FGF23 Induction of O-Linked N-Acetylglucosamine Regulates IL-6 Secretion in Human Bronchial Epithelial Cells
FGF23 Induction of O-Linked N-Acetylglucosamine Regulates IL-6 Secretion in Human Bronchial Epithelial Cells
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DOI：
10.3389/fendo.2018.00708
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发表时间：
2018-11-27
影响因子：
5.2
通讯作者：
Barnes, Jarrod W.
中科院分区：
文献类型：
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作者：
Krick, Stefanie;Helton, Eric Scott;Barnes, Jarrod W.
己糖胺生物合成途径（HBP）产生O-linked β - n -乙酰氨基葡萄糖（O-GlcNAc）修饰蛋白质的底物。HBP还可以作为应激传感器，并被报道参与活化t细胞核因子（NFAT）的激活，这可以促进多种细胞过程，包括细胞代谢、增殖和炎症。在我们之前发表的报告中，成纤维细胞生长因子（FGF） 23，一种重要的内分泌促炎介质，被证明在慢性炎症性气道疾病如囊性纤维化（CF）和慢性阻塞性肺疾病（COPD）中激活FGFR4/磷脂酶C γ (PLC γ)/活化t细胞核因子（NFAT）信号。在这里，我们证明FGF23增加了HBECs中蛋白质的O-GlcNAc修饰。此外，FGF23刺激O-GlcNAc水平升高导致下游NFAT激活和白细胞介素-6 （IL-6）分泌。相反，抑制FGF23信号传导和/或O-GlcNAc转移酶(OGT)/O-GlcNAc可逆转这些作用。总的来说，这些数据表明，FGF23诱导的IL-6上调和分泌至少部分是通过激活HBP和O-GlcNAc水平介导的。这些发现确定了一种新的联系，即FGF23和O-GlcNAc水平的增加通过NFAT激活和IL-6上调在HBECs中调节气道炎症。这些信号通路之间的相互作用可能有助于慢性炎症性气道疾病（如COPD和CF）以及代谢综合征（包括糖尿病）的发病机制。
The hexosamine biosynthetic pathway (HBP) generates the substrate for the O-linked beta-N-acetylglucosamine (O-GlcNAc) modification of proteins. The HBP also serves as a stress sensor and has been reported to be involved with nuclear factor of activated T-cells (NFAT) activation, which can contribute to multiple cellular processes including cell metabolism, proliferation, and inflammation. In our previously published report, Fibroblast Growth Factor (FGF) 23, an important endocrine pro-inflammatory mediator, was shown to activate the FGFR4/phospholipase C gamma (PLC gamma)/nuclear factor of activated T-cells (NFAT) signaling in chronic inflammatory airway diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Here, we demonstrate that FGF23 increased the O-GlcNAc modification of proteins in HBECs. Furthermore, the increase in O-GlcNAc levels by FGF23 stimulation resulted in the downstream activation of NFAT and secretion of interleukin-6 (IL-6). Conversely, inhibition of FGF23 signaling and/or O-GlcNAc transferase (OGT)/O-GlcNAc reversed these effects. Collectively, these data suggest that FGF23 induced IL-6 upregulation and secretion is, at least, partially mediated via the activation of the HBP and O-GlcNAc levels in HBECs. These findings identify a novel link whereby FGF23 and the augmentation of O-GlcNAc levels regulate airway inflammation through NFAT activation and IL-6 upregulation in HBECs. The crosstalk between these signaling pathways may contribute to the pathogenesis of chronic inflammatory airway diseases such as COPD and CF as well as metabolic syndromes, including diabetes.