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Masahiko Okuno, Masao Nakagawa, Morimi Shimada, Mikiyoshi Saito, Shigemichi
Hishinuma, and Keiko Yamauchi-Takihara
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Department
of Pediatrics (MO, MN, MS), Shiga University of Medical Science, Shiga;
Chugai Pharmaceutical Company, Ltd. (MS), Shizuoka; and Department of Molecular
Medicine (SH, KY-T), Osaka University Medical School, Osaka, Japan |
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SUMMARY: To determine the
role of cytokines in acute myocarditis, we examined expressional patterns
of cardiotrophin-1 (CT-1), TNF- [alpha], and IL-1 [alpha] in a murine model
of acute myocarditis. Ten-day-old Institute of Cancer Research mice were
injected with Coxsackievirus B3 and killed on Days 1, 2, 3, 4, 5, 7, 10,
14, and 28 of injection. TNF- [alpha] and IL-1 [alpha] expressions were
investigated on histological sections from each heart, and mRNA expression
of TNF- [alpha] , IL-1 [alpha], and CT-1 in the heart was examined by reverse
transcription-polymerase chain reaction and RNase protection assay. To determine
myocardial regeneration, cardiomyocytic DNA synthesis was investigated using
bromodeoxyuridine on Days 3, 5, 7, and 10, and the labeling index was calculated
in each heart. Age-matched uninfected mice were used as controls. TNF-ALPHA
and IL-1 [alpha] expression was first detected in the cardiomyocytes on
Day 3 and reached the maximum level on Day 7, when inflammatory changes
were most prominent. Although an increased expression of TNF-[alpha] and
IL-1 [alpha] mRNA was also detected on Day 3, CT-1 mRNA expression was distinctly
augmented on Day 2. The labeling indices in the hearts with myocarditis
were significantly higher than in those of the controls in all of the time
points examined. CT-1 expression preceded TNF-[alpha] and IL-1 [alpha] expressions
and active DNA synthesis in a murine model of acute myocarditis. All CVB3-infected
mice with anti-glycoprotein-130 antibody treatment died within 6 days. CT-1
may exert a protective role by modulating cytokine production and by inducing
cardiomyocytic proliferation in CVB3-infected murine hearts.(Lab Invest
2000, 80: 433-440).
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