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Monocyte Cell Surface Glycosaminoglycans Positively Modulate IL-4-Induced Differentiation toward Dendritic Cells¹

Els den Dekker^*, Sander Grefte^*, Tonnie Huijs^*, Gerdy B. ten Dam, Elly M. M. Versteeg, Lieke C. J. van den Berk^*, Bellinda A. Bladergroen^*, Toin H. van Kuppevelt, Carl G. Figdor^* and Ruurd Torensma^2,*

^* Department of Tumor Immunology and Department of Matrix Biochemistry, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

IL-4 induces the differentiation of monocytes toward dendritic cells (DCs). The activity of many cytokines is modulated by glycosaminoglycans (GAGs). In this study, we explored the effect of GAGs on the IL-4-induced differentiation of monocytes toward DCs. IL-4 dose-dependently up-regulated the expression of DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), CD80, CD206, and CD1a. Monocytes stained positive with Abs against heparan sulfate (HS) and chondroitin sulfate (CS) B (CSB; dermatan sulfate), but not with Abs that recognize CSA, CSC, and CSE. Inhibition of sulfation of monocyte/DC cell surface GAGs by sodium chlorate reduced the reactivity of sulfate-recognizing single-chain Abs. This correlated with hampered IL-4-induced DC differentiation as evidenced by lower expression of DC-SIGN and CD1a and a decreased DC-induced PBL proliferation, suggesting that sulfated monocyte cell surface GAGs support IL-4 activity. Furthermore, removal of cell surface chondroitin sulfates by chondroitinase ABC strongly impaired IL-4-induced STAT6 phosphorylation, whereas removal of HS by heparinase III had only a weak inhibitory effect. IL-4 bound to heparin and CSB, but not to HS, CSA, CSC, CSD, and CSE. Binding of IL-4 required iduronic acid, an N-sulfate group (heparin) and specific O sulfates (CSB and heparin). Together, these data demonstrate that monocyte cell surface chondroitin sulfates play an important role in the IL-4-driven differentiation of monocytes into DCs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Technology Foundation Stichting Technische Wetenschappen (NGC 5611 and NGC 5926) and the Dutch Cancer Society (KWF 2002-2762).

² Address correspondence and reprint requests to Dr. Ruurd Torensma, Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences 278, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands. E-mail address: r.torensma{at}ncmls.ru.nl

³ Abbreviations used in this paper: DC, dendritic cell; GAG, glycosaminoglycan; CS, chondroitin sulfate; HS, heparan sulfate; FGF, fibroblast growth factor; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin; MHC-I, MHC class I; VSV, vesicular stomatitis virus.