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Role of the Heparan Sulfate Proteoglycan Syndecan-1 (CD138) in Delayed-Type Hypersensitivity ¹

Behzad Kharabi Masouleh^*, Gerdy B. Ten Dam, Martin K. Wild, Ruth Seelige, Johan van der Vlag, Angelique L. Rops, Frank G. Echtermeyer^¶, Dietmar Vestweber, Toin H. van Kuppevelt, Ludwig Kiesel^* and Martin Götte^2,*

^* Department of Gynecology and Obstetrics, Medical Center, University of Münster, Münster, Germany; Department of Biochemistry and Nephrology Research Laboratory, Division of Nephrology, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; Max Planck Institute for Molecular Biomedicine, Münster, Germany; and ^¶ Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany

The cell surface heparan sulfate proteoglycan syndecan-1 (CD138) modulates the activity of chemokines, cytokines, integrins, and other adhesion molecules which play important roles in the regulation of inflammation. We have previously shown that syndecan-1-deficient murine leukocytes display increased interactions with endothelial cells and increased diapedesis in vivo and in vitro. In this study, we demonstrate that syndecan-1 has an important function as a negative modulator in the murine contact allergy model of oxazolone-mediated delayed-type hypersensitivity (DTH). Following elicitation of the DTH response, syndecan-1-deficient mice showed an increase in leukocyte recruitment, resulting in an increased and prolonged edema formation. Expression of the cytokines TNF- and IL-6 of the chemokines CCL5/RANTES and CCL-3/MIP-1 and of the adhesion molecule ICAM-1 were significantly increased in syndecan-1-deficient compared with wild-type mice. In wild-type mice, syndecan-1 mRNA and protein expression was reduced during the DTH response. The differentially increased adhesion of syndecan-1-deficient leukocytes to ICAM-1 was efficiently inhibited in vitro by CD18-blocking Abs, which emerges as one mechanistic explanation for the anti-inflammatory effects of syndecan-1. Collectively, our results show an important role of syndecan-1 in the contact DTH reaction, identifying syndecan-1 as a novel target in anti-inflammatory therapy.

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 a grant from the Münster University Hospital Innovative Medizinische Forschung IMF GÖ 120415 (to M.G.). M.K.W. and D.V. are supported by Grant SFB 293 of the Deutsche Forschungsgemeinschaft and by the Max Planck Society.

² Address correspondence and reprint requests to Dr. Martin Götte, Department of Gynecology and Obstetrics, Medical Center, University of Münster, Domagkstrasse 11, D-48149 Münster, Germany. E-mail address: martingotte{at}uni-muenster.de

³ Abbreviations used in this paper: DTH, delayed-type hypersensitivity; KO, knockout; MPO, myeloperoxidase; PMN, polymorphonuclear cell; Sdc, syndecan; WT, wild type; GBM, glomerular basement membrane; Ct, threshold cycle.

⁴ The online version of this article contains supplemental material.