The role of cytokines in inflammation-induced cardiomyopathy: Pathogenesis and therapeutic implications

  • Jesus G. Vallejo
  • Douglas L. Mann
Part of the Progress in Inflammation Research book series (PIR)


Heart failure of diverse etiology is now recognized to have an important immune component, with proinflammatory cytokines such as TNF influencing the process of cardiac remodeling and prognosis. A complex relationship seems to exist between the adaptive and maladaptive immune response, cytoprotective, growth, and contractile effects of inflammatory mediators. Understanding the mechanisms underlying this innate cytoprotection has the potential to identify new strategies and targets to treat cardiac disease in the future.


Tumor Necrosis Factor Proinflammatory Cytokine Chronic Fatigue Syndrome Negative Inotropic Effect Viral Myocarditis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Levine B, Kalman J, Mayer L, Fillit HM, Packer M (1990) Elevated circulating levels of tumor-necrosis-factor in severe chronic heart-failure. N Engl J Med 323: 236–41CrossRefPubMedGoogle Scholar
  2. 2.
    Tang, WH, Francis GS (2006) The year in heart failure. J Am Coll Cardiol: 48(12): 2575–83CrossRefPubMedGoogle Scholar
  3. 3.
    Mann DL (2002) Inflammatory mediators and the failing heart — Past, present, and the foreseeable future. Circ Res 91: 988–98CrossRefPubMedGoogle Scholar
  4. 4.
    Kapadia S, Lee J, Torre-Amione G, Birdsall HH, Ma TS, Mann DL (1995) Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 96: 1042–52CrossRefPubMedGoogle Scholar
  5. 5.
    Kapadia SR, Oral H, Lee J, Nakano M, Taffet GE, Mann DL (1997) Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res 81: 187–95PubMedGoogle Scholar
  6. 6.
    Mann DL (2003) Stress-activated cytokines and the heart: From adaptation to maladaptation. Annu Rev Physiol 65: 81–101CrossRefPubMedGoogle Scholar
  7. 7.
    Eddy LJ, Goeddel DV, Wong GHW (1992) Tumor necrosis factor-alpha pretreatment is protective in a rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun 184: 1056–9CrossRefPubMedGoogle Scholar
  8. 8.
    Wong GHW, Goeddel DV (1998) Induction of manganous superoxide-dismutase by tumor necrosis factor — possible protective mechanism. Science 242: 941–4CrossRefGoogle Scholar
  9. 9.
    Löw-Friedrich I, Weisensee D, Mitrou P, Schoeppe W (1992) Cytokines induce stress protein formation in cultured cardiac myocytes. Basic Res Cardiol 87: 12–8CrossRefPubMedGoogle Scholar
  10. 10.
    Nakano M, Knowlton AA, Yokoyama T, Lesslauer W, Mann DL (1996) Tumor necrosis factor-alpha-induced expression of heat shock protein 72 in adult feline cardiac myocytes. Am J Physiol-Heart Circ Physiol 39: H1231–H1239Google Scholar
  11. 11.
    Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM, Dillmann WH (1995) Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 95: 1446–56CrossRefPubMedGoogle Scholar
  12. 12.
    Plumier JCL, Ross BM, Currie RW, Angelidis CE, Kazlaris H, Kollias G et al (1995) Transgenic mice expressing the human heat shock protein-70 have improved postischemic myocardial recovery. J Clin Invest 95: 1854–60CrossRefPubMedGoogle Scholar
  13. 13.
    Erl W, Hansson GK, de Martin R, Draude G, Weber KSC, Weber C (1999) Nuclear factor-kappa B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells. Circ Res 84: 668–77PubMedGoogle Scholar
  14. 14.
    Lee JP, Palfrey HC, Bindokas VP, Ghadge GD, Ma L, Miller RJ et al (1999) The role of immunophilins in mutant superoxide dismutase-1-linked familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 96: 3251–6CrossRefPubMedGoogle Scholar
  15. 15.
    Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie FD et al (1999) Apoptosis in heart failure: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci USA 96: 8144–9CrossRefPubMedGoogle Scholar
  16. 16.
    Nelson SK, Wong GHW, Mccord JM (1995) Leukemia inhibitory factor and tumor necrosis factor induce manganese superoxide-dismutase and protect rabbit hearts from reperfusion injury. J Mol Cell Cardiol 27: 223–9CrossRefPubMedGoogle Scholar
  17. 17.
    Wang F, Seta Y, Baumgarten G, Engel DJ, Sivasubramanian N, Mann DL (2001) Functional significance of hemodynamic overload-induced expression of leukemia-inhibitory factor in the adult mammalian heart. Circulation 103: 1296–302PubMedGoogle Scholar
  18. 18.
    Fujio Y, Kunisada K, Hirota H, Yamauchi-Takihara K, Kishimoto T (1997) Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes. J Clin Invest 99: 2898–905CrossRefPubMedGoogle Scholar
  19. 19.
    Yokoyama T, Nakano M, Bednarczyk JL, McIntyre BW, Entman M, Mann DL (1997) Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation 95: 1247–52PubMedGoogle Scholar
  20. 20.
    Bozkurt B, Kribbs S, Clubb FJ Jr, Michael LH, Didenko VV, Hornsby PJ et al (1998) Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 97: 1382–91PubMedGoogle Scholar
  21. 21.
    Bryant D, Becker L, Richardson J, Shelton J, Franco F, Pechock RM et al (1998) Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 97: 1375–81PubMedGoogle Scholar
  22. 22.
    Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM (1997) Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J Am Coll Cardiol 29: 29165Google Scholar
  23. 23.
    Franco F, Thomas GD, Giroir B, Bryant D, Bullock MC, Chwialkowski MC et al (1999) Magnetic resonance imaging and invasive evaluation of development of heart failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 99: 448–54PubMedGoogle Scholar
  24. 24.
    Oral H, Dorn GW, Mann DL (1997) Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem 272: 4836–42CrossRefPubMedGoogle Scholar
  25. 25.
    Balligand JL, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T et al (1993) Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage conditioned medium. J Clin Invest 91: 2314–9CrossRefPubMedGoogle Scholar
  26. 26.
    Gulick TS, Chung MK, Pieper SJ, Lange LG, Schreiner GF (1989) Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci USA 86: 6753–7CrossRefPubMedGoogle Scholar
  27. 27.
    Dinarello CA (1999) Interleukin-18. Methods 19: 121–32CrossRefPubMedGoogle Scholar
  28. 28.
    Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA (2001) Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1 beta. Proc Natl Acad Sci USA 98: 2871–6CrossRefPubMedGoogle Scholar
  29. 29.
    Raeburn CD, Dinarello CA, Zimmerman MA, Calkins CM, Pomerantz BJ, McIntyre RC et al (2002) Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction. Am J Physiol Heart Circ Physiol 283: H650–H657PubMedGoogle Scholar
  30. 30.
    Yu XW, Kennedy RH, Liu SJ (2003) JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in contractility of adult ventricular myocytes. J Biol Chem 278: 16304–9CrossRefPubMedGoogle Scholar
  31. 31.
    Satoh M, Tamura G, Segawa I, Tashiro A, Hiramori K, Satodate R (1996) Expression of cytokine genes and presence of enteroviral genomic RNA in endomyocardial biopsy tissues of myocarditis and dilated cardiomyopathy. Virchows Arch 427: 503–9CrossRefPubMedGoogle Scholar
  32. 32.
    Matsumori A, Yamada T, Suzuki H, Matoba Y, Sasayama S (1994) Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 72: 561–6CrossRefPubMedGoogle Scholar
  33. 33.
    Kubota T, Bounoutas GS, Miyagishima M, Kadokami T, Sanders VJ, Bruton C et al (2000) Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy. Circulation 101: 2518–25PubMedGoogle Scholar
  34. 34.
    Yamada T, Matsumori A, Sasayama S (1994) Therapeutic effect of anti-tumor necrosis factor-alpha antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus. Circulation 89: 846–51PubMedGoogle Scholar
  35. 35.
    Wada H, Saito K, Kanda T, Kobayashi I, Fujii H, Fujigaki S et al (2001) Tumor necrosis factor-alpha (TNF-alpha) plays a protective role in acute viral myocarditis in mice: A study using mice lacking TNF-alpha. Circulation 103: 743–9PubMedGoogle Scholar
  36. 36.
    Huber SA, Polgar J, Schultheiss P, Schwimmbeck P (1994) Augmentation of pathogenesis of coxsackievirus B3 infections in mice by exogenous administration of interleukin-1 and interleukin-2. J Virol 68: 195–206PubMedGoogle Scholar
  37. 37.
    Lim BK, Choe SC, Shin JO, Ho SH, Kim JM, Yu SS et al (2002) Local expression of interleukin-1 receptor antagonist by plasmid DNA improves mortality and decreases myocardial inflammation in experimental coxsackieviral myocarditis. Circulation 105: 1278–81PubMedGoogle Scholar
  38. 38.
    Shioi T, Matsumori A, Sasayama S (1996) Persistent expression of cytokine in the chronic stage of viral myocarditis in mice. Circulation 94: 2930–7PubMedGoogle Scholar
  39. 39.
    Eriksson U, Kurrer MO, Sonderegger I, Iezzi G, Tafuri A, Hunziker L et al (2003) Activation of dendritic cells through the interleukin 1 receptor 1 is critical for the induction of autoimmune myocarditis. J Exp Med 197: 323–31CrossRefPubMedGoogle Scholar
  40. 40.
    DiSanto E, Alonzi T, Poli V, Fattori E, Toniatti C, Sironi M et al (1997) Differential effects of IL-6 on systemic and central production of TNF: A study with IL-6-deficient mice. Cytokine 9: 300–6CrossRefGoogle Scholar
  41. 41.
    Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA (1990) Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells — IL-6 suppresses IL-1 and TNF. Blood 75: 40–7PubMedGoogle Scholar
  42. 42.
    Kanda T, McManus JE, Nagai R, Imai S, Suzuki T, Yang D et al (1996) Modification of viral myocarditis in mice by interleukin-6. Circ Res 78: 848–56PubMedGoogle Scholar
  43. 43.
    Tanaka T, Kanda T, McManus BM, Kanai H, Akiyama H, Sekiguchi K et al (2001) Overexpression of interleukin-6 aggravates viral myocarditis: Impaired increase in tumor necrosis factor-alpha. J Mol Cell Cardiol 33: 1627–35CrossRefPubMedGoogle Scholar
  44. 44.
    Zaragoza C, Ocampo C, Saura M, Leppo M, Wei XQ, Quick R et al (1998) The role of inducible nitric oxide synthase in the host response to Coxsackievirus myocarditis. Proc Natl Acad Sci USA 95: 2469–74CrossRefPubMedGoogle Scholar
  45. 45.
    Badorff C, Fichtlscherer B, Rhoads RE, Zeiher AM, Muelsch A, Dimmeler S et al (2000) Nitric oxide inhibits dystrophin proteolysis by coxsackieviral protease 2A through S-nitrosylation: A protective mechanism against enteroviral cardiomyopathy. Circulation 102: 2276–81PubMedGoogle Scholar
  46. 46.
    Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME et al (1995) A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 333: 269–75CrossRefPubMedGoogle Scholar
  47. 47.
    Bowles NE, Richardson PJ, Olsen EGJ, Archard LC (1986) Detection of coxsackie-Bvirus specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1: 1120–4CrossRefPubMedGoogle Scholar
  48. 48.
    Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L et al (1993) Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy. J Med 24: 145–60PubMedGoogle Scholar

Copyright information

© Springer Basel 2010

Authors and Affiliations

  • Jesus G. Vallejo
    • 1
  • Douglas L. Mann
    • 2
    • 3
  1. 1.Section of Infectious Diseases, Department of Pediatrics and Winters Center for Heart Failure ResearchBaylor College of Medicine and Texas Children’s HospitalHoustonUSA
  2. 2.Division of CardiologyWashington University School of MedicineSt. LouisUSA
  3. 3.Section of CardiologyTexas Heart Institute at St. Luke’s Episcopal Hospital, and Winters Center for Heart Failure Research, Baylor College of MedicineHoustonUSA

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