TSG-6 modulates the interaction between hyaluronan and cell surface CD44
TSG-6 modulates the interaction between hyaluronan and cell surface CD44
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DOI：
10.1074/jbc.m313319200
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发表时间：
2004-06-11
影响因子：
4.8
通讯作者：
Mikecz, K
中科院分区：
文献类型：
--
作者：
Lesley, J;Gál, I;Mikecz, K
CD44和透明质酸之间的相互作用与炎症部位淋巴细胞与内皮细胞的原发性粘附有关。本研究表明，透明质酸与全长重组TSG-6或其Link模块结构域（Link_TSG6）的预孵育分别在组成型和诱导型细胞背景下增强或诱导透明质酸与细胞表面CD44结合。这些作用被cd44特异性抗体阻断，在cd44阴性细胞中不存在。cd44介导的淋巴细胞与透明质酸的相互作用被TSG-6蛋白增强，在毛细管后小静脉发生剪切力流动的条件下。与单独含有透明质酸的底物相比，在含有tsg -6-透明质酸复合物的底物上观察到滚动细胞的数量增加。在配体竞争实验中，细胞表面结合的tsg -6透明质酸复合物比单独的透明质酸更有效地抑制细胞对固定化透明质酸的粘附。透明质酸结合功能受损的Link_TSG6突变体通过细胞表面CD44调节配体结合的能力降低。然而，一些表现出接近野生型透明质酸结合的突变体被发现活性降低或增加，这表明透明质酸结合位点外的一些氨基酸残基可能参与蛋白质自结合，可能导致交联透明质酸纤维的形成。反过来，交联透明质酸可以通过诱导受体聚集增加CD44的结合度。TSG-6调节透明质酸与CD44相互作用的能力对炎症部位CD44介导的细胞活性具有重要意义，而炎症部位正是TSG-6表达的地方。
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.