Expression of tumor necrosis factor-alpha–converting enzyme and tumor necrosis factor-alpha in human myocarditis
Mamoru Satoh, MD, PhDa,
Motoyuki Nakamura, MDa,
Hidetoshi Satoh, MD*,
Hidenori Saitoh, MDa,
Ikuo Segawa, MDa and
Katsuhiko Hiramori, MDa
a Second Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan
* Second Department of Pathology, Iwate Medical University School of Medicine, Iwate, Japan
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Figure 1 Comparison of TACE/GAPDH (a) and TNF-alpha/GAPDH (b) levels in serial endomyocardial biopsy samples of patients and control subjects. Both TNF-alpha/GAPDH and TACE/GAPDH mRNAs were expressed to a higher level in initial biopsy samples than in repeat biopsy samples (TNF-alpha/GAPDH ratio 5.54 ± 0.67 vs. 3.33 ± 0.52, p = 0.03; TACE/GAPDH ratio 4.36 ± 0.29 vs. 1.74 ± 0.17, p < 0.01). MC = myocarditis.
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Figure 2 Immunohistochemical analysis for TNF-alpha and TACE in serial endomyocardial biopsy tissues obtained from patients with myocarditis. Detection of TNF-alpha (a) and TACE (c) proteins with primary and secondary antibodies in the initial biopsy. TNF-alpha and TACE proteins were found in myocytes, infiltrating macrophages and mononuclear cells. Immunostaining of TNF-alpha (b) and TACE (d) was markedly decreased in myocytes and interstitial cells in repeat biopsy. Magnification for a and c, x230; for b and d, x240, reduced by XX%.
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Figure 3 Comparison of TACE (a) and TNF-alpha (b) mRNA expression according to NYHA functional class. TNF-alpha and TACE mRNAs were expressed to a higher level in the myocarditis subgroup in functional class III or IV than in the subgroup in class I or II (TACE/GAPDH ratio 3.58 ± 0.56 vs. 0.93 ± 0.19, p = 0.02; TNF-alpha/GAPDH ratio 5.04 ± 0.59 vs. 1.92 ± 0.44, p = 0.01).
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Figure 4 Comparison of TACE (a) and TNF-alpha (b) mRNA expressions in two myocarditis subgroups classified according to maximal CK concentration levels. TACE and TNF-alpha expression levels were significantly higher in the subgroup with CK >500 IU/liter than in the subgroup with CK <500 IU/liter (TACE/GAPDH ratio 3.84 ± 0.57 vs. 1.04 ± 0.20, p = 0.006; TNF-alpha/GAPDH ratio 5.29 ± 0.62 vs. 2.12 ± 0.42, p = 0.001).
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Figure 5 The hypothetical role of TACE in myocarditis. First, viral infection or autoimmune dysfunction, or both, occurred in myocardial tissues. These immune responses in infiltrating inflammatory cells (infiltrating macrophages and lymphocytes) and cardiac myocytes mediated expression of TACE and pro-TNF-alpha. Activated TACE cleaved from pro-TNF-alpha to its mature form. The mature form of TNF-alpha induced myocytic injury and left ventricular dysfunction through the paracrine or autocrine process, or both.
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