Tumor necrosis factor-alpha (TNF-alpha) plays a protective role in acute viralmyocarditis in mice: A study using mice lacking TNF-alpha.
BACKGROUND
It has been reported that tumor necrosis factor-alpha (TNF-alpha) is expressed in the heart with viral myocarditis and that its expression aggravates the condition. The pathophysiological effects of TNF-alpha on viral myocarditis, however, have not been fully elucidated.


RESULTS
To investigate the role of TNF-alpha in the progression of viral myocarditis, we used TNF-alpha gene-deficient mice (TNF-alpha(-/-)) and induced acute myocarditis by infection with encephalomyocarditis virus (EMCV). The survival rate of TNF-alpha(-/-) mice after EMCV infection was significantly lower than that of TNF-alpha(+/+) mice (0% versus 67% on day 14). Injection of recombinant human TNF-alpha (0.2 to 4.0 microg/mouse IV) improved the survival of TNF-alpha(-/-) mice in a dose-dependent manner, indicating that TNF-alpha 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-alpha(-/-) than in TNF-alpha(+/+) mice. Histopathological examination showed that the inflammatory changes of the myocardium were less marked in TNF-alpha(-/-) than in TNF-alpha(+/+) 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-alpha(-/-) mice compared with TNF-alpha(+/+) mice.


CONCLUSIONS
These observations suggested that TNF-alpha 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-alpha plays a protective role in the acute stage of viral myocarditis.
Wada
H
H
Department of Laboratory Medicine, Gifu University School of Medicine, Gifu, Japan. wadah@cc.gifu-u.ac.jp
Saito
K
K
Kanda
T
T
Kobayashi
I
I
Fujii
H
H
Fujigaki
S
S
Maekawa
N
N
Takatsu
H
H
Fujiwara
H
H
Sekikawa
K
K
Seishima
M
M
D000208:Acute Disease; D000410:Alanine Transaminase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001806:Blood Urea Nitrogen; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000627:therapeutic use*; D019562:Viral Load
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D003402:Creatine Kinase