Interleukin-11 Links Oxidative Stress and Compensatory Proliferation
Interleukin-11 Links Oxidative Stress and Compensatory Proliferation
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DOI：
10.1126/scisignal.2002056
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发表时间：
2012-01-17
影响因子：
7.3
通讯作者：
Nakano, Hiroyasu
中科院分区：
文献类型：
--
作者：
Nishina, Takashi;Komazawa-Sakon, Sachiko;Nakano, Hiroyasu
凋亡细胞可以刺激周围细胞的代偿性增殖，维持组织的动态平衡。虽然氧化应激与细胞凋亡和坏死有关，但它是否促进代偿性增殖尚不清楚。在这里，我们发现IL-11(IL-11)是IL-6促炎症细胞因子家族的成员，是由细胞以氧化应激依赖的方式产生的。IL-11的产生依赖于死亡细胞中细胞外信号调节激酶2的激活，后者通过阻止转录因子Fra-1的蛋白酶体依赖的降解而导致转录因子Fra-1的磷酸化和积聚。FRA-1随后被招募到IL11启动子并激活基因转录。在小鼠急性肝损伤时，IL-11主要是由肝细胞对死亡的肝细胞释放的活性氧作出反应而产生的。死亡细胞分泌的IL-11诱导邻近健康肝细胞转录因子STAT3的磷酸化，导致其代偿性增殖。此外，IL-11受体(IL-11R)激动剂可促进肝细胞增殖，减轻对乙酰氨基酚所致肝损伤时的氧化应激反应。相反，在缺乏IL-11Ra亚单位的小鼠中，对乙酰氨基酚的影响加剧。综上所述，这些结果表明，IL-11在氧化应激和代偿性增殖之间提供了一种功能联系。
Apoptotic cells can stimulate the compensatory proliferation of surrounding cells to maintain tissue homeostasis. Although oxidative stress is associated with apoptosis and necrosis, whether it contributes to compensatory proliferation is unknown. Here, we showed that interleukin-11 (IL-11), a member of the IL-6 family of proinflammatory cytokines, was produced by cells in an oxidative stress-dependent manner. IL-11 production depended on the activation in dying cells of extracellular signal-regulated kinase 2, which in turn caused the phosphorylation and accumulation of the transcription factor Fra-1 by preventing its proteasome-dependent degradation. Fra-1 was subsequently recruited to the Il11 promoter and activated gene transcription. Upon acute liver injury in mice, IL-11 was mainly produced by hepatocytes in response to reactive oxygen species that were presumably released from dying hepatocytes. IL-11 that was secreted by the dying cells then induced the phosphorylation of the transcription factor STAT3 in adjacent healthy hepatocytes, which resulted in their compensatory proliferation. Furthermore, an IL-11 receptor (IL-11R) agonist enhanced the proliferation of hepatocytes and ameliorated oxidative stress upon acetaminophen-induced liver injury. Conversely, the effects of acetaminophen were exacerbated in mice deficient in the IL-11R a subunit. Together, these results suggest that IL-11 provides a functional link between oxidative stress and compensatory proliferation.