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J. Biol. Chem., Vol. 279, Issue 24, 25745-25754, June 11, 2004

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 279/24/25745    most recent M313319200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lesley, J. Articles by Mikecz, K. Search for Related Content PubMed PubMed Citation Articles by Lesley, J. Articles by Mikecz, K. Social Bookmarking                      What's this?

TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44^*

Jayne Lesley, István Gál, David J. Mahoney¶, Martin R. Cordell¶, Marilyn S. Rugg¶, Robert Hyman, Anthony J. Day¶||, and Katalin Mikecz**

From the Molecular and Cell Biology Laboratory, The Salk Institute, San Diego, California 92186, Departments of Orthopedic Surgery and Biochemistry, Rush University Medical Center, Chicago, Illinois 60612, and ^¶Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom

Interactions between CD44 and hyaluronan are implicated in the primary adhesion of lymphocytes to endothelium at inflammatory locations. Here we show that preincubation of hyaluronan with full-length recombinant TSG-6 or its Link module domain (Link_TSG6) enhances or induces the binding of hyaluronan to cell surface CD44 on constitutive and inducible cell backgrounds, respectively. These effects are blocked by CD44-specific antibodies and are absent in CD44-negative cells. Enhancement of CD44-mediated interactions of lymphoid cells with hyaluronan by TSG-6 proteins was seen under conditions of flow at shear forces that occur in post-capillary venules. Increases in the number of rolling cells were observed on substrates comprising TSG-6-hyaluronan complexes as compared with a substrate containing hyaluronan alone. In ligand competition experiments, cell surface-bound TSG-6-hyaluronan complexes were more potent than hyaluronan alone in inhibiting cell adhesion to immobilized hyaluronan. Link_TSG6 mutants with impaired hyaluronan binding function had a reduced ability to modulate ligand binding by cell surface CD44. However, some mutants that exhibited close to wild-type hyaluronan binding were found to have either reduced or increased activity, suggesting that some amino acid residues outside of the hyaluronan binding site might be involved in protein self-association, potentially leading to the formation of cross-linked hyaluronan fibers. In turn, cross-linked hyaluronan could increase the binding avidity of CD44 by inducing receptor clustering. The ability of TSG-6 to modulate the interaction of hyaluronan with CD44 has important implications for CD44-mediated cell activity at sites of inflammation, where TSG-6 is expressed.

Received for publication, December 5, 2003 , and in revised form, March 31, 2004.

^* This work was supported by National Institutes of Health Grants AI31613 (to R. H.) and AR45652 (to K. M.) and Arthritis Research Campaign Grants D0562 and M0625 (to A. J. D.). Flow cytometry facilities at the Salk Institute were supported by NCI, National Institutes of Health Core Grant CA14195 and the H. N. and Frances C. Berger Foundation. 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.

The on-line version of this article (available at http://www.jbc.org)contains Supplemental Figs. S1 and S2.

^|| To whom correspondence may be addressed: MRC Immunochemistry Unit, Dept. of Biochemistry, University of Oxford, South Park Rd., Oxford OX1 3QU, UK. Tel.: 44-1865-275349; Fax: 44-1865-275729; E-mail: tony.day{at}bioch.ox.ac.uk.

^** To whom correspondence may be addressed: Dept. of Orthopedic Surgery, Rush University Medical Center, 1735 W. Harrison St., 712 Cohn, Chicago, IL 60612. Tel.: 312-942-5767; Fax: 312-942-8828; E-mail: Katalin_Mikecz{at}rsh.net.

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