Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling
Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling
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DOI：
10.1161/circulationaha.106.642454
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发表时间：
2006-11-28
期刊：
影响因子：
37.8
通讯作者：
Knowlton, Kirk U.
中科院分区：
文献类型：
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作者：
Yajima, Toshitaka;Yasukawa, Hideo;Knowlton, Kirk U.
背景-心肌细胞内决定肠道病毒感染易感性的先天免疫机制知之甚少，肠道病毒感染是心肌炎和随后心力衰竭的重要原因。虽然干扰素（IFN）通常在先天免疫中起关键作用，但IFN受体的消融对心脏中的急性柯萨奇病毒B3感染几乎没有影响。有趣的是，gp 130-精氨酸介导的刺激新生心室肌细胞具有抗病毒感染的细胞保护作用，可以被细胞因子信号转导抑制因子（SOCS）-3抑制，SOCS-3是gp 130信号转导的生理抑制剂，不影响IFN信号转导。因此，我们假设，抑制gp 130信号SOCS 3将改变心肌细胞对病毒感染的易感性，而不影响IFN signaling.Methods和结果-我们产生了心脏特异性SOCS 3转基因小鼠。尽管在成年转基因心肌细胞中IFN介导的抗病毒反应是完整的，但在SOCS 3转基因小鼠心脏中对病毒感染的易感性显著增加。这表明在心肌细胞内存在IFN非依赖性先天防御机制。随后，我们证明了心脏特异性gp 130基因敲除小鼠对病毒感染的易感性也增加。此外，我们证明了gp 130介导的感染心肌细胞存活率的增加是通过不影响病毒复制的信号转导和转录激活因子3依赖性机制发生的。这是伴随着持续表达的全长肌营养不良蛋白柯萨奇病毒B3感染后。此外，我们发现，SOCS 3转基因和gp 130缺陷的小鼠有减少α-sarcoglycan.Conclusions -SOCS 3介导的调节gp 130信号可以影响心脏病毒感染的易感性。通过gp 130-信号转导子和转录激活子-3信号转导增加心肌细胞存活似乎在保护非分裂心肌细胞直到特异性免疫应答开始清除病毒方面发挥重要作用。
Background - Little is known about innate immune mechanisms within the cardiac myocyte that determine susceptibility to enterovirus infection, an important cause of myocarditis and subsequent heart failure. Although interferon (IFN) generally plays a key role in innate immunity, ablation of IFN receptors has little or no effect on acute coxsackievirus B3 infection in the heart. Interestingly, gp130-cytokine-mediated stimulation of neonatal ventricular myocytes has a cytoprotective effect against virus infection in culture that can be inhibited by suppressors of cytokine signaling (SOCS)-3, a physiological inhibitor of gp130 signaling that does not affect IFN signaling. Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling.Methods and Results - We generated cardiac-specific SOCS3 transgenic mice. Despite an intact IFN-mediated antiviral response in adult transgenic myocytes, there was a marked increase in susceptibility to viral infection in the SOCS3 transgenic mouse hearts. This indicated the presence of IFN-independent innate defense mechanisms within the cardiac myocyte. Subsequently, we demonstrated that cardiac-specific gp130-knockout mice also had increased susceptibility to viral infection. Furthermore, we demonstrated that the gp130-mediated increase in survival of infected myocytes occurred through a signal transducers and activators of transcription-3-dependent mechanism that did not affect viral replication. This was accompanied by a persistent expression of full-length dystrophin after coxsackievirus B3 infection. In addition, we found that both SOCS3 transgenic and gp130-deficient mice had a decrease in alpha-sarcoglycan.Conclusions - SOCS3-mediated regulation of gp130 signaling can affect susceptibility to viral infection in the heart. Increased cardiac cell survival through gp130-signal transducers and activators of transcription-3 signaling appears to play an important role in preserving nondividing cardiac myocytes until specific immune responses begin to clear the virus.