An immunoprotective privilege of corneal epithelial stem cells against Th17 inflammatory stress by producing glial cell-derived neurotrophic factor.
An immunoprotective privilege of corneal epithelial stem cells against Th17 inflammatory stress by producing glial cell-derived neurotrophic factor.
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DOI：
10.1002/stem.539
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发表时间：
2010-12
期刊：
影响因子：
5.2
通讯作者：
Li, De-Quan
中科院分区：
文献类型：
--
作者：
Bian, Fang;Qi, Hong;Ma, Ping;Zhang, Lili;Yoon, Kyung-Chul;Pflugfelder, Stephen C.;Li, De-Quan
成体干细胞以其自我更新和再生能力而闻名。保护这些细胞免受炎性损伤的机制尚未得到很好的阐明。本研究探讨了角膜上皮干细胞通过产生胶质细胞源性神经营养因子（GDNF）对炎症的免疫保护作用。用白细胞介素（IL）-17 A、肿瘤坏死因子（TNF）-α或高渗培养液处理原代人角膜缘上皮细胞（HLECs）4-48 h，同时加入或不加入GDNF或核因子κ B（NF-κB）抑制剂（NF-κB-I）。通过实时聚合酶链反应、酶联免疫吸附试验和免疫珠试验测定炎症介质和Th 17诱导细胞因子。通过p65磷酸化、免疫组化和Western blotting检测NF-κB活化。GDNF及其受体GDNF家族受体α-1仅免疫定位于角膜缘上皮基底层，而IL-17受体在这些细胞中为阴性。外源性IL-17 A刺激HLEC表达和产生炎性细胞因子（TNF-α、IL-6和IL-1β）和趋化因子IL-8。TNF-α或高渗培养液可使HLECs的Th 17诱导细胞因子转化生长因子（TGF）-β1、IL-6、IL-23和IL-1β在mRNA和蛋白水平显著升高。IL-17通过p65丝氨酸536位磷酸化和核转位激活NF-κB。GDNF或NF-κB-I阻断IL-17诱导的NF-κB p65活化和炎症介质的产生。GDNF通过抑制NF-κB的活化，抑制Th 17诱导的细胞因子的产生。这些结果表明，角膜缘祖细胞产生的神经营养因子GDNF通过NF-κB信号通路抑制IL-17介导的炎症。这可能代表了角膜缘干细胞对眼表炎症挑战的独特免疫保护特性。
Adult stem cells are well known for their self-renewal and regenerative capacity. The mechanisms protecting these cells from inflammatory damage have not been well elucidated. This study investigated the immunoprotective properties of corneal epithelial stem cells from inflammation by producing glial cell-derived neurotrophic factor (GDNF). Primary human limbal epithelial cells (HLECs) cultured from limbal explants were treated with interleukin (IL)-17A, tumor necrosis factor (TNF)-α, or hyperosmotic media, with or without GDNF or nuclear factor kappa B (NF-κB) inhibitor (NF-κB-I) for 4–48 hours. Inflammatory mediators and Th17-inducing cytokines were determined by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunobead assays. NF-κB activation was detected by p65 phosphorylation, immunostaining and Western blotting. GDNF and its receptor, GDNF family receptor α-1, were exclusively immunolocalized in the basal layer of limbal epithelium, whereas IL-17 receptor was negative in these cells. Exogenous IL-17A stimulated the expression and production of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and chemokine IL-8 by HLECs. Th17-inducing cytokines, transforming growth factor (TGF)-β1, IL-6, IL-23, and IL-1β, were significantly increased at mRNA and protein levels by HLECs exposed to TNF-α or hyperosmotic media. IL-17 activated NF-κB by p65 phosphorylation at serine 536 and nuclear translocation. GDNF or NF-κB-I blocked IL-17-induced NF-κB p65 activation and production of inflammatory mediators. Furthermore, GDNF suppressed the production of Th17-inducing cytokines through inhibiting NF-κB activation. These findings demonstrate that limbal progenitor cell-produced neurotrophic factor GDNF suppresses IL-17-mediated inflammation via NF-κB signaling pathway. This may represent a unique immunoprotective property of limbal stem cells against inflammatory challenges on the ocular surface.
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