Journal 15(3): 218–223.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Lim WH, Kireta S, Leedham E, Russ GR, Coates PT. 2007. Uremia impairs monocyte and monocyte-derived dendritic cell function in hemodialysis patients.

  30. Lim, W.H., S. Kireta, A.W. Thomson, G.R. Russ, and P.T. Coates. 2006. Renal transplantation reverses functional deficiencies in circulating dendritic cell subsets in chronic renal failure patients. Transplantation 81(2): 160–168.

    Article  PubMed  Google Scholar 

  31. Devereux, R.B., M.J. Roman, V. Palmieri, J.E. Liu, E.T. Lee, L.G. Best, R.R. Fabsitz, R.J. Rodeheffer, and B.V. Howard. 2003. Prognostic implications of ejection fraction from linear echocardiographic dimensions: the Strong Heart Study. American Heart Journal 146(3): 527–534.

    Article  PubMed  Google Scholar 

  32. Niethammer, M., M. Sieber, S. von Haehling, S.D. Anker, T. Munzel, G. Horstick, and S. Genth-Zotz. 2008. Inflammatory pathways in patients with heart failure and preserved ejection fraction. International Journal of Cardiology 129(1): 111–117.

    Article  PubMed  Google Scholar 

  33. Gullestad, L., T. Ueland, J.G. Fjeld, E. Holt, T. Gundersen, K. Breivik, M. Folling, A. Hodt, R. Skardal, J. Kjekshus, A. Andreassen, E. Kjekshus, R. Wergeland, A. Yndestad, S.S. Froland, A.G. Semb, and P. Aukrust. 2005. Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study. Circulation 112(22): 3408–3414.

    Article  CAS  PubMed  Google Scholar 

  34. Sliwa, K., O. Forster, E. Libhaber, J.D. Fett, J.B. Sundstrom, D. Hilfiker-Kleiner, and A.A. Ansari. 2006. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. European Heart Journal 27(4): 441–446.

    Article  CAS  PubMed  Google Scholar 

  35. Dhingra S, Sharma AK, Singla DK, Singal PK. 2007. p38 and ERK1/2 MAPKs mediate the interplay of TNF-α and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis. Vol 293; .

  36. Kaur, K., A.K. Sharma, S. Dhingra, and P.K. Singal. 2006. Interplay of TNF-alpha and IL-10 in regulating oxidative stress in isolated adult cardiac myocytes. Journal of Molecular and Cellular Cardiology 41(6): 1023–1030.

    Article  CAS  PubMed  Google Scholar 

  37. Stumpf, C., C. Lehner, A. Yilmaz, W.G. Daniel, and C.D. Garlichs. 2003. Decrease of serum levels of the anti-inflammatory cytokine interleukin-10 in patients with advanced chronic heart failure. Clinical Science 105(1): 45–50.

    Article  CAS  PubMed  Google Scholar 

  38. Waehre, T., B. Halvorsen, J.K. Damas, A. Yndestad, F. Brosstad, L. Gullestad, J. Kjekshus, S.S. Froland, and P. Aukrust. 2002. Inflammatory imbalance between IL-10 and TNFalpha in unstable angina potential plaque stabilizing effects of IL-10. European Journal of Clinical Investigation 32(11): 803–810.

    Article  CAS  PubMed  Google Scholar 

  39. Kelly, Á., A. Lynch, E. Vereker, Y. Nolan, P. Queenan, E. Whittaker, L.A.J. O’Neill, and M.A. Lynch. 2001. The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1β on long term potentiation. A role for JNK. Journal of Biological Chemistry 276(49): 45564–45572.

    Article  CAS  PubMed  Google Scholar 

  40. Mann, D.L. 1996. The effect of tumor necrosis factor-alpha on cardiac structure and function: a tale of two cytokines. Journal of Cardiac Failure 2(4 Suppl): S165–172.

    Article  CAS  PubMed  Google Scholar 

  41. Della Bella, S., S. Giannelli, A. Taddeo, P. Presicce, and M.L. Villa. 2008. Application of six-color flow cytometry for the assessment of dendritic cell responses in whole blood assays. Journal of Immunological Methods 339(2): 153–164.

    Article  CAS  PubMed  Google Scholar 

  42. Giannelli, S., A. Taddeo, P. Presicce, M.L. Villa, and S.D. Bella. 2008. A six-color flow cytometric assay for the analysis of peripheral blood dendritic cells. Cytometry. Part B, Clinical Cytometry 74B(6): 349–355.

    Article  Google Scholar 

  43. Dopheide, J.F., V. Obst, C. Doppler, M.C. Radmacher, M. Scheer, M.P. Radsak, T. Gori, A. Warnholtz, C. Fottner, A. Daiber, T. Munzel, and C. Espinola-Klein. 2012. Phenotypic characterisation of pro-inflammatory monocytes and dendritic cells in peripheral arterial disease. Thrombosis and Haemostasis 108(6): 1198–1207.

    Article  PubMed  Google Scholar 

  44. Zawada, A.M., K.S. Rogacev, B. Rotter, P. Winter, R.R. Marell, D. Fliser, and G.H. Heine. 2011. SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset. Blood 118(12): e50–61.

    Article  CAS  PubMed  Google Scholar 

  45. Heimbeck, I., T.P. Hofer, C. Eder, A.K. Wright, M. Frankenberger, A. Marei, G. Boghdadi, J. Scherberich, and L. Ziegler-Heitbrock. 2010. Standardized single-platform assay for human monocyte subpopulations: lower CD14+CD16++ monocytes in females. Cytometry. Part A 77(9): 823–830.

    Article  Google Scholar 

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Acknowledgments

Authors thank Martina and Urban Sester for methodological and technical support for the initiation of the study. This paper contains in part data reported in the medical thesis of Pascal Knopf.

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Authors and Affiliations

  1. Department of Internal Medicine II, Universitätsmedizin of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Jörn F. Dopheide, Pascal Knopf, Markus Vosseler, Nico Abegunewardene, Thomas Münzel & Christine Espinola-Klein

  2. Department of Internal Medicine I, Universitätsmedizin of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Geraldine C. Zeller

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  1. Jörn F. Dopheide
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  2. Pascal Knopf
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Dopheide, J.F., Knopf, P., Zeller, G.C. et al. Low IL-10/TNFα Ratio in Patients with Coronary Artery Disease and Reduced Left Ventricular Ejection Fraction with a Poor Prognosis After 10 Years. Inflammation 38, 911–922 (2015). https://doi.org/10.1007/s10753-014-0053-5

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