This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wada, H. Articles by Seishima, M. Search for Related Content PubMed PubMed Citation Articles by Wada, H. Articles by Seishima, M. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Growth factors/cytokines

(Circulation. 2001;103:743.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Tumor Necrosis Factor- (TNF-) Plays a Protective Role in Acute Viral Myocarditis in Mice

A Study Using Mice Lacking TNF-

Hisayasu Wada, MD, PhD; Kuniaki Saito, PhD; Tsugiyasu Kanda, MD, PhD; Isao Kobayashi, MD, PhD; Hidehiko Fujii, MD, PhD; Suwako Fujigaki, BSc; Naoya Maekawa, BSc; Hisato Takatsu, MD, PhD; Hisayoshi Fujiwara, MD, PhD; Kenji Sekikawa, PhD; Mitsuru Seishima, MD, PhD

From the Department of Laboratory Medicine (H.W., K. Saito, H. Fujii, S.F., N.M., M.S.) and Second Department of Internal Medicine (H.T., H. Fujiwara), Gifu University School of Medicine, Gifu; Department of Laboratory Medicine, Gunma University School of Medicine, Gunma (T.K., I.K.); and Department of Immunology, National Institute of Animal Health (K. Sekikawa), Japan.

Correspondence to Hisayasu Wada, MD, PhD, Department of Laboratory Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. E-mail wadah{at}cc.gifu-u.ac.jp

Background—It has been reported that tumor necrosis factor- (TNF-) is expressed in the heart with viral myocarditis and that its expression aggravates the condition. The pathophysiological effects of TNF- on viral myocarditis, however, have not been fully elucidated.

Methods and Results—To investigate the role of TNF- in the progression of viral myocarditis, we used TNF- gene–deficient mice (TNF-^-/-) and induced acute myocarditis by infection with encephalomyocarditis virus (EMCV). The survival rate of TNF-^-/- mice after EMCV infection was significantly lower than that of TNF-^+/+ mice (0% versus 67% on day 14). Injection of recombinant human TNF- (0.2 to 4.0 µg/mouse IV) improved the survival of TNF-^-/- mice in a dose-dependent manner, indicating that TNF- is essential for protection against viral myocarditis. The levels of viral titer and viral genomic RNA of EMCV in the myocardium were significantly higher in TNF-^-/- than in TNF-^+/+ mice. Histopathological examination showed that the inflammatory changes of the myocardium were less marked in TNF-^-/- than in TNF-^+/+ mice. Immunohistochemical analysis revealed that the levels of immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the myocardium were decreased in TNF-^-/- mice compared with TNF-^+/+ mice.

Conclusions—These observations suggested that TNF- is necessary for adhesion molecule expression and to recruit leukocytes to inflammatory sites, and thus, the lack of this cytokine resulted in failure of elimination of infectious agents. We concluded that TNF- plays a protective role in the acute stage of viral myocarditis.

Key Words: tumor necrosis factor- • myocarditis • viruses • cell adhesion molecules

This article has been cited by other articles:

				K. A. Binymin Comment on: Adult-onset Still's disease and myocarditis: successful treatment with intravenous immunoglobulin and maintenance of remission with etanercept Rheumatology, November 1, 2007; 46(11): 1741 - 1742. [Full Text] [PDF]

				E. A. Jankowska, P. Ponikowski, M. F. Piepoli, W. Banasiak, S. D. Anker, and P. A. Poole-Wilson Autonomic imbalance and immune activation in chronic heart failure - Pathophysiological links Cardiovasc Res, June 1, 2006; 70(3): 434 - 445. [Abstract] [Full Text] [PDF]

				M. Li, D. Georgakopoulos, G. Lu, L. Hester, D. A. Kass, J. Hasday, and Y. Wang p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart Circulation, May 17, 2005; 111(19): 2494 - 2502. [Abstract] [Full Text] [PDF]

				S. A. Huber and D. Sartini Roles of Tumor Necrosis Factor Alpha (TNF-{alpha}) and the p55 TNF Receptor in CD1d Induction and Coxsackievirus B3-Induced Myocarditis J. Virol., March 1, 2005; 79(5): 2659 - 2665. [Abstract] [Full Text] [PDF]

				L. Guilherme, P. Cury, L. M.F. Demarchi, V. Coelho, L. Abel, A. P. Lopez, S. E. Oshiro, S. Aliotti, E. Cunha-Neto, P. M.A. Pomerantzeff, et al. Rheumatic Heart Disease: Proinflammatory Cytokines Play a Role in the Progression and Maintenance of Valvular Lesions Am. J. Pathol., November 1, 2004; 165(5): 1583 - 1591. [Abstract] [Full Text] [PDF]

				Y. CHEN, Q. KE, Y. YANG, J. S. RANA, J. TANG, J. P. MORGAN, and Y.-F. XIAO Cardiomyocytes overexpressing TNF-{alpha} attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase FASEB J, December 1, 2003; 17(15): 2231 - 2239. [Abstract] [Full Text] [PDF]

				A. Martire, B. Fernandez, A. Buehler, C. Strohm, J. Schaper, R. Zimmermann, P. E Kolattukudy, and W. Schaper Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice mimics ischemic preconditioning through SAPK/JNK1/2 activation Cardiovasc Res, February 1, 2003; 57(2): 523 - 534. [Abstract] [Full Text] [PDF]

				P. Liu, P. Lee, K. Fuse, and M. Nian Molecular pathophysiological mechanisms in virus infected host myocardium Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I37 - I41. [Abstract] [PDF]

				R. M Smith, S. Lecour, and M. N Sack Innate immunity and cardiac preconditioning: a putative intrinsic cardioprotective program Cardiovasc Res, August 15, 2002; 55(3): 474 - 482. [Abstract] [Full Text] [PDF]

				R. M Smith, N. Suleman, J. McCarthy, and M. N Sack Classic ischemic but not pharmacologic preconditioning is abrogated following genetic ablation of the TNF{alpha} gene Cardiovasc Res, August 15, 2002; 55(3): 553 - 560. [Abstract] [Full Text] [PDF]

				P. Knuefermann, S. Nemoto, G. Baumgarten, A. Misra, N. Sivasubramanian, B. A. Carabello, and J. G. Vallejo Cardiac Inflammation and Innate Immunity in Septic Shock* : Is There a Role for Toll-Like Receptors? Chest, April 1, 2002; 121(4): 1329 - 1336. [Abstract] [Full Text] [PDF]

				R. J. Scheubel, B. Bartling, A. Simm, R.-E. Silber, K. Drogaris, D. Darmer, and J. Holtz Apoptotic pathway activation from mitochondria and death receptors without caspase-3 cleavage in failing human myocardium: Fragile balance of myocyte survival? J. Am. Coll. Cardiol., February 6, 2002; 39(3): 481 - 488. [Abstract] [Full Text] [PDF]

				D. L. Mann Tumor Necrosis Factor and Viral Myocarditis: The Fine Line Between Innate and Inappropriate Immune Responses in the Heart Circulation, February 6, 2001; 103(5): 626 - 629. [Full Text] [PDF]