GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates directs disease activity of ulcerative colitis.
GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates directs disease activity of ulcerative colitis.
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DOI：
10.1002/ibd.20827
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发表时间：
2009-05
影响因子：
4.9
通讯作者：
Nakayama, Jun
中科院分区：
文献类型：
--
作者：
Kobayashi, Motohiro;Hoshino, Hitomi;Masumoto, Junya;Fukushima, Mana;Suzawa, Kenichi;Kageyama, Shunsuke;Suzuki, Manabu;Ohtani, Haruo;Fukuda, Minoru;Nakayama, Jun
关键词：
弥漫性淋巴细胞浸润是溃疡性结肠炎（UC）的特征之一。这种淋巴细胞募集需要由L-选择素配体碳水化合物（6-磺基唾液酸刘易斯X-加帽的O-聚糖）和/或在高内皮微静脉（HEV）样血管上表达的粘膜地址素细胞粘附分子1（MAdCAM-1）介导的淋巴细胞滚动。本研究旨在阐明用L-选择素配体碳水化合物后修饰（“修饰”）的MAdCAM-1在UC发病机制和随后的临床结果中的作用。对UC活动期和缓解期以及正常结肠粘膜的活检标本进行CD 34、MAdCAM-1和MECA-79免疫染色，并对免疫染色切片进行定量分析。进行RT-PCR以评估MAdCAM-1和N-乙酰葡糖胺-6-O-磺基转移酶（GlcNAc 6STs）的转录物。通过免疫荧光、流式细胞术和蛋白质印迹分析用CD 34和MAdCAM-1以及参与L-选择素配体碳水化合物生物合成的酶转染的CHO和Lec 2细胞以表征GlcNAc 6ST的生化性质。UC患者MAdCAM-1+血管数量增加，活动期和缓解期之间无显著差异。与缓解期相比，在UC的活动期观察到具有优先GlcNAc 6ST-1转录物的MECA-79+与MAdCAM-1+血管的比率增加。MAdCAM-1蛋白与L-选择素配体碳水化合物共定位于HEV样血管的腔表面原位。GlcNAc 6ST-1优先利用MAdCAM-1作为L-选择素配体碳水化合物生物合成中GlcNAc-6-O-硫酸化的支架蛋白。UC疾病活性不受MAdCAM-1蛋白本身表达的调节，而是受GlcNAc 6ST-1介导的用L-选择素配体碳水化合物修饰MAdCAM-1蛋白的调节。
A diffuse lymphocyte infiltrate is one of the characteristic features of ulcerative colitis (UC). Such lymphocyte recruitment requires lymphocyte rolling mediated by L-selectin ligand carbohydrates (6-sulfo sialyl Lewis X-capped O-glycans) and/or mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on high endothelial venule (HEV)-like vessels. The present study was undertaken to elucidate the role of MAdCAM-1 posttranslationally modified (“decorated”) with L-selectin ligand carbohydrates in UC pathogenesis and consequent clinical outcomes. Biopsy specimens composed of active and remission phases of UC as well as normal colonic mucosa were immunostained for CD34, MAdCAM-1 and MECA-79, and the immunostained sections were quantitatively analyzed. RT-PCR was carried out to evaluate transcripts of MAdCAM-1 and N-acetylglucosamine-6-O-sulfotransferases (GlcNAc6STs). CHO and Lec2 cells transfected with CD34 and MAdCAM-1 together with enzymes involved in L-selectin ligand carbohydrate biosynthesis were analyzed by immunofluorescence, FACS and Western blotting to characterize biochemical property of GlcNAc6STs. The number of MAdCAM-1+ vessels was increased in UC, with no significant difference between active and remission phases. An increased ratio of MECA-79+ to MAdCAM-1+ vessels with preferential GlcNAc6ST-1 transcripts was observed in the active phase of UC compared to remission phase. MAdCAM-1 protein was co-localized with L-selectin ligand carbohydrates at the luminal surface of HEV-like vessels in situ. GlcNAc6ST-1 preferentially utilizes MAdCAM-1 as a scaffold protein for GlcNAc-6-O-sulfation in L-selectin ligand carbohydrate biosynthesis. UC disease activity is not regulated by expression of MAdCAM-1 protein itself, but rather by GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates.
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158.5
作者：
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通讯作者：
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