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Expression of cytokine genes and presence of enteroviral genomic RNA in endomyocardial biopsy tissues of myocarditis and dilated cardiomyopathy

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Abstract

Viral infection, especially by enteroviruses, has been considered to be the most common cause of myocarditis, which may progress to dilated cardiomyopathy (DCM). Although the mechanism of progression remains uncertain, a cytokine-associated injury of myocytes has been proposed. Using reverse transcriptase polymerase chain reaction (RT-PCR), we examined the expression of interleukin 1β (IL-1β), IL-6, IL-8 and tumour necrosis factor alpha (TNF-α) and the presence of enteroviral genomic RNA in endomyocardial biopsy tissues obtained from patients with myocarditis and DCM. We examined endomyocardial biopsy tissues obtained from 6 patients with myocarditis, 21 with DCM and 15 with non-infectious cardiac diseases as controls. In patients with myocarditis, endomyocardial biopsy was performed twice at an interval of 1 month to 8 years after the onset of myocarditis. We used RT-PCR to detect IL-1β, IL-6, IL-8 and TNF-α genes expression and nested RT-PCR (nRT-PCR) to detect enteroviral genomic RNA. IL-1β, IL-6, IL-8 and TNF-α genes were expressed in 100% (6/6) and enteroviral genomic RNA in 67% (4/6) of myocarditis patients at the first biopsy. At the second biopsy, IL-1β, IL-6, IL-8 and TNF-α genes were expressed in none, 50% (3/6), 67% (4/6) and 67% (4/6), respectively, and enteroviral genomic RNA in 67% (4/6). Four patients with myocarditis, in whom IL-8 and TNF-α genes and enteroviral genomic RNA were detected, progressed to DCM at the second biopsy. IL-1β, IL-6, IL-8 and TNF-α genes were expressed in none, 24% (5/21), 38% (8/21), 57% (12/21) of DCM patients, respectively. Enteroviral genomic RNA was detected in 43% (9/21) of DCM. Neither cytokine expression nor enteroviral genomic RNA were detected in the controls. The high incidence of cytokines, especially IL-6, IL-8 and TNF-α, expression in myocarditis and DCM, which might be induced by enteroviral infection, suggests that cytokines play an important role in myocytic damage leading to DCM.

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References

  1. Archard LC, Freeke CA, Richardson PJ, Meany B, Olsen EGJ, Morgan-Capner P, Rose ML, Taylor P, Banner NR, Yacoub MH, Bowles NE (1988) Persistence of enterovirus RNA in dilated cardiomyopathy: a progression from myocarditis. In: Schultheiss H-P (ed) New concepts in viral heart disease. Springer, Berlin Heidelberg New York, pp 349–362

    Google Scholar 

  2. Archard LC, Bowles NE, Cunninghan L, Freeke CA, Olsen EGJ, Rose ML, Meany B, Why HJF, Richardson PJ (1991) Molecular probes for detection of persisting enterovirus infection of human heart and their prognostic value. Eur Heart J 12 [Suppl D]:56–59

    Google Scholar 

  3. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ Jr, Olsen EGJ, Schoen FJ (1986) Myocarditis: a histopathologic definition and classification. Am J Cardiovasc Pathol 1:3–14

    Google Scholar 

  4. Becker AE (1991) Viral myocarditis. In: Silver MD (ed) Cardiovascular pathology, 2nd edn. Churchill Livingstone, New York, pp 719–741

    Google Scholar 

  5. Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A (1986) Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science 232:977–980

    Google Scholar 

  6. Bowles NE, Richardson PJ, Olsen EGJ, Archard LC (1986) Detection of coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy. Lancet 1:1120–1122

    Google Scholar 

  7. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-choroform extraction. Anal Biochem 162:156–159

    Article  CAS  PubMed  Google Scholar 

  8. Gauntt CJ, Trousdale MD, LaBadie DRL, Paque RE, Nealon T (1979) Properties of coxsackievirus B3 variants which are amyocarditic or myocarditic for mice. J Med Virol 3:207–220

    Google Scholar 

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

    Google Scholar 

  10. Jin O, Sole MJ, Butany JW, Chai W-K, McLaughlin PR, Liu P, Liew C-C (1990) Detection of enterovirus RNA in myocardial biopsies from patients with myocarditis and cardiomyopathy using gene amplification by polymerase chain reaction. Circulation 82:8–16

    Google Scholar 

  11. Kandolf R, Hofschneider PH (1989) Viral heart disease. Springer Semin Immunopathol 11:1–13

    Google Scholar 

  12. Kawai S, Okada R (1987) A histopathological study of dilated cardiomyopathy — with special reference to clinical and pathological comparisons of the degeneration-predominant type and fibrosis-predominant type. Jpn Circ J 51:654–660

    Google Scholar 

  13. Kornbluth RS, Edgington TS (1986) Tumor necrosis factor production by human monocytes is a regulated event: induction of TNF-α-mediated cellular cytotoxicity by endotoxin. J Immunol 137:2585–2591

    Google Scholar 

  14. Kyu B, Matsumori A, Sato Y, Okada I, Chapman NM, Tracy S (1992) Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy. Circulation 86:522–530

    Google Scholar 

  15. Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR (1991) LPS promotes CB3-induced myocarditis in resistant B 10. A mice. Cell Immunol 136:219–233

    Google Scholar 

  16. Larsen CG, Anderson AO, Oppenheim JJ, Matsushima K (1989) Production of interleukin-8 by human dermal fibroblasts and keratinocytes in response to interleukin-1 or tumor necrosis factor. Immunology 68:31–36

    Google Scholar 

  17. March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, Conlon PJ, Hopp TP, Cosman D (1985) Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 315:641–647

    Google Scholar 

  18. Mukaida N, Shiroo M, Matsushima K (1989) Genomic structure of the human monocyte-derived neutrophil chemotactic factor IL-8. J Immunol 143:1366–1371

    Google Scholar 

  19. Nakajima-Iijima S, Hamada H, Reddy P, Kakunaga T (1985) Molecular structure of the human cytoplasmic β-actin gene: interspecies homology of sequences in the introns. Proc Natl Acad Sci USA 82:6133–6137

    Google Scholar 

  20. Report of the WHO/ISFC task force on the definition and classification of cardiomyopathy (1980) Br Heart J 44:672–673

    Google Scholar 

  21. Sato S, Tsutsumi R, Burke A, Carlson G, Porro V, Seko Y, Okumura K, Kawana R, Virmani R (1994) Persistence of replicating coxsackievirus B3 in the athymic murine heart is associated with development of myocarditic lesions. J Gen Virol 75:2911–2924

    Google Scholar 

  22. Satoh M, Tamura G, Segawa I (1994) Enteroviral RNA in endomyocardial biopsy tissues of myocarditis and dilated cardiomyopathy. Pathol Int 44:345–351

    Google Scholar 

  23. Satoh M, Tamura G, Segawa I, Hiramori K, Satodate R (1994) Enteroviral RNA in dilated cardiomyopathy. Eur Heart J 15:934–939

    Google Scholar 

  24. Seko Y, Matsuda H, Kato K, Hashimoto Y, Yagita H, Okumura K, Yazaki Y (1993) Expression of intercellular adhesion molecule-1 in murine hearts with acute myocarditis caused by coxsackievirus B3. J Clin Invest 91:1327–1336

    Google Scholar 

  25. Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB (1985) Cloning and expression in Escherichia coli of the gene for human tumor necrosis factor. Nature 313:803–806

    Google Scholar 

  26. Tracy S, Chapman NM, McManus BM, Pallansch MA, Beck MA, Carstens J (1990) A molecular and serologic evaluation of enteroviral involvement in human myocarditis. J Mol Cell Cardiol 22:403–414

    Google Scholar 

  27. Urban JL, Shepard HM, Rothstein JL, Sugarman BJ, Schreiber H (1986) Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages. Proc Natl Acad Sci USA 1986; 83:5233–5237

    Google Scholar 

  28. Wee L, Liu P, Penn L, Butany JW, McLaughlin PR, Sole MJ, Liew C-C (1992) Persistence of viral genome into late stages of murine myocarditis detected by polymerase chain reaction. Circulation 86:1605–1614

    Google Scholar 

  29. Woodruff JF (1980) Viral myocarditis: a review. Am J Pathol 101:427–484

    Google Scholar 

  30. Wulff H, Anderson LJ, Pallansch MA, Desouzacarvalho RP (1987) Diagnosis of enterovirus 70 infection by demonstration of IgM antibodies. J Med Virol 21:321–327

    Google Scholar 

  31. Yasukawa K, Hirano T, Watanabe Y, Muratani K, Matsuda T, Nakai S, Kishimoto T (1987) Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J 6:2939–2945

    CAS  PubMed  Google Scholar 

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Satoh, M., Segawa, I., Tashiro, A. et al. Expression of cytokine genes and presence of enteroviral genomic RNA in endomyocardial biopsy tissues of myocarditis and dilated cardiomyopathy. Vichows Archiv A Pathol Anat 427, 503–509 (1996). https://doi.org/10.1007/BF00199511

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  • DOI: https://doi.org/10.1007/BF00199511

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