The role of proinflammatory cytokines in the development and progression of viral myocarditis

干扰素-γ、肿瘤坏死因子-γ和白介素1等促炎细胞因子在病毒性心肌炎心脏中的表达被广泛接受，它们的表达改变了疾病的状态，但它们在病毒性心肌炎中的作用尚不清楚。我们利用细胞因子基因敲除(KO)小鼠研究了致炎细胞因子在病毒性心肌炎中的作用。结果表明：(1)与野生型(WT)小鼠相比，脑心肌炎病毒(EMCV，500PFU)接种γ-KO小鼠后，小鼠的死亡率明显升高。干扰素-γKO组小鼠心肌细胞浸润和坏死明显增加。这些结果表明干扰素-γ对病毒性心肌炎有保护作用。(2)α-KO小鼠接种EMCV(50或500pfu)后的存活率明显低于WT小鼠。αKO组小鼠心肌组织中EMCV的病毒滴度和基因组核糖核酸均显著高于WT小鼠。静脉注射重组人肿瘤坏死因子-α可提高肿瘤坏死因子-αKO小鼠的存活率。组织病理学检查显示，α-KO小鼠的细胞浸润和细胞间黏附分子-1免疫反应明显减少。因此，肿瘤坏死因子-α可能通过诱导黏附分子的表达和白细胞的募集而对病毒性心肌炎具有保护作用。(3)IL-1αKO和IL-1αβKO小鼠接种EMCV(500pfu)后的存活率与WT小鼠无差异。IL-1KO小鼠和WT小鼠的组织病理学结果也相同，表明IL-1对病毒性心肌炎没有影响。

It is widely accepted that proinflammatory cytokines, such as interferon-γ(IFN-γ), tumor necrosis factor-α(TNF-α) and interleukin-1 (IL-1), are expressed in the heart with viral myocarditis and their expression modifies the condition of the disease, but their role in viral myocarditis is still unclear. We examined the role of proinflammatory cytokines in viral myocarditis using cytokine-knockout (KO) mice. The following results were obtained:(1) IFN-γ KO mice showed increased mortality after the inoculation of encephalomyocarditis virus (EMCV, 500 PFU) compared with wild-type (WT) mice. Cellular infiltration and necrosis in the myocardium were significantly increased in IFN-γ KO mice. These results indicate that IFN-γ has protective action against viral myocarditis.(2) The survival rate of TNF-α KO mice after the inoculation of EMCV (50 or 500 PFU) was significantly lower than that of WT mice. The viral titer and viral genomic RNA of EMCV in the myocardium were significantly higher in TNF-α KO than in WT mice. Intravenous injection of recombinant human TNF-α improved the survival of TNF-α KO mice. Histopathological study revealed that cellular infiltration and ICAM-1 immunoreactivity were significantly reduced in TNF-α KO mice. Thus, TNF-α is thought to have protective action against viral myocarditis via inducing adhesion molecule expression and leukocyte recruitment.(3) The survival rate of IL-1α KO and IL-1αβ KO mice after the inoculation of EMCV (500 PFU) did not differ from that of WT mice. Histopathological findings in IL-1 KO mice were also same as that in WT mice, indicating that IL-1 has no effect on viral myocarditis.