TNF regulates sialyl-Lewisx and 6-sulfo-sialyl-Lewisx expression in human lung through up-regulation of ST3GAL4 transcript isoform BX
TNF regulates sialyl-Lewisx and 6-sulfo-sialyl-Lewisx expression in human lung through up-regulation of ST3GAL4 transcript isoform BX
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DOI：
10.1016/j.biochi.2012.05.030
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发表时间：
2012-09-01
期刊：
影响因子：
3.9
通讯作者：
Groux-Degroote, Sophie
中科院分区：
文献类型：
--
作者：
Colomb, Florent;Krzewinski-Recchi, Marie-Ange;Groux-Degroote, Sophie
来自患有肺部疾病如慢性支气管炎或囊性纤维化的严重感染患者的支气管粘蛋白表现出增加量的唾液酸-路易斯（x）（NeuAc α 2-3Gal β 1-4[Fuc α 1-3]GlcNAc-R，sLe（x））聚糖结构。在囊性纤维化中，sLe（x）及其硫酸化形式6-磺基-唾液酰-刘易斯（x）（NeuAc α 2-3Gal β 1-4 [Fuc α 1-3]（HO 3S-6）GlcNAc-R，6-磺基-sLe（x））作为铜绿假单胞菌的受体，并参与气道感染的慢性化。然而，很少有人知道的分子机制，调节糖基化和硫酸化的气道粘蛋白的变化。在此，我们表明，促炎细胞因子TNF增加α 2，3-唾液酸转移酶基因ST 3GAL 4的表达，在人支气管粘膜和A549肺癌细胞。通过siRNA沉默ST 3GAL 4基因证实了唾液酸转移酶ST 3Gal IV在sLe（x）生物合成中的作用。BX是在健康支气管粘膜和A549细胞中表达的主要转录异构体，并且在两种模型中均被TNF上调。生物信息学分析和荧光素酶分析证实，BX外显子周围的2kb基因组序列包含一个受TNF相关转录因子调控的启动子区。这些结果支持旨在开发抗炎策略以减少囊性纤维化等疾病中的慢性气道感染的进一步工作。(C)2012年Elsevier Masson SAS。All rights reserved.
Bronchial mucins from severely infected patients suffering from lung diseases such as chronic bronchitis or cystic fibrosis exhibit increased amounts of sialyl-Lewis(x) (NeuAc alpha 2-3Gal beta 1-4[Fuc alpha 1-3]GlcNAc-R, sLe(x)) glycan structures. In cystic fibrosis, sLe(x) and its sulfated form 6-sulfo-sialyl-Lewis(x) (NeuAc alpha 2-3Gal beta 1-4 [Fuc alpha 1-3](HO3S-6)GlcNAc-R, 6-sulfo-sLe(x)) serve as receptors for Pseudomonas aeruginosa and are involved in the chronicity of airway infection. However, little is known about the molecular mechanisms regulating the changes in glycosylation and sulfation of mucins in airways. Herein, we show that the proinflammatory cytokine TNF increases the expression of alpha 2,3-sialyltransferase gene ST3GAL4, both in human bronchial mucosa and in A549 lung carcinoma cells. The role of sialyltransferase ST3Gal IV in sLe(x) biosynthesis was confirmed by siRNA silencing of ST3GAL4 gene. BX is the major transcript isoform expressed in healthy bronchial mucosa and in A549 cells, and is up-regulated by TNF in both models. Bioinformatics analysis and luciferase assays have confirmed that the 2 kb genomic sequence surrounding BX exon contains a promoter region regulated by TNF-related transcription factors. These results support further work aiming at the development of anti-inflammatory strategy to reduce chronic airway infection in diseases such as cystic fibrosis. (C) 2012 Elsevier Masson SAS. All rights reserved.