Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA.
Nat Commun. 2018 Aug 14;9(1):3244. doi: 10.1038/s41467-018-05485-x.
IL-33 is an epithelium-derived, pro-inflammatory alarmin with enigmatic nuclear localization and chromatin binding. Here we report the functional properties of nuclear IL-33. Overexpression of IL-33 does not alter global gene expression in transduced epithelial cells. Fluorescence recovery after photobleaching data show that the intranuclear mobility of IL-33 is ~10-fold slower than IL-1α, whereas truncated IL-33 lacking chromatin-binding activity is more mobile. WT IL-33 is more resistant to necrosis-induced release than truncated IL-33 and has a relatively slow, linear release over time after membrane dissolution as compared to truncated IL-33 or IL-1α. Lastly, IL-33 and histones are released as a high-molecular weight complex and synergistically activate receptor-mediated signaling. We thus propose that chromatin binding is a post-translational mechanism that regulates the releasability and ST2-mediated bioactivity of IL-33 and provide a paradigm to further understand the enigmatic functions of nuclear cytokines.
IL-33 是一种上皮细胞衍生的、促炎的警报素，具有神秘的核定位和染色质结合。在这里，我们报告核 IL-33 的功能特性。过表达 IL-33 不会改变转导上皮细胞中的全局基因表达。光漂白后荧光恢复数据表明，核内 IL-33 的迁移率比 IL-1α 慢约 10 倍，而缺乏染色质结合活性的截断 IL-33 迁移率更快。WT IL-33 比截断的 IL-33 更能抵抗坏死诱导的释放，并且与截断的 IL-33 或 IL-1α 相比，在膜溶解后，其释放速度相对较慢，呈线性。最后，IL-33 和组蛋白以高分子量复合物的形式释放，并协同激活受体介导的信号转导。因此，我们提出染色质结合是一种翻译后机制，可调节 IL-33 的释放性和 ST2 介导的生物活性，并为进一步了解核细胞因子的神秘功能提供了范例。
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