Interferon regulatory factor-1, interferon-β, and reovirus-induced myocarditis
Interferon regulatory factor-1, interferon-β, and reovirus-induced myocarditis
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DOI：
10.1006/viro.2002.1470
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发表时间：
2002-06-20
期刊：
影响因子：
3.7
通讯作者：
Sherry, B
中科院分区：
文献类型：
--
作者：
Azzam-Smoak, K;Noah, DL;Sherry, B
病毒性心肌炎是一种重要的人类疾病，呼肠孤病毒诱导的小鼠心肌炎为研究病毒对心脏的直接损伤提供了一个很好的模型。先前，我们发现呼肠孤病毒诱导干扰素- β (ifn - β)和对ifn - β的敏感性是病毒在心脏致病性的重要决定因素，并且转录因子干扰素调节因子-3 （IRF-3）是呼肠孤病毒在原代心肌细胞培养物中诱导ifn - β所必需的。鉴于几条证据表明心脏中irf可能具有独特的环境，我们现在将重点放在IRF-1上。双链rna （dsRNA）和ifn - α / β都可以诱导IRF-1， IRF-1在dsRNA中发挥作用，但可能不是病毒诱导ifn - α / β。重要的是，这些研究都没有使用具有dsRNA基因组的病毒（如呼肠孤病毒），没有使用高度分化的非淋巴细胞类型，也没有研究病毒诱导IRF-1是直接的还是通过病毒诱导ifn - β介导的。事实上，就在今年，人们一直认为病毒对IRF-1的诱导是直接的。在这里，我们发现呼肠孤病毒在原代心肌细胞培养中诱导IRF-1，但IRF-1不是呼肠孤病毒诱导ifn - β所必需的。令人惊讶的是，我们发现呼肠孤病毒在没有ifn - α / β反应的情况下无法诱导IRF-1。这提供了病毒可能不会直接诱导IRF-1的第一个证据。最后，非心肌呼肠孤病毒株在缺乏IRF-1的小鼠中诱导的心脏病变比野生型小鼠多，直接证明了IRF-1的保护作用。总之，结果表明，虽然IRF-1是ifn - β反应的下游，但它对病毒性心肌炎起着重要的保护作用。(C) 2002 Elsevier Science （USA）。
Viral myocarditis is an important human disease, and reovirus-induced myocarditis in mice provides an excellent model to study direct viral damage to the heart. Previously, we showed that reovirus induction of and sensitivity to interferon-beta (IFN-beta) is an important determinant of viral pathogenicity in the heart and that the transcription factor interferon regulatory factor-3 (IRF-3) is required for reovirus induction of IFN-beta in primary cardiac myocyte cultures Given several lines of evidence suggesting a possible distinctive environment for IRFs in the heart, we have now focused on IRF-1 Previous studies demonstrated that viruses, double-stranded-RNA (dsRNA), and IFN-alpha/beta can each induce IRF-1 and that IRF-1 plays a role in dsRNA, but perhaps not viral, induction of IFN-alpha/beta Importantly, none of these studies used a virus with a dsRNA genome (such as reovirus), none of them used a highly differentiated nonlymphoid cell type, and none of them addressed whether viral induction of IRF-1 is direct or is mediated through viral induction of IFN-beta. Indeed, as recently as this year it has been assumed that viral induction of IRF-1 is direct. Here, we found that reovirus induced IRF-1 in primary cardiac myocyte cultures, but that IRF-1 was not required for reovirus induction of IFN-beta. Surprisingly, we found that reovirus failed to induce IRF-1 in the absence of the IFN-alpha/beta response. This provides the first evidence that viruses may not induce IRF-1 directly. Finally, nonmyocarditic reovirus strains induced more cardiac lesions in mice deficient for IRF-1 than they did in wildtype mice, directly demonstrating a protective role for IRF-1. Together, the results indicate that while IRF-1 is downstream of the IFN-beta response, it plays an important protective role against viral myocarditis. (C) 2002 Elsevier Science (USA).