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Extracellular Matrix Heparan Sulfate Macrophages Regulates Cell Surface Localization of Heparanase on Macrophages Regulates Degradation of Extracellular Matrix Heparan Sulfate This information is current as Norihiko Sasaki, Nobuaki Higashi, Tomohiro Taka, Motowo of September 23, 2021. Nakajima and Tatsuro Irimura J Immunol 2004; 172:3830-3835; ; doi: 10.4049/jimmunol.172.6.3830 http://www.jimmunol.org/content/172/6/3830 Downloaded from References This article cites 39 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/172/6/3830.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 23, 2021 *average 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Cell Surface Localization of Heparanase on Macrophages Regulates Degradation of Extracellular Matrix Heparan Sulfate1 Norihiko Sasaki,2* Nobuaki Higashi,* Tomohiro Taka,* Motowo Nakajima,† and Tatsuro Irimura3* Extravasation of peripheral blood monocytes through vascular basement membranes requires degradation of extracellular matrix components including heparan sulfate proteoglycans (HSPGs). Heparanase, the heparan sulfate-specific endo-␤-glucuronidase, has previously been shown to be a key enzyme in melanoma invasion, yet its involvement in monocyte extravasation has not been elucidated. We examined a potential regulatory mechanism of heparanase in HSPG degradation and transmigration through basement membranes in leukocyte trafficking using human promonocytic leukemia U937 and THP-1 cells. PMA-treated cells were shown to degrade 35S-sulfated HSPG in endothelial extracellular matrix into fragments of an approximate molecular mass of 5 kDa. This was not found with untreated cells. The gene expression levels of heparanase or the enzyme activity of the amount of Downloaded from cell lysates were no different between untreated and treated cells. Immunocytochemical staining with anti-heparanase mAb revealed pericellular distribution of heparanase in PMA-treated cells but not in untreated cells. Cell surface heparanase capped into a restricted area on PMA-treated cells when they were allowed to adhere. Addition of a chemoattractant fMLP induced polarization of the PMA-treated cells and heparanase redistribution at the leading edge of migration. Therefore a major regu- latory process of heparanase activity in the cells seems to be surface expression and capping of the enzyme. Addition of the anti-heparanase Ab significantly inhibited enzymatic activity and transmigration of the PMA-treated cells, suggesting that the cell http://www.jimmunol.org/ surface redistribution of heparanase is involved in monocyte extravasation through basement membranes. The Journal of Im- munology, 2004, 172: 3830–3835. acrophages and related cells play essential roles in the HS. The HS moieties play essential roles in the interaction of immune system, such as inflammation, defense against HSPG with a wide range of molecules including ECM components M microbial infection, immunity to foreign substances, (collagen, laminin, fibronectin, and others), cytokines (basic fibro- wound healing, and angiogenesis. Monocytes circulate throughout blast growth factor, platelet-derived growth factor, hepatocyte the body, extravasate through the endothelial lining of the blood growth factor, and others), and enzymes (lipoprotein lipase and vessel wall, and enter the underlying tissue in response to local others) (1–3). Degradation of HS causes loss of mechanical integ- by guest on September 23, 2021 inflammation. During the process, monocytes should pass through rity of basement membrane and release of soluble mediators. the vascular basement membrane that supports the structure and The first indication that HS maintains the mechanical integrity survival of endothelial cells and also prevents the vessels from of basement membrane came from a work in which heparitinase mechanical destruction. The basement membrane mainly consists 4 digestion of glomerular basement membranes resulted in a loss of of type IV collagen, laminin, and heparan sulfate (HS) proteo- function (4). The ability of tumor cells to degrade basement mem- glycans (HSPGs). Degradation of these basement membrane com- brane was shown to be due to a HS-specific endo-␤-glucuronidase ponents results in disintegration of the structure and it is conceiv- (5, 6). cDNA cloning and expression of human heparanase have able that such processes are a regulatory step for the extravasation. recently been reported by four groups (7–10). The cDNA encodes HSPGs are ubiquitous in extracellular matrices (ECMs) including a unique protein of 543 amino acids that contains a potential signal basement membranes, and consist of diverse core polypeptides and peptide sequence and six putative N-linked glycosylation sites. It was predicted that the 543-aa polypeptide formed a proenzyme *Laboratory of Cancer Biology and Molecular Immunology, Graduate School of that was processed to be a mature 50 kDa active enzyme after Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; and †Tsukuba Research removal of 157 N-terminal amino acids. The active enzyme has Institute, Novartis Pharma, Tsukuba, Japan been claimed to be a heterodimer that comprises the 50-kDa Received for publication August 26, 2003. Accepted for publication January 7, 2004. polypeptide and a short fragment of 8-kDa peptide derived from The costs of publication of this article were defrayed in part by the payment of page the N terminus of heparanase proenzyme (11). The active enzyme charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. shows at least 100-fold HS degradation activity in comparison to 1 This work was supported by Grants-in-Aid from the Ministry of Education, Science, the proenzyme (8), therefore this processing could be one of the Sports and Culture of Japan (11557180, 11672162, and 12307054), and from the critical regulatory steps of heparanase. Although it was assumed Program for Promotion of Basic Research Activities for Innovative Biosciences. that secreted or membrane-associated heparanase is responsible for 2 Current address: Division of Cell Biology, Institute of Life Science, Soka Univer- the degradation of ECM, the mechanisms involved in translocation sity, Tokyo 192-8577, Japan. of the enzyme have not been elucidated. 3 Address correspondence and reprint requests to Dr. Tatsuro Irimura, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Heparanase activity was reported in platelets, neutrophils, Tokyo 113-0033, Japan. E-mail address: [email protected] monocytes, macrophages, Langerhans cells, astrocytes, activated 4 Abbreviations used in this paper: HS, heparan sulfate; HSPG, HS proteoglycan; (but not resting) rat T lymphocytes, and umbilical vein endothelial ECM, extracellular matrix; FL-HS, fluoresceinamine-labeled HS; SVBCE, simian virus bovine corneal endothelial cell; EDC, 1-ethyl-3-(3-dimethylaminopropyl)car- cells or smooth-muscle cells (12–19). It is likely that heparanase is bodiimide hydrochloride; MMP, matrix metalloproteinase. required for extravasation of the cells in the immune system, and Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 The Journal of Immunology 3831 the activity should be under tight regulation to avoid tissue dam- X-100, 1 mM PMSF, 0.2 mM AEBSF, 10 ␮g/ml leupeptin, 10 ␮g/ml age. In the present study, we asked whether the heparanase is in- pepstatin A, 1 ␮g/ml aprotinin, pH 7.5) on ice for 30 min, followed by volved in macrophage extravasation by use of macrophage-like centrifugation at 15,000 rpm for 10 min. Protein concentrations of the supernatants were determined with bicinchoninic acid protein assay using cell lines. Regulation of heparanase activity during macrophage BSA as a standard (Pierce). For preparation of fluoresceinated HS as the differentiation and attachment to basement membranes was also heparanase substrate, HS (sodium salt, 1 mg), EDC (0.2 mg), and fluores- investigated. A major regulatory process seems to be its unique ceinamine (FL; Fluka, Tokyo, Japan) (5 ␮g) were dissolved in water, and spatial distribution. stirred for1hatroom temperature, followed by dialysis overnight with water. The solution was then concentrated with a Centricon 30 concentrator (Amicon, Bedford, MA). The ratio of attached fluorescein to unmodified Materials and Methods carboxyl group was determined using the carbazole-sulfuric acid method. Chemicals An enzymatic reaction was conducted in a 100 ␮l mixture containing 25 mM sodium acetate buffer (pH 5.5), 5 ␮g of FL-HS, 20 mM D-saccharic RPMI 1640 medium was purchased from Nissui Pharmaceuticals (Tokyo, acid 1,4-lactone (Sigma-Aldrich), and cell lysates at 37°C for 24 h. The
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