Interferon-γ induces chronic active myocarditis and cardiomyopathy in transgenic mice
Interferon-γ induces chronic active myocarditis and cardiomyopathy in transgenic mice
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DOI：
10.2353/ajpath.2007.060906
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发表时间：
2007-08-01
影响因子：
6
通讯作者：
Loehler, Juergen
中科院分区：
文献类型：
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作者：
Reifenberg, Kurt;Lehr, Hans-Anton;Loehler, Juergen
慢性心力衰竭与免疫系统的激活有关，除其他因素外，其特征是心脏合成和血清促炎症细胞因子的表达。有明确的临床和实验证据表明，细胞因子肿瘤坏死因子-a参与了慢性心力衰竭的发生，但促炎症细胞因子干扰素(IEFN)-γ的潜在心脏毒性尚不清楚。为了研究这个问题，我们分析了SAP-IEFN-Gamma转基因小鼠的心脏表型，这些小鼠的五个器官中结构性地表达IEFN-Gamma，因此显示出循环中这种细胞因子的高水平。SAPIFN-Gamma小鼠自发发生慢性活动性心肌炎，其特征是不仅有CD4(+)和CD8(+)T细胞的浸润，而且还有Mac2(+)(Galectin 3(+))巨噬细胞和CD11c(+)树突状细胞的浸润，最终导致心肌病。超声心动图分析显示rFN-γ过度表达引起的左心室扩张和收缩功能受损。干扰素-γ介导的心脏毒性与促炎细胞因子肿瘤坏死因子-a和白介素12以及巨噬细胞趋化因子MCP1和MIEP1-α的高水平转录有关。在平滑或横纹肌组织中不能检测到肌毒性ILFN-γ效应，提示毒性干扰素-γ效应具有心肌细胞特异性。RFN-γ心脏毒性的确切机制仍有待阐明。
Chronic heart failure is associated with an activation of the immune system characterized among other factors by the cardiac synthesis and serum expression of proinflammatory cytokines. There is unequivocal clinical and experimental evidence that the cytokine tumor necrosis factor-a is involved in the development of chronic heart failure, but a putative cardiotoxic potential of the proinflammatory cytokine interferon (IEFN)-gamma remains primarily unknown. To investigate this issue we analyzed the cardiac phenotype of SAP-IEFN-gamma transgenic mice, which constitutively express IEFN-gamma in their fivers and hence exhibit high circulating serum levels of this cytokine. SAPIFN-gamma mice spontaneously developed chronic active myocarditis, characterized by the infiltration of not only CD4(+) and CD8(+) T cells but also Mac2(+) (galectin 3(+)) macrophages and CD11c(+) dendritic cells, eventually culminating in cardiomyopathy. Echocardiographic analyses exhibited a left ventricular dilation and impaired systolic function induced by rFN-gamma over- expression. IFN-gamma-mediated cardiotoxicity was associated with high-level cardiac transcription of the proinflammatory cytokines tumor necrosis factor-a and interleukin-12 and the macrophage-attracting chemokines MCP1 and MIEP1-alpha. Myotoxic ILFN-gamma effects could not be detected in smooth or striated muscle tissue, suggesting cardiomyocellular specificity of the toxic IFN-gamma effect. The precise mechanism of rFN-gamma cardiotoxicity remains to be elucidated.