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01.04.2016 | Original Article—Alimentary Tract

N-Acetylglucosaminyltransferase V exacerbates murine colitis with macrophage dysfunction and enhances colitic tumorigenesis

verfasst von: Shinichiro Shinzaki, Mayuko Ishii, Hironobu Fujii, Hideki Iijima, Kana Wakamatsu, Shoichiro Kawai, Eri Shiraishi, Satoshi Hiyama, Takahiro Inoue, Yoshito Hayashi, Ryusuke Kuwahara, Shinji Takamatsu, Yoshihiro Kamada, Eiichi Morii, Masahiko Tsujii, Tetsuo Takehara, Eiji Miyoshi

Erschienen in: Journal of Gastroenterology | Ausgabe 4/2016

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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.

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Hart GW, Copeland RJ. Glycomics hits the big time. Cell. 2010;143:672–6.CrossRefPubMedPubMedCentral

Keusch J, Lydyard PM, Delves PJ. The effect on IgG glycosylation of altering β1,4-galactosyltransferase-1 activity in B cells. Glycobiology. 1998;8:1215–20.CrossRefPubMed

Zhao Y, Sato Y, Isaji T, et al. Branched N-glycans regulate the biological functions of integrins and cadherins. FEBS J. 2008;275:1939–48.CrossRefPubMed

Taniguchi N, Miyoshi E, Ko JH, et al. Implication of N-acetylglucosaminyltransferases III and V in cancer: gene regulation and signaling mechanism. Biochim Biophys Acta. 1999;1455:287–300.CrossRefPubMed

Taniguchi N, Ihara S, Saito T, et al. Implication of GnT-V in cancer metastasis: a glycomic approach for identification of a target protein and its unique function as an angiogenic cofactor. Glycoconj J. 2001;18:859–65.CrossRefPubMed

Granovsky M, Fata J, Pawling J, et al. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med. 2000;6:306–12.CrossRefPubMed

Li D, Li Y, Wu X, et al. Knockdown of Mgat5 inhibits breast cancer cell growth with activation of CD4+ T cells and macrophages. J Immunol. 2008;180:3158–65.CrossRefPubMed

Miyoshi E, Nishikawa A, Ihara Y, et al. N-Acetylglucosaminyltransferase III and V messenger RNA levels in LEC rats during hepatocarcinogenesis. Cancer Res. 1993;53:3899–902.PubMed

Miyoshi E, Ihara Y, Nishikawa A, et al. Gene expression of N-acetylglucosaminyltransferases III and V: a possible implication for liver regeneration. Hepatology. 1995;22:1847–55.PubMed

10.

Kimura A, Terao M, Kato A, et al. Upregulation of N-acetylglucosaminyltransferase-V by heparin-binding EGF-like growth factor induces keratinocyte proliferation and epidermal hyperplasia. Exp Dermatol. 2012;21:515–9.CrossRefPubMed

11.

Terao M, Ishikawa A, Nakahara S, et al. Enhanced epithelial-mesenchymal transition-like phenotype in N-acetylglucosaminyltransferase V transgenic mouse skin promotes wound healing. J Biol Chem. 2011;286:28303–11.CrossRefPubMedPubMedCentral

12.

Leone V, Chang EB, Devkota S. Diet, microbes, and host genetics: the perfect storm in inflammatory bowel diseases. J Gastroenterol. 2013;48:315–21.CrossRefPubMedPubMedCentral

13.

Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;287:G7–17.CrossRefPubMed

14.

Shinzaki S, Iijima H, Nakagawa T, et al. IgG oligosaccharide alterations are a novel diagnostic marker for disease activity and the clinical course of inflammatory bowel disease. Am J Gastroenterol. 2008;103:1173–81.CrossRefPubMed

15.

Shinzaki S, Iijima H, Fujii H, et al. Altered oligosaccharide structures reduce colitis induction in mice defective in β-1,4-galactosyltransferase. Gastroenterology. 2012;142:1172–82.CrossRefPubMed

16.

Theodoratou E, Campbell H, Ventham NT, et al. The role of glycosylation in IBD. Nat Rev Gastroenterol Hepatol. 2014;11:588–600.PubMed

17.

Iijima H, Neurath MF, Nagaishi T, et al. Specific regulation of T helper cell 1-mediated murine colitis by CEACAM1. J Exp Med. 2004;199:471–82.CrossRefPubMedPubMedCentral

18.

Dohi T, Ejima C, Kato R, et al. Therapeutic potential of follistatin for colonic inflammation in mice. Gastroenterology. 2005;128:411–23.CrossRefPubMed

19.

Long E, Huynh HT, Zhao X. Involvement of insulin-like growth factor-1 and its binding proteins in proliferation and differentiation of murine bone marrow-derived macrophage precursors. Endocrine. 1998;9:185–92.CrossRefPubMed

20.

Aicher WK, Fujihashi K, Yamamoto M, et al. Effects of the lpr/lpr mutation on T and B cell populations in the lamina propria of the small intestine, a mucosal effector site. Int Immunol. 1992;4:959–68.CrossRefPubMed

21.

Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J Surg Res. 1990;49:186–96.CrossRefPubMed

22.

Weisser SB, Brugger HK, Voglmaier NS, et al. SHIP-deficient, alternatively activated macrophages protect mice during DSS-induced colitis. J Leukoc Biol. 2011;90:483–92.CrossRefPubMed

23.

Dieleman LA, Ridwan BU, Tennyson GS, et al. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology. 1994;107:1643–52.PubMed

24.

Wirtz S, Neufert C, Weigmann B, et al. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–6.CrossRefPubMed

25.

Inoue T, Murano M, Abe Y, et al. Therapeutic effect of nimesulide on colorectal carcinogenesis in experimental murine ulcerative colitis. J Gastroenterol Hepatol. 2007;22:1474–81.CrossRefPubMed

26.

Kuhn R, Lohler J, Rennick D, et al. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–74.CrossRefPubMed

27.

Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.CrossRefPubMed

28.

Edwards JP, Zhang X, Frauwirth KA, et al. Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol. 2006;80:1298–307.CrossRefPubMedPubMedCentral

29.

Boonstra A, Rajsbaum R, Holman M, et al. Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals. J Immunol. 2006;177:7551–8.CrossRefPubMed

30.

Murai M, Turovskaya O, Kim G, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10:1178–84.CrossRefPubMedPubMedCentral

31.

Lacy-Hulbert A, Smith AM, Tissire H, et al. Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. Proc Natl Acad Sci U S A. 2007;104:15823–8.CrossRefPubMedPubMedCentral

32.

Chung EY, Liu J, Homma Y, et al. Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1. Immunity. 2007;27:952–64.CrossRefPubMedPubMedCentral

33.

Kamada N, Hisamatsu T, Okamoto S, et al. Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. J Immunol. 2005;175:6900–8.CrossRefPubMed

34.

Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol. 2003;3:169–76.CrossRefPubMed

35.

Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.CrossRefPubMed

36.

Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–41.CrossRefPubMed

37.

Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–8.CrossRefPubMed

38.

Yang H, Hreggvidsdottir HS, Palmblad K, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A. 2010;107:11942–7.CrossRefPubMedPubMedCentral

39.

Means TK. Fungal pathogen recognition by scavenger receptors in nematodes and mammals. Virulence. 2010;1:37–41.CrossRefPubMedPubMedCentral

40.

Nishitani C, Takahashi M, Mitsuzawa H, et al. Mutational analysis of Cys⁸⁸ of Toll-like receptor 4 highlights the critical role of MD-2 in cell surface receptor expression. Int Immunol. 2009;21:925–34.CrossRefPubMed

41.

Fiala M, Liu PT, Espinosa-Jeffrey A, et al. Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer’s disease patients are improved by bisdemethoxycurcumin. Proc Natl Acad Sci U S A. 2007;104:12849–54.CrossRefPubMedPubMedCentral

Titel: N-Acetylglucosaminyltransferase V exacerbates murine colitis with macrophage dysfunction and enhances colitic tumorigenesis
verfasst von: Shinichiro Shinzaki
Mayuko Ishii
Hironobu Fujii
Hideki Iijima
Kana Wakamatsu
Shoichiro Kawai
Eri Shiraishi
Satoshi Hiyama
Takahiro Inoue
Yoshito Hayashi
Ryusuke Kuwahara
Shinji Takamatsu
Yoshihiro Kamada
Eiichi Morii
Masahiko Tsujii
Tetsuo Takehara
Eiji Miyoshi
Publikationsdatum: 01.04.2016
Verlag: Springer Japan
Erschienen in: Journal of Gastroenterology / Ausgabe 4/2016
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-015-1119-3

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