Interleukin 33 as a mechanically responsive cytokine secreted by living cells
Interleukin 33 as a mechanically responsive cytokine secreted by living cells
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白细胞介素 33 作为活细胞分泌的机械响应细胞因子
DOI：
10.1055/s-0034-1367392
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发表时间：
2014
影响因子：
1.5
通讯作者：
Richard T. Lee
中科院分区：
文献类型：
--
作者：
R. Kakkar;Hillary Hei;S. Dobner;H. Reichenspurner;Richard T. Lee
背景资料：白细胞介素33（IL-33）是白细胞介素1细胞因子家族的成员，与许多人类炎症性疾病如哮喘、动脉粥样硬化和类风湿性关节炎有关。尽管其病理生理学的重要性，关于IL-33的基础生物学的基本问题仍然存在。核定位和缺乏输出信号序列与IL-33作为具有抑制RNA转录能力的核因子的观点一致。然而，信号通过跨膜受体ST 2和记录半胱天冬酶依赖性失活表明IL-33释放细胞坏死过程中的影响旁分泌signaling.Methods和结果：我们确定了IL-33的亚细胞定位和跟踪其细胞内的流动性和细胞外释放。与已发表的数据相反，IL-33同时定位于核常染色质和膜结合的胞质囊泡。荧光脉冲追踪记录动态核质通量，这是依赖于核孔复合体功能。在小鼠成纤维细胞在体外和体内，机械应变诱导IL-33分泌的情况下cellularnecrosis.Conclusions：这些数据文件IL-33的动态细胞器间的贩运和释放过程中的生物力学过载。因此，我们将IL-33重新定性为活细胞分泌的炎症性细胞因子和机械反应性细胞因子。
Background: Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling.Methods and results: We determined the sub-cellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleocytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis.Conclusions: These data document IL-33's dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells.