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

人们普遍认为，促炎细胞因子如干扰素-γ(IFN-γ)、肿瘤坏死因子-α(TNF-α)和白细胞介素-1 （IL-1）在病毒性心肌炎的心脏中表达，它们的表达改变了疾病的状况，但它们在病毒性心肌炎中的作用尚不清楚。我们用细胞因子敲除（KO）小鼠研究了促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，IFN-γ KO小鼠接种脑心肌炎病毒（EMCV, 500 PFU）后死亡率增高。IFN-γ KO小鼠心肌细胞浸润和坏死明显增加。提示IFN-γ对病毒性心肌炎具有保护作用。(2)接种EMCV（50或500 PFU）后TNF-α KO小鼠的存活率显著低于WT小鼠。TNF-α KO心肌中EMCV的病毒滴度和病毒基因组RNA明显高于WT小鼠。静脉注射重组人TNF-α可提高TNF-α KO小鼠的存活率。组织病理学研究显示，TNF-α KO小鼠的细胞浸润和ICAM-1免疫反应性显著降低。因此，TNF-α被认为通过诱导粘附分子表达和白细胞募集对病毒性心肌炎具有保护作用。(3)接种EMCV （500 PFU）后IL-1α KO和IL-1αβ KO小鼠的存活率与WT小鼠无显著差异。IL-1 KO小鼠的组织病理学结果与WT小鼠相同，表明IL-1对病毒性心肌炎无影响。

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.