Skip to main content

Advertisement

SpringerLink
Log in

Induction of a broad spectrum of inflammation-related genes by Coxsackievirus B3 requires Interleukin-1 signaling

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Coxsackievirus B3 (CVB3) is a major cause of acute and chronic forms of myocarditis. Previously, direct viral injury and post-infectious autoimmune response were suspected as main pathogenetic mechanisms. However, induction of pro-inflammatory cytokines may be crucial for pathogenesis in spite of host protein shut off caused by CVB3 replication. We investigated the global expression profile of pro-inflammatory genes induced by acute and persistent (carrier state) CVB3 infection in human fibroblast cell cultures with DNA microarrays, quantitative RT-PCR and ELISA. Rapid induction of a typical spectrum of about 30 inflammation-related genes (e.g., PTGS2, CCL2, IL-1β, IL-6, IL-8, CSF2, MMP-1, MMP-3, and MMP-15) suggested an essential, autocrine role of IL-1. This hypothesis was confirmed by over-expression of IL-1RI, which resulted in a cytokine response upon CVB3 infection in HEK 293 cells otherwise refractory to CVB3-caused gene expression. Blocking IL-1 receptor type I (IL-1RI)-signaling during CVB3 infection with an IL-1 receptor antagonist (IL-1ra) as well as knockdown of IL-1RI using siRNA abrogated cytokine response in human fibroblasts. Both IL-1α and IL-1β are relevant for the induction of inflammation-related genes during CVB3 infection as shown by neutralization experiments. Paracrine effects of IL-1 on the subset of non-infected cells in carrier state infected fibroblast cultures enhanced induction of inflammation-related genes. Conclusions: A broad spectrum of inflammatory cytokines was induced by CVB3 replication via a pathway that requires IL-1 signaling. Our results suggest that IL-1ra may be used as a therapeutic agent to limit inflammation and tissue destruction in myocarditis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

BIRC:

Baculoviral IAP repeat-containing

CAR:

Coxsackie-adenovirus receptor

CSF1:

Macrophage colony-stimulating factor

CSF2:

Granulocyte macrophage colony-stimulating factor

CVB3:

Coxsackievirus B3

DCM:

Dilated cardiomyopathy

E6, E7:

Early gene 6 and 7 (oncogenes)

FGF:

Fibroblast growth factor

GCH:

GTP cyclohydrolase

HMF:

Human myocardial fibroblasts

HPV16:

Human papillomavirus type 16

IL:

Interleukin

IL-1ra:

Interleukin-1 receptor antagonist

IL-1RI:

Interleukin-1 receptor type I

MIP:

Macrophage inflammatory protein

MMP:

Matrix metalloprotease

moi:

Multiplicity of infection

mRNA:

Messenger RNA

MWCO:

Molecular weight cut-off

NOS2A:

Nitric oxide synthase, inducible

PLAU:

Plasminogen activator, urokinase

PLAUR:

Plasminogen activator, urokinase receptor

PTGS2:

Prostaglandin-endoperoxide synthase 2

siRNA:

Short interfering RNA

SOD2:

Manganese superoxide dismutase

ssRNA:

Single-stranded RNA

TCID50 :

Tissue culture infectious dose 50 % (a measure of infectious virus units)

TLR:

Toll-like receptor

TREM:

Triggering receptor expressed on myeloid cells

References

  1. Feldman AM, McNamara D (2000) Myocarditis. N Engl J Med 343(19):1388–1398

    Article  PubMed  CAS  Google Scholar 

  2. Taylor DO, Stehlik J, Edwards LB, Aurora P, Christie JD, Dobbels F, Kirk R, Kucheryavaya AY, Rahmel AO, Hertz MI (2009) Registry of the international society for heart and lung transplantation: twenty-sixth official adult heart transplant report-2009. J Heart Lung Transplant 28(10):1007–1022

    Article  PubMed  Google Scholar 

  3. Kawai C (1999) From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 99(8):1091–1100

    Article  PubMed  CAS  Google Scholar 

  4. Knowlton KU (2008) CVB infection and mechanisms of viral cardiomyopathy. Curr Top Microbiol Immunol 323:315–335

    Article  PubMed  CAS  Google Scholar 

  5. Leslie K, Blay R, Haisch C, Lodge A, Weller A, Huber S (1989) Clinical and experimental aspects of viral myocarditis. Clin Microbiol Rev 2(2):191–203

    PubMed  CAS  Google Scholar 

  6. Neumann DA, Burek CL, Baughman KL, Rose NR, Herskowitz A (1990) Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy. J Am Coll Cardiol 16(6):839–846

    Article  PubMed  CAS  Google Scholar 

  7. Schwimmbeck PL, Bigalke B, Schulze K, Pauschinger M, Kuhl U, Schultheiss HP (2004) The humoral immune response in viral heart disease: characterization and pathophysiological significance of antibodies. Med Microbiol Immunol 193(2–3):115–119

    PubMed  CAS  Google Scholar 

  8. Kishimoto C, Thorp KA, Abelmann WH (1990) Immunosuppression with high doses of cyclophosphamide reduces the severity of myocarditis but increases the mortality in murine Coxsackievirus B3 myocarditis. Circulation 82(3):982–989

    Article  PubMed  CAS  Google Scholar 

  9. Latham RD, Mulrow JP, Virmani R, Robinowitz M, Moody JM (1989) Recently diagnosed idiopathic dilated cardiomyopathy: incidence of myocarditis and efficacy of prednisone therapy. Am Heart J 117(4):876–882

    Article  PubMed  CAS  Google Scholar 

  10. Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE (1995) A clinical trial of immunosuppressive therapy for myocarditis. The myocarditis treatment trial investigators. N Engl J Med 333(5):269–275

    Article  PubMed  CAS  Google Scholar 

  11. Parrillo JE, Cunnion RE, Epstein SE, Parker MM, Suffredini AF, Brenner M, Schaer GL, Palmeri ST, Cannon RO III, Alling D et al (1989) A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 321(16):1061–1068

    Article  PubMed  CAS  Google Scholar 

  12. Chapman NM, Kim KS (2008) Persistent coxsackievirus infection: enterovirus persistence in chronic myocarditis and dilated cardiomyopathy. Curr Top Microbiol Immunol 323:275–292

    Article  PubMed  CAS  Google Scholar 

  13. McManus BM, Chow LH, Wilson JE, Anderson DR, Gulizia JM, Gauntt CJ, Klingel KE, Beisel KW, Kandolf R (1993) Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis. Clin Immunol Immunopathol 68(2):159–169

    Article  PubMed  CAS  Google Scholar 

  14. Yuan J, Cheung PK, Zhang H, Chau D, Yanagawa B, Cheung C, Luo H, Wang Y, Suarez A, McManus BM, Yang D (2004) A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts. Lab Invest 84(6):703–714

    Article  PubMed  CAS  Google Scholar 

  15. Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, Gatewood SJ, Njoku DB, Rose NR (2004) Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart. Am J Pathol 165(6):1883–1894

    Article  PubMed  CAS  Google Scholar 

  16. Figulla HR, Stille-Siegener M, Mall G, Heim A, Kreuzer H (1995) Myocardial enterovirus infection with left ventricular dysfunction: a benign disease compared with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 25(5):1170–1175

    Article  PubMed  CAS  Google Scholar 

  17. Heim A, Stille-Seigener M, Pring-Akerblom P, Grumbach I, Brehm C, Kreuzer H, Figulla HR (1996) Recombinant Interferons beta and gamma have a higher antiviral activity than interferon-alpha in coxsackievirus B3-infected carrier state cultures of human myocardial fibroblasts. J Interferon Cytokine Res 16(4):283–287

    Article  PubMed  CAS  Google Scholar 

  18. Heim A, Weiss S (2004) Interferons in enteroviral heart disease: modulation of cytokine expression and antiviral activity. Med Microbiol Immunol (Berl) 193(2–3):149–154

    Article  CAS  Google Scholar 

  19. Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP (2003) Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107(22):2793–2798

    Article  PubMed  Google Scholar 

  20. Matsumori A, Tomioka N, Kawai C (1988) Protective effect of recombinant alpha interferon on coxsackievirus B3 myocarditis in mice. Am Heart J 115(6):1229–1232

    Article  PubMed  CAS  Google Scholar 

  21. Klingel K, Rieger P, Mall G, Selinka HC, Huber M, Kandolf R (1998) Visualization of enteroviral replication in myocardial tissue by ultrastructural in situ hybridization: identification of target cells and cytopathic effects. Lab Invest 78(10):1227–1237

    PubMed  CAS  Google Scholar 

  22. Koide H, Kitaura Y, Deguchi H, Ukimura A, Kawamura K, Hirai K (1992) Genomic detection of enteroviruses in the myocardium–studies on animal hearts with coxsackievirus B3 myocarditis and endomyocardial biopsies from patients with myocarditis and dilated cardiomyopathy. Jpn Circ J 56(10):1081–1093

    Article  PubMed  CAS  Google Scholar 

  23. Eghbali M, Czaja MJ, Zeydel M, Weiner FR, Zern MA, Seifter S, Blumenfeld OO (1988) Collagen chain mRNAs in isolated heart cells from young and adult rats. J Mol Cell Cardiol 20(3):267–276

    Article  PubMed  CAS  Google Scholar 

  24. Heim A, Brehm C, Stille-Siegener M, Muller G, Hake S, Kandolf R, Figulla HR (1995) Cultured human myocardial fibroblasts of pediatric origin: natural human interferon-alpha is more effective than recombinant interferon-alpha 2a in carrier-state coxsackievirus B3 replication. J Mol Cell Cardiol 27(10):2199–2208

    Article  PubMed  CAS  Google Scholar 

  25. Kandolf R, Canu A, Hofschneider PH (1985) Coxsackie B3 virus can replicate in cultured human foetal heart cells and is inhibited by interferon. J Mol Cell Cardiol 17(2):167–181

    Article  PubMed  CAS  Google Scholar 

  26. Bedard KM, Semler BL (2004) Regulation of picornavirus gene expression. Microbes Infect 6(7):702–713

    Article  PubMed  CAS  Google Scholar 

  27. Heim A, Zeuke S, Weiss S, Ruschewski W, Grumbach IM (2000) Transient induction of cytokine production in human myocardial fibroblasts by coxsackievirus B3. Circ Res 86(7):753–759

    Article  PubMed  CAS  Google Scholar 

  28. Henke A, Mohr C, Sprenger H, Graebner C, Stelzner A, Nain M, Gemsa D (1992) Coxsackievirus B3-induced production of tumor necrosis factor-alpha, IL-1 beta, and IL-6 in human monocytes. J Immunol 148(7):2270–2277

    PubMed  CAS  Google Scholar 

  29. Garmaroudi FS, Marchant D, Si X, Khalili A, Bashashati A, Wong BW, Tabet A, Ng RT, Murphy K, Luo H, Janes KA, McManus BM (2010) Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection. Proc Natl Acad Sci USA 107(39):17053–17058

    Article  PubMed  CAS  Google Scholar 

  30. Shen Y, Xu W, Chu YW, Wang Y, Liu QS, Xiong SD (2004) Coxsackievirus group B type 3 infection upregulates expression of monocyte chemoattractant protein 1 in cardiac myocytes, which leads to enhanced migration of mononuclear cells in viral myocarditis. J Virol 78(22):12548–12556

    Article  PubMed  CAS  Google Scholar 

  31. Gluck B, Schmidtke M, Merkle I, Stelzner A, Gemsa D (2001) Persistent expression of cytokines in the chronic stage of CVB3-induced myocarditis in NMRI mice. J Mol Cell Cardiol 33(9):1615–1626

    Article  PubMed  CAS  Google Scholar 

  32. Kishimoto C, Kuroki Y, Hiraoka Y, Ochiai H, Kurokawa M, Sasayama S (1994) Cytokine and murine coxsackievirus B3 myocarditis. Interleukin-2 suppressed myocarditis in the acute stage but enhanced the condition in the subsequent stage. Circulation 89(6):2836–2842

    Article  PubMed  CAS  Google Scholar 

  33. Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR (1992) Interleukin 1 or tumor necrosis factor can promote Coxsackie B3-induced myocarditis in resistant B10.A mice. J Exp Med 175(4):1123–1129

    Article  PubMed  CAS  Google Scholar 

  34. Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR (1993) Role of IL-1 and tumor necrosis factor in coxsackie virus-induced autoimmune myocarditis. J Immunol 151(3):1682–1690

    PubMed  CAS  Google Scholar 

  35. Schmidtke M, Selinka HC, Heim A, Jahn B, Tonew M, Kandolf R, Stelzner A, Zell R (2000) Attachment of coxsackievirus B3 variants to various cell lines: mapping of phenotypic differences to capsid protein VP1. Virology 275(1):77–88

    Article  PubMed  CAS  Google Scholar 

  36. Zautner AE, Korner U, Henke A, Badorff C, Schmidtke M (2003) Heparan sulfates and coxsackievirus-adenovirus receptor: each one mediates coxsackievirus B3 PD infection. J Virol 77(18):10071–10077

    Article  PubMed  CAS  Google Scholar 

  37. Zautner AE, Jahn B, Hammerschmidt E, Wutzler P, Schmidtke M (2006) N- and 6-O-sulfated heparan sulfates mediate internalization of coxsackievirus B3 variant PD into CHO-K1 cells. J Virol 80(13):6629–6636

    Article  PubMed  CAS  Google Scholar 

  38. Harms W, Rothamel T, Miller K, Harste G, Grassmann M, Heim A (2001) Characterization of human myocardial fibroblasts immortalized by HPV16 E6–E7 genes. Exp Cell Res 268(2):252–261

    Article  PubMed  CAS  Google Scholar 

  39. Reed L, Muench, HA (1938) A simple method of estimating fifty per cent endpoints. Am J Hyg (27)

  40. Dierssen U, Rehren F, Henke-Gendo C, Harste G, Heim A (2008) Rapid routine detection of enterovirus RNA in cerebrospinal fluid by a one-step real-time RT-PCR assay. J Clin Virol 42(1):58–64

    Article  PubMed  CAS  Google Scholar 

  41. Dittrich-Breiholz O, Schneider H, Wehmeier L, Resch K, Kracht M (2003) Entwicklung und Evaluierung eines DNA Mikroarrays für entzündungsrelevante Gene. Biospketrum 1/03:88–92

    Google Scholar 

  42. Kettner-Buhrow D, Dittrich-Breiholz O, Schneider H, Wolter S, Resch K, Kracht M (2006) Small interfering RNAs generated by recombinant dicer induce inflammatory gene expression independent from the TAK1-NFkappaB-MAPK signaling pathways. Biochem Biophys Res Commun 347(3):566–573

    Article  PubMed  CAS  Google Scholar 

  43. Wolf K, Schulz C, Riegger GA, Pfeifer M (2002) Tumour necrosis factor-alpha induced CD70 and interleukin-7R mRNA expression in BEAS-2B cells. Eur Respir J 20(2):369–375

    Article  PubMed  CAS  Google Scholar 

  44. Birkenkamp-Demtroder K, Christensen LL, Olesen SH, Frederiksen CM, Laiho P, Aaltonen LA, Laurberg S, Sorensen FB, Hagemann R, TF OR (2002) Gene expression in colorectal cancer. Cancer Res 62(15):4352–4363

  45. Houliston RA, Keogh RJ, Sugden D, Dudhia J, Carter TD, Wheeler-Jones CP (2002) Protease-activated receptors upregulate cyclooxygenase-2 expression in human endothelial cells. Thromb Haemost 88(2):321–328

    PubMed  CAS  Google Scholar 

  46. Elliott SF, Coon CI, Hays E, Stadheim TA, Vincenti MP (2002) Bcl-3 is an interleukin-1-responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene. Arthritis Rheum 46(12):3230–3239

    Article  PubMed  CAS  Google Scholar 

  47. Nagaeva O, Jonsson L, Mincheva-Nilsson L (2002) Dominant IL-10 and TGF-beta mRNA expression in gammadeltaT cells of human early pregnancy decidua suggests immunoregulatory potential. Am J Reprod Immunol 48(1):9–17

    Article  PubMed  Google Scholar 

  48. Jung M, Romer A, Keyszer G, Lein M, Kristiansen G, Schnorr D, Loening SA, Jung K (2003) mRNA expression of the five membrane-type matrix metalloproteinases MT1-MT5 in human prostatic cell lines and their down-regulation in human malignant prostatic tissue. Prostate 55(2):89–98

    Article  PubMed  CAS  Google Scholar 

  49. Zarember KA, Godowski PJ (2002) Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168(2):554–561

    PubMed  CAS  Google Scholar 

  50. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30(9):e36

    Article  PubMed  Google Scholar 

  51. Henke A, Jarasch N, Martin U, Zell R, Wutzler P (2008) Characterization of the protective capability of a recombinant coxsackievirus B3 variant expressing interferon-gamma. Viral Immunol 21(1):38–48

    Article  PubMed  CAS  Google Scholar 

  52. Tonew M, Wagner B, Wagner M, Schmidtke M, Stelzner A (1996) Permissiveness of human embryonal fibroblasts for coxsackieviruses B3. Investigations on virus genetic markers in vitro and localization of virus receptor distribution by immunogold replica technique. Zentralbl Bakteriol 284(2–3):443–456

    Article  PubMed  CAS  Google Scholar 

  53. O’Neill LA, Dinarello CA (2000) The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense. Immunol Today 21(5):206–209

    Article  PubMed  Google Scholar 

  54. Triantafilou K, Orthopoulos G, Vakakis E, Ahmed MA, Golenbock DT, Lepper PM, Triantafilou M (2005) Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent. Cell Microbiol 7(8):1117–1126

    Article  PubMed  CAS  Google Scholar 

  55. Liu P, Aitken K, Kong YY, Opavsky MA, Martino T, Dawood F, Wen WH, Kozieradzki I, Bachmaier K, Straus D, Mak TW, Penninger JM (2000) The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nat Med 6(4):429–434

    Article  PubMed  CAS  Google Scholar 

  56. Luo H, Yanagawa B, Zhang J, Luo Z, Zhang M, Esfandiarei M, Carthy C, Wilson JE, Yang D, McManus BM (2002) Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. J Virol 76(7):3365–3373

    Article  PubMed  CAS  Google Scholar 

  57. Esfandiarei M, Luo H, Yanagawa B, Suarez A, Dabiri D, Zhang J, McManus BM (2004) Protein kinase B/Akt regulates coxsackievirus B3 replication through a mechanism which is not caspase dependent. J Virol 78(8):4289–4298

    Article  PubMed  CAS  Google Scholar 

  58. Kishimoto C, Kawamata H, Sakai S, Shinohara H, Ochiai H (2000) Role of MIP-2 in coxsackievirus B3 myocarditis. J Mol Cell Cardiol 32(4):631–638

    Article  PubMed  CAS  Google Scholar 

  59. Yuan H, Ito S, Senga T, Hyodo T, Kiyono T, Kikkawa F, Hamaguchi M (2009) Human papillomavirus type 16 oncoprotein E7 suppresses cadherin-mediated cell adhesion via ERK and AP-1 signaling. Int J Oncol 35(2):309–314

    PubMed  CAS  Google Scholar 

  60. Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ Jr (1998) HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci USA 95(6):2979–2984

    Article  PubMed  CAS  Google Scholar 

  61. Lim BK, Choe SC, Shin JO, Ho SH, Kim JM, Yu SS, Kim S, Jeon ES (2002) Local expression of interleukin-1 receptor antagonist by plasmid DNA improves mortality and decreases myocardial inflammation in experimental coxsackieviral myocarditis. Circulation 105(11):1278–1281

    PubMed  CAS  Google Scholar 

  62. Weinstock-Guttman B, Ramanathan M, Zivadinov R (2008) Interferon-beta treatment for relapsing multiple sclerosis. Exp Opin Biol Ther 8(9):1435–1447

    Article  CAS  Google Scholar 

  63. Walther EU, Hohlfeld R (1999) Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology 53(8):1622–1627

    Article  PubMed  CAS  Google Scholar 

  64. Nuki G, Bresnihan B, Bear MB, McCabe D (2002) Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46(11):2838–2846

    Article  PubMed  CAS  Google Scholar 

  65. Heymans S, Pauschinger M, De Palma A, Kallwellis-Opara A, Rutschow S, Swinnen M, Vanhoutte D, Gao F, Torpai R, Baker AH, Padalko E, Neyts J, Schultheiss HP, Van de Werf F, Carmeliet P, Pinto YM (2006) Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis. Circulation 114(6):565–573

    Article  PubMed  CAS  Google Scholar 

  66. Tanaka T, Kanda T, McManus BM, Kanai H, Akiyama H, Sekiguchi K, Yokoyama T, Kurabayashi M (2001) Overexpression of interleukin-6 aggravates viral myocarditis: impaired increase in tumor necrosis factor-alpha. J Mol Cell Cardiol 33(9):1627–1635

    Article  PubMed  CAS  Google Scholar 

  67. 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(1):195–206

    PubMed  CAS  Google Scholar 

  68. Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y (2000) Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med 191(2):313–320

    Article  PubMed  CAS  Google Scholar 

  69. Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW (2000) Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med 191(2):303–312

    Article  PubMed  CAS  Google Scholar 

  70. Westphal E, Rohrbach S, Buerke M, Behr H, Darmer D, Silber RE, Werdan K, Loppnow H (2008) Altered interleukin-1 receptor antagonist and interleukin-18 mRNA expression in myocardial tissues of patients with dilatated cardiomyopathy. Mol Med 14(1–2):55–63

    Google Scholar 

  71. Apte RN, Voronov E (2008) Is interleukin-1 a good or bad ‘guy’ in tumor immunobiology and immunotherapy? Immunol Rev 222:222–241

    Article  PubMed  CAS  Google Scholar 

  72. Crossman DC, Morton AC, Gunn JP, Greenwood JP, Hall AS, Fox KA, Lucking AJ, Flather MD, Lees B, Foley CE (2008) Investigation of the effect of Interleukin-1 receptor antagonist (IL-1ra) on markers of inflammation in non-ST elevation acute coronary syndromes (The MRC-ILA-HEART Study). Trials 9:8

    Article  PubMed  Google Scholar 

  73. Ikonomidis I, Lekakis JP, Nikolaou M, Paraskevaidis I, Andreadou I, Kaplanoglou T, Katsimbri P, Skarantavos G, Soucacos PN, Kremastinos DT (2008) Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 117(20):2662–2669

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Amgen (Thousand Oaks, CA) for kindly providing the recombinant IL-1ra and HEK 293/IL-1RI cells, Detlef Neumann (Hannover, Germany) for providing recombinant human IL-1β, Michaela Schmidtke (Jena, Germany) for providing the CVB3 PD strain and Stefan Bauer (Marburg, Germany) for providing HEK 293/TLR7 and HEK 293/TLR8 cells. We thank Lars Steinbrück (Hannover, Germany) and Diana Rothe (Berlin, Germany) for technical support. F. Rehren was funded by the Ministry for Science and Culture of Lower Saxony through a Georg-Christoph-Lichtenberg Scholarship theme.

Author information

Authors and Affiliations

  1. Institute of Virology, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany

    Fabienne Rehren, Barbara Ritter, Elena Lam, Semra Kati & Albert Heim

  2. Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany

    Oliver Dittrich-Breiholz

  3. Department of Virology and Antiviral Therapy, University Hospital Jena, Jena, Germany

    Andreas Henke

  4. Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, Giessen, Germany

    Michael Kracht

Authors
  1. Fabienne Rehren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Ritter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oliver Dittrich-Breiholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Henke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elena Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Semra Kati
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Kracht
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Albert Heim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Albert Heim.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 1807 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rehren, F., Ritter, B., Dittrich-Breiholz, O. et al. Induction of a broad spectrum of inflammation-related genes by Coxsackievirus B3 requires Interleukin-1 signaling. Med Microbiol Immunol 202, 11–23 (2013). https://doi.org/10.1007/s00430-012-0245-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-012-0245-2

Keywords

Search

Navigation