Shinichiro Shinzaki1, Mayuko Ishii2, Hironobu Fujii2, Hideki Iijima1, Kana Wakamatsu2, Shoichiro Kawai1, Eri Shiraishi1, Satoshi Hiyama1, Takahiro Inoue1, Yoshito Hayashi1, Ryusuke Kuwahara3, Shinji Takamatsu2, Yoshihiro Kamada1,2, Eiichi Morii4, Masahiko Tsujii1, Tetsuo Takehara1, Eiji Miyoshi5. 1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1, Yamadaoka, Suita, Osaka, 565-0871, Japan. 2. Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 565-0871, Japan. 3. Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, 7-1, Mihogaoka, Ibaraki, Osaka, 567-0047, Japan. 4. Department of Pathology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. 5. Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamadaoka, Suita, Osaka, 565-0871, Japan. emiyoshi@sahs.med.osaka-u.ac.jp.
Abstract
BACKGROUND: Oligosaccharide structures and their alterations have important roles in modulating intestinal inflammation. N-Acetylglucosaminyltransferase V (GnT-V) is involved in the biosynthesis of N-acetylglucosamine (GlcNAc) by β1,6-branching on N-glycans and is induced in various pathologic processes, such as inflammation and regeneration. GnT-V alters host immune responses by inhibiting the functions of CD4(+) T cells and macrophages. The present study aimed to clarify the role of GnT-V in intestinal inflammation using GnT-V transgenic mice. METHODS: Colitis severity was compared between GnT-V transgenic mice and wild-type mice. β1,6-GlcNAc levels were investigated by phytohemagglutinin-L4 lectin blotting and flow cytometry. We investigated phagocytosis of macrophages by measuring the number of peritoneal-macrophage-ingested fluorescent latex beads by flow cytometry. Cytokine production in the culture supernatant of mononuclear cells from the spleen, mesenteric lymph nodes, and bone-marrow-derived macrophages was determined by enzyme-linked immunosorbent assay. Clodronate liposomes were intravenously injected to deplete macrophages in vivo. Chronic-colitis-associated tumorigenesis was assessed after 9 months of repeated administration of dextran sodium sulfate (DSS). RESULTS: DSS-induced colitis and colitis induced by trinitrobenzene sulfonic acid were markedly exacerbated in GnT-V transgenic mice compared with wild-type mice. Production of interleukin-10 and phagocytosis of macrophages were significantly impaired in GnT-V transgenic mice compared with wild-type mice. Clodronate liposome treatment to deplete macrophages blocked the exacerbation of DSS-induced colitis and impairment of interleukin-10 production in GnT-V transgenic mice. Chronic-colitis-associated tumorigenesis was significantly increased in GnT-V transgenic mice. CONCLUSIONS: Overexpression of GnT-V exacerbated murine experimental colitis by inducing macrophage dysfunction, thereby enhancing colorectal tumorigenesis.
BACKGROUND:Oligosaccharide structures and their alterations have important roles in modulating intestinal inflammation. N-Acetylglucosaminyltransferase V (GnT-V) is involved in the biosynthesis of N-acetylglucosamine (GlcNAc) by β1,6-branching on N-glycans and is induced in various pathologic processes, such as inflammation and regeneration. GnT-V alters host immune responses by inhibiting the functions of CD4(+) T cells and macrophages. The present study aimed to clarify the role of GnT-V in intestinal inflammation using GnT-Vtransgenic mice. METHODS:Colitis severity was compared between GnT-Vtransgenic mice and wild-type mice. β1,6-GlcNAc levels were investigated by phytohemagglutinin-L4 lectin blotting and flow cytometry. We investigated phagocytosis of macrophages by measuring the number of peritoneal-macrophage-ingested fluorescent latex beads by flow cytometry. Cytokine production in the culture supernatant of mononuclear cells from the spleen, mesenteric lymph nodes, and bone-marrow-derived macrophages was determined by enzyme-linked immunosorbent assay. Clodronate liposomes were intravenously injected to deplete macrophages in vivo. Chronic-colitis-associated tumorigenesis was assessed after 9 months of repeated administration of dextran sodium sulfate (DSS). RESULTS:DSS-induced colitis and colitis induced by trinitrobenzene sulfonic acid were markedly exacerbated in GnT-Vtransgenic mice compared with wild-type mice. Production of interleukin-10 and phagocytosis of macrophages were significantly impaired in GnT-Vtransgenic mice compared with wild-type mice. Clodronate liposome treatment to deplete macrophages blocked the exacerbation of DSS-induced colitis and impairment of interleukin-10 production in GnT-Vtransgenic mice. Chronic-colitis-associated tumorigenesis was significantly increased in GnT-Vtransgenic mice. CONCLUSIONS: Overexpression of GnT-V exacerbated murine experimental colitis by inducing macrophage dysfunction, thereby enhancing colorectal tumorigenesis.
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