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Inflamm Bowel Dis. 2009 May;15(5):697-706. doi: 10.1002/ibd.20827.

GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates directs disease activity of ulcerative colitis.

Author information

1
Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan. motokoba@shinshu-u.ac.jp

Abstract

BACKGROUND:

A diffuse lymphocyte infiltrate is 1 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.

METHODS:

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. Reverse-transcriptase polymerase chain reaction (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 the biochemical properties of GlcNAc6STs.

RESULTS:

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 the remission phase. MAdCAM-1 protein was colocalized 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.

CONCLUSIONS:

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.

PMID:
19067429
PMCID:
PMC2696616
DOI:
10.1002/ibd.20827
[Indexed for MEDLINE]
Free PMC Article

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