Adenoviral-mediated overexpression of SOCS3 enhances IgG immune complex-induced acute lung injury
Adenoviral-mediated overexpression of SOCS3 enhances IgG immune complex-induced acute lung injury
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DOI：
10.4049/jimmunol.177.1.612
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Gao, Hongwei;Hoesel, L. Marco;Ward, Peter A.
由IgG免疫复合物（IC）的肺内沉积引起的肺部炎症反应包括IL-6的产生，IL-6通过STAT转录因子的激活发出信号。近年来，细胞因子信号转导抑制因子3（SOCS 3）被证实是IL-6/gp 130/Jak/STAT 3信号转导的关键负调节因子。尽管SOCS 3与几种炎症性疾病有关，但关于其在急性炎症期间在肺中的激活和功能知之甚少。我们的前期研究表明，肺内沉积IgG IC后，肺内IL-6/STAT 3激活被触发。在目前的研究中，我们试图确定SOCS 3是否在肺部炎症反应中发挥调节作用。SOCS 3诱导发生在肺损伤的IgG IC模型中的炎症发展期间。使用编码鼠SOCS 3的重组腺病毒在肺中过表达SOCS 3导致肺血管通透性和肺髓过氧化物酶的显著增加，以及支气管肺泡灌洗液中TNF-α、MIP-2和角质形成细胞激活的细胞因子水平的增加。在该炎症模型中，SOCS 3在肺中的过表达导致支气管肺泡灌洗液IL-6而不是IL-10的过度产生。我们进一步表明，STAT 3的激活抑制SOCS 3过表达，以及抗IL-6治疗IgG IC诱导的肺损伤，如EMSA所确定的。在体外，SOCS 3过表达废除了IL-6诱导的肺上皮细胞中STAT 3的活化。这些发现表明SOCS 3是IgG IC沉积后肺炎症损伤的重要调节因子。
The lung inflammatory response caused by intratracheal deposition of IgG immune complexes (IC) includes the production of IL-6, which signals through activation of STAT transcription factors. Recently, suppressor of cytokine signaling 3 (SOCS3) has been shown to be a key negative regulator of IL-6/gp130/Jak/STAT3 signal transduction. Although SOCS3 has been implicated in several inflammatory diseases, very little is known regarding its activation and its function in the lung during acute inflammation. Our previous study showed that IL-6/STAT3 activation was triggered in lungs after intrapulmonary deposition of IgG IC in rats. In the current study, we sought to determine whether SOCS3 is playing a regulatory role in the lung inflammatory response. SOCS3 induction occurred during development of inflammation in the IgG IC model of lung injury. Overexpression of SOCS3 in lung using a recombinant adenovirus encoding murine SOCS3 resulted in substantial increases in lung vascular permeability and lung myeloperoxidase, together with enhanced levels of TNF-alpha, MIP-2, and keratinocyte-activated cytokine in bronchoalveolar lavage fluids. SOCS3 overexpression in lungs led to overproduction of bronchoalveolar lavage IL-6, but not IL-10, in this inflammatory model. We further show that activation of STAT3 was inhibited by SOCS3 overexpression as well as by anti-IL-6 treatment during IgG IC-induced lung injury, as determined by EMSA. In vitro, SOCS3 overexpression abrogated IL-6-induced activation of STAT3 in lung epithelial cells. These findings suggest SOCS3 is an important regulator of lung inflammatory injury after deposition of IgG IC.