Ross Bing X, Gao Nan, Cui Xinhan, Standiford Theodore J, Xu Jianjiang, Yu Fu-Shin X
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI 48201.
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201.
J Immunol. 2017 May 1;198(9):3536-3547. doi: 10.4049/jimmunol.1602087. Epub 2017 Mar 22.
The aim of this study was to elucidate the expression and functions of IL-24 in C57BL/6 mouse corneas in response to infection. Among IL-20R cytokines, only IL-24 was induced at both mRNA and protein levels by infection at early time points. The upregulation of IL-24 was dampened by flagellin pretreatment, which protects the corneas from microbial infection. Time course studies revealed bimodal early and later peaks of IL-24 expression, a pattern shared with suppressor of cytokine signaling (SOCS)3 but not IL-1β or IL-6. Silencing of IL-24 enhanced S100A8/A9 expression and suppressed SOCS3, IL-1β, IL-1RN, and matrix metalloproteinase 13 expression at 6 h postinfection. Downregulation of the IL-24 signaling pathway significantly reduced the severity of keratitis, whereas rIL-24 exacerbated -mediated tissue destruction. In vitro, rIL-1β induced the expression of SOCS3, IL-24, IL-1β, and IL-6 in primary cultured human corneal epithelial cells. rIL-24, alternatively, stimulated the expression of SOCS3, but not the others. In conclusion, IL-24 promotes keratitis through the suppression of early protective mucosal immunity, culminating in increased severity of keratitis.
本研究的目的是阐明白细胞介素-24（IL-24）在C57BL/6小鼠角膜中对感染的反应中的表达及功能。在白细胞介素-20受体（IL-20R）细胞因子中，只有IL-24在感染早期的mRNA和蛋白质水平均被诱导。鞭毛蛋白预处理可抑制IL-24的上调，而鞭毛蛋白预处理可保护角膜免受微生物感染。时间进程研究显示IL-24表达出现早期和后期双峰模式，这一模式与细胞因子信号转导抑制因子（SOCS）3相同，但与白细胞介素-1β（IL-1β）或白细胞介素-6（IL-6）不同。感染后6小时，IL-24沉默增强了S100A8/A9的表达，并抑制了SOCS3、IL-1β、白细胞介素-1受体拮抗剂（IL-1RN）和基质金属蛋白酶13的表达。IL-24信号通路的下调显著降低了角膜炎的严重程度，而重组IL-24（rIL-24）则加剧了介导的组织破坏。在体外，重组IL-1β诱导原代培养的人角膜上皮细胞中SOCS3、IL-24、IL-1β和IL-6的表达。相反，rIL-24刺激了SOCS3的表达，但不刺激其他因子的表达。总之，IL-24通过抑制早期保护性黏膜免疫促进角膜炎，最终导致角膜炎严重程度增加。
