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Mediated by Fucosylated Proteoglycans Neutrophils With CD11b/CD18-Dependent Interactions of Neutrophils with Intestinal Epithelium Are Mediated by Fucosylated Proteoglycans This information is current as Ke Zen, Yuan Liu, Dana Cairo and Charles A. Parkos of September 29, 2021. J Immunol 2002; 169:5270-5278; ; doi: 10.4049/jimmunol.169.9.5270 http://www.jimmunol.org/content/169/9/5270 Downloaded from References This article cites 54 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/169/9/5270.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD11b/CD18-Dependent Interactions of Neutrophils with Intestinal Epithelium Are Mediated by Fucosylated Proteoglycans1 Ke Zen,2 Yuan Liu, Dana Cairo, and Charles A. Parkos CD11b/CD18-mediated adhesive interactions play a key role in regulating polymorphonuclear leukocytes (PMN)) migration across intestinal epithelium. However, the identity of epithelial ligands for migrating PMN remains obscure. In this study we investigated the role of carbohydrates in mediating adhesive interactions between T84 intestinal epithelial cells and CD11b/CD18 purified from PMN. Fucoidin, heparin/heparin sulfate, N-acetyl-D-glucosamine, mannose-6-phosphate, and laminarin were found to inhibit adhesion of T84 cells to CD11b/CD18. The most potent inhibitory effects were observed with fucoidin (50% inhibition -at 1–5 ؋ 10؊8 M). Binding assays demonstrated that fucoidin directly bound to CD11b/CD18 in a divalent cation- and sulfation Downloaded from dependent fashion that was blocked by anti-CD11b mAbs. Experiments employing CD11b/CD18 as a probe to blot T84 cell fucosylated proteins purified via fucose-specific lectin column revealed several candidate CD11b/CD18 binding proteins with molecular masses of 95, 50, 30, 25, and 20 kDa. Fucosidase treatment of T84 cells resulted in significantly reduced cell adhesion to CD11b/CD18, while no inhibition was observed after neuraminidase treatment. Finally, significant inhibition of T84 cell ad- hesion to CD11b/CD18 was observed after blocking cell proteoglycan synthesis with p-nitrophenyl-␤-D-xylopyranoside. These findings implicate epithelial cell surface proteoglycans decorated with sulfated fucose moieties as ligands for CD11b/CD18 during http://www.jimmunol.org/ PMN migration across mucosal surfaces. The Journal of Immunology, 2002, 169: 5270–5278. pithelial dysfunction and patient symptoms in inflamma- CD18 (6). While the precise localization of the lectin-like domain tory intestinal diseases such as ulcerative colitis and on CD11b is not known, results from a previous study suggested Crohn’s disease correlate with migration of polymorpho- localization between the I domain and C-terminal regions of E 3 nuclear leukocytes (PMN) across epithelial surfaces (1, 2). In CD11b (7). studies modeling the process of PMN migration across mucosal The unique structure of CD11b/CD18 enables it to bind to a surfaces, it has been shown that PMN transepithelial migration is wide variety of proteins and carbohydrates. Previously reported ␤ by guest on September 29, 2021 dependent on the leukocyte 2 integrin CD11b/CD18 (Mac-1, ligands for CD11b/CD18 include cell membrane proteins such as CR3), but not CD11a/CD18 (3). It is generally believed that ICAM-1 (6, 8) and soluble factors such as iC3b (9, 10), fibrinogen CD11b/CD18 mediates initial adhesion of PMN to epithelial (11), LPS (12, 13), elastase (14), oligodeoxynucleotide (15), zy- monolayers by interactions with a counter-receptor(s) on the epi- mosan (16), ␤-glucan (17), heparin (heparin sulfate) (18, 19), de- thelial cell surface. The nature of these counter-receptors or adhe- natured proteins (20), and a hookworm-derived neutrophil adhe- sive ligands that play an important role in regulating PMN trans- sion inhibitor (21). While ICAM-1 is the only cell membrane ␤ epithelial migration, however, have not been defined. Like other 2 protein ligand that has been reported for CD11b/CD18 and has integrins, CD11b/CD18 contains both an I or an A domain and a been shown to play an important role in PMN transendothelial lectin-like domain that mediate ligand specificity. An ϳ200-aa re- migration, it does not appear to play a role in PMN migration gion comprising the I domain has been extensively characterized, across intestinal epithelium. In particular, ICAM-1 expression is revealing homology to plasma proteins such as von Willebrand induced on the apical membrane of intestinal epithelial cells only factor, complement factor II, and extracellular matrix proteins, in- under certain inflammatory conditions (3, 22). Under these condi- cluding collagen and cartilage matrix protein (4, 5). It is also re- tions apically expressed ICAM-1 is not accessible as a ligand for garded as a major recognition site for several ligands of CD11b/ migrating PMN, because transepithelial migration is dependent on interactions of PMN with the basolateral membrane of intestinal Division of Gastrointestinal Pathology, Department of Pathology and Laboratory epithelial cells. These observations argue against a role for Medicine, Emory University, Atlanta, GA 30322 ICAM-1 as an adhesive ligand for PMN during transepithelial mi- Received for publication June 19, 2002. Accepted for publication August 30, 2002. gration in the intestine. Previous studies have also suggested that The costs of publication of this article were defrayed in part by the payment of page heparin binds to CD11b/CD18 (18, 19). It was proposed that ep- charges. This article must therefore be hereby marked advertisement in accordance ithelial cell surface proteoglycans decorated with heparin sulfate with 18 U.S.C. Section 1734 solely to indicate this fact. moieties (HSPGs) might serve as adhesive ligands for CD11b/ 1 This work was supported by National Institutes of Health Grant HL54229 (to CD18. However, no such HSPGs have yet been identified. Fur- C.A.P.). thermore, syndecan-1, a heparan sulfate proteoglycan that is ex- 2 Address correspondence and reprint requests to Dr. Ke Zen, Department of Pathol- ogy and Laboratory Medicine, Emory University, Whitehead Biomedical Building, pressed primarily on epithelial cells, does not support PMN Room 115, 615 Michael Street, Atlanta, GA 30322. E-mail address: [email protected] adhesion (18). 3 Abbreviations used in this paper: PMN, polymorphonuclear leukocytes; BCECF- Lectin-like properties of CD11b/CD18 have been borne out by AM, 2Ј,7Ј-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein, acetoxymethyl ester; several reports demonstrating carbohydrate binding to CD11b/ biotin-X-NHS, biotin-⑀-aminocaproic acid N-hydroxysuccinimide ester; BSA-F, BSA-fucoidin conjugate; HSPG, heparin sulfate proteoglycan; ␣-xy, p-nitrophenyl- CD18 (7, 16, 18). However, the role of epithelial cell surface car- ␣-D-xylopyranoside; ␤-xy, p-nitrophenyl-␤-D-xylopyranoside. bohydrates in CD11b/CD18-mediated adhesive interactions has Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 The Journal of Immunology 5271 not been characterized. Previously, it was shown that certain car- characteristic of CD11b and CD18, respectively (not shown). The typical bohydrates, such as mannose-6-phosphate, glucose-6-phosphate, yield of CD11b/CD18 from 1010 PMN ranged from 1 to 2 mg. heparin, and fucoidin, are effective inhibitors of PMN migration across T84 cell monolayers (23). These results strongly suggested T84 cell adhesion to purified CD11b/CD18 that carbohydrates play a role in regulating PMN transepithelial T84 cell adhesion to immobilized, purified CD11b/CD18 was performed as migration. However, the mechanism by which these carbohydrates previously described (25). Briefly, purified CD11b/CD18 (ϳ100 ␮g/ml in regulate PMN transepithelial migration and demonstration of their 150 mM NaCl, 2 mM MgCl2, 2 mM CaCl2, 100 mM Tris, and 1% N-octyl- ␤-D-glucopyranoside, pH 7.4) was diluted 20-fold with HBSS and imme- existence on the epithelial cell surface have not been reported. diately added to 96-well, flat-bottom, microtiter plates (ICN Biomedical, In the present study we tested a wide range of mono- and poly- Aurora, OH; 50 ␮l/well). Microtiter plates were kept at 4°C overnight to saccharides for inhibition of epithelial T84 cell adhesion to puri- allow for protein binding. Nonspecific protein binding was blocked by fied CD11b/CD18. We demonstrate that several carbohydrates, in- adding 1% BSA in HBSS solution for1hatroom temperature. Trypsin/ EDTA-elicited T84 cells were then washed twice with HBSS and incu- cluding fucoidin, heparin/heparin sulfate, N-acetyl-D-glucosamine, bated with 5 ␮g/ml BCECF-AM (Molecular Probe) in HBSS for 15 min at mannose-6-phosphate, and laminarin, can significantly inhibit the 37°C. After
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