Interleukin-6 Promotes Pulmonary Emphysema Associated with Apoptosis in Mice
Interleukin-6 Promotes Pulmonary Emphysema Associated with Apoptosis in Mice
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DOI：
10.1165/rcmb.2010-0462oc
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发表时间：
2011-10-01
影响因子：
6.4
通讯作者：
Jenkins, Brendan J.
中科院分区：
文献类型：
--
作者：
Ruwanpura, Saleela M.;McLeod, Louise;Jenkins, Brendan J.
IL-6细胞因子家族通过共同的gp 130辅助受体传递信号，与肺气肿的发病机制相关。然而，这些细胞因子引起肺气肿的确切机制仍不清楚。我们采用了体内遗传互补的方法来鉴定导致肺气肿的特异性IL-6细胞因子家族成员和gp 130调节的细胞过程。我们使用gp 130（F/F）小鼠纯合子的一个微妙的敲入突变gp 130，去调节细胞内信号的IL-6细胞因子家族。gp 130（F/F）小鼠在6月龄时自发地发展肺气肿。在IL-6细胞因子家族中，只有IL-6在gp 130（F/F）小鼠的肺中显著上调，并且gp 130（F/F）小鼠中IL-6的遗传靶向（gp 130（F/F）：IL-6（-/-））预防肺气肿。相比之下，通过IL-11的受体信号传导的基因消融，其类似于通过gp 130同源二聚体的IL-6信号传导，并使用相同的信号传导机制，未能改善gp 130（F/F）小鼠的肺气肿。在检查的疾病相关过程中，肺气肿与肺泡细胞凋亡升高密切相关。急性（4天）暴露于香烟烟雾（CS）进一步增加了gp 130（F/F）小鼠肺中IL-6的表达，亚慢性（6周）暴露于CS加剧了gp 130（F/F）小鼠肺中的肺气肿和凋亡变化，但对gp 130（F/F）：IL-6（-/-）小鼠没有影响。IL-6是IL-6细胞因子家族诱导的肺气肿的主要病原体，并在肺中诱导细胞凋亡。我们认为，IL-6信号的离散靶向可能提供一种有效的治疗策略，对人类肺部疾病。
The IL-6 cytokine family, which signals via the shared gp130 coreceptor, is linked with the pathogenesis of emphysema. However, the definitive mechanisms by which these cytokines cause emphysema remain ill-defined. We took an in vivo genetic complementation approach to identify the specific IL-6 cytokine family members and gp130-regulated cellular processes that cause emphysema. We used gp130(F/F) mice homozygous for a subtle knock-in mutation in gp130 that deregulates intracellular signaling by the IL-6 cytokine family. The gp130(F/F) mice spontaneously develop emphysema by age 6 months. Within the IL-6 cytokine family, only IL-6 was significantly up-regulated in the lungs of gp130(F/F) mice, and the genetic targeting of IL-6 in gp130(F/F) mice (gp130(F/F): IL-6(-/-)) prevented emphysema. By contrast, the genetic ablation of receptor signaling via IL-11, which like IL-6 signals via a gp130 homodimer and uses the same signaling machinery, failed to ameliorate emphysema in gp130(F/F) mice. Among the disease-associated processes examined, emphysema strongly correlated with elevated alveolar cell apoptosis. Acute (4-day) exposure to cigarette smoke (CS) further augmented the expression of IL-6 in lungs of gp130(F/F) mice, and subchronic (6-week) exposure to CS exacerbated emphysematous and apoptotic changes in the lungs of gp130(F/F) but not gp130(F/F): IL-6(-/-) mice. IL-6 is the main causative agent of IL-6 cytokine family-induced emphysema, and operates to induce apoptosis in the lung. We propose that the discrete targeting of IL-6 signaling may provide an effective therapeutic strategy against human lung disease.