TSG-6 modulates the interaction between hyaluronan and cell surface CD44

被引:149
作者
Lesley, J
Gál, I
Mahoney, DJ
Cordell, MR
Rugg, MS
Hyman, R
Day, AJ
Mikecz, K
机构
[1] Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL 60612 USA
[2] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA
[3] Salk Inst, Mol & Cell Biol Lab, San Diego, CA 92186 USA
[4] Univ Oxford, Dept Biochem, MRC, Immunochem Unit, Oxford OX1 3QU, England
关键词
D O I
10.1074/jbc.M313319200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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收藏
页码:25745 / 25754
页数:10
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