IL-6 Cytoprotection in Hyperoxic Acute Lung Injury Occurs via Suppressor of Cytokine Signaling-1-Induced Apoptosis Signal-Regulating Kinase-1 Degradation
IL-6 Cytoprotection in Hyperoxic Acute Lung Injury Occurs via Suppressor of Cytokine Signaling-1-Induced Apoptosis Signal-Regulating Kinase-1 Degradation
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DOI：
10.1165/rcmb.2007-0287oc
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发表时间：
2009-03-01
影响因子：
6.4
通讯作者：
Waxman, Aaron B.
中科院分区：
文献类型：
--
作者：
Kolliputi, Narasaiah;Waxman, Aaron B.
高氧急性肺损伤（HALI）的特征在于细胞死亡反应，其被IL-6抑制。细胞因子信号转导抑制因子-1（SOCS-1）是IL-6介导的Janus激酶信号转导和转录激活因子信号转导途径的抗凋亡负调节因子。我们假设SOCS-1是IL-6诱导的HALI细胞保护的关键调节因子和关键介质。为了验证这一假设，我们的特点表达SOCS-1和下游凋亡信号调节激酶（ASK）-1-Jun N-末端激酶信号分子在小气道上皮细胞中的H2 O2的存在下，诱导氧化应激。我们还在暴露于100%氧气72小时的野生型和肺特异性IL-6转基因（Tg（+））小鼠中检测了这些分子。在暴露于H2 O2的对照小气道上皮细胞或暴露于100%氧气的野生型小鼠中，观察到ASK-1和plun N-末端激酶的显著诱导。IL-6刺激的内源性SOCS-1和SOCS-1过表达都能抑制H2 O2诱导的ASK-1活化。此外，与野生型小鼠相比，暴露于100%氧气的IL-6 Tg+小鼠表现出降低的ASK-1水平和增强的SOCS-1表达。有趣的是，在野生型和IL-6 Tg（+）小鼠之间没有观察到关键的ASK-1激活剂，肿瘤坏死因子受体-1//肿瘤坏死因子受体相关因子-2的活化的显著变化。此外，SOCS-1和ASK-1之间的相互作用促进了体内和体外泛素介导的降解。这些研究表明，SOCS-1是IL-6诱导的抗HALL细胞保护作用的重要调节因子
Hyperoxic acute lung injury (HALI) is characterized by a cell death response that is inhibited by IL-6. Suppressor of cytokine signaling-1 (SOCS-1) is an antiapoptotic negative regulator of the IL-6-mediated Janus kinase-signal transducer and activator of transcription signaling pathway. We hypothesized that SOCS-1 is a critical regulator and key mediator of IL-6-induced cytoprotection in HALI. To test this hypothesis, we characterized the expression of SOCS-1 and downstream apoptosis signal-regulating kinase (ASK)-1-Jun N-terminal kinase signaling molecules in small airway epithelial cells in the presence of H2O2, which induces oxidative stress. We also examined these molecules in wild-type and lung-specific IL-6 trans genic (Tg(+)) mice exposed to 100% oxygen for 72 hours. In control small airway epithelial cells exposed to H2O2 or in wild-type mice exposed to 100% oxygen, a marked induction of ASK-1 and plun N-terminal kinase was observed. Both IL-6-stimulated endogenous SOCS-1 and SOCS-1 overexpression abolished H2O2-induced ASK-1 activation. In addition, IL-6 Tg+ mice exposed to 100% oxygen exhibited reduced ASK-1 levels and enhanced SOCS-1 expression compared with wild-type mice. Interestingly, no significant changes in activation of the key ASK-1 activator, tumor necrosis factor receptor-1//tumor necrosis factor receptor-associated factor-2 were observed between wild-type and IL-6 Tg(+) mice. Furthermore, the interaction between SOCS-1 and ASK-1 promotes ubiquitin-mediated degradation both in vivo and in vitro. These studies demonstrate that SOCS-1 is an important regulator in IL-6-induced cytoprotection against HALL