The anti-inflammatory protein TSG-6 regulates chemokine function by inhibiting chemokine:glycosaminoglycan interactions

Dyer, D. P. , Salanga, C. L., Johns, S. C., Valdambrini, E., Fuster, M. M., Milner, C. M., Day, A. J. and Handel, T. M. (2016) The anti-inflammatory protein TSG-6 regulates chemokine function by inhibiting chemokine:glycosaminoglycan interactions. Journal of Biological Chemistry, 291, pp. 12627-12640. (doi: 10.1074/jbc.M116.720953) (PMID:27044744) (PMCID:27044744)

Abstract

TNF-stimulated gene-6 (TSG-6) is a multifunctional protein secreted in response to pro-inflammatory stimuli by a wide range of cells including neutrophils, monocytes and endothelial cells. It has been shown to mediate anti-inflammatory and protective effects when administered in disease models, in part, by reducing neutrophil infiltration. Human TSG-6 inhibits neutrophil migration by binding CXCL8 through its Link module (Link_TSG6) and interfering with the presentation of CXCL8 on cell-surface glycosaminoglycans (GAGs), an interaction that is vital for the function of many chemokines. TSG-6 was also found to interact with chemokines CXCL11 and CCL5, suggesting the possibility that it may function as a broad specificity chemokine-binding protein, functionally similar to those encoded by viruses. The present study was therefore undertaken to explore the ability of TSG-6 to regulate the function of other chemokines. Herein, we demonstrate that Link_TSG6 binds chemokines from both the CXC and CC families, including CXCL4, CXCL12, CCL2, CCL5, CCL7, CCL19, CCL21 and CCL27. We also show that the Link_TSG6 binding sites on chemokines overlap with chemokine GAG-binding sites, and that the affinity of Link_TSG6 for these chemokines (KD values 1-85 nM) broadly correlates with chemokine:GAG affinity. Link_TSG6 also inhibits chemokine presentation on endothelial cells not only through a direct interaction with chemokines, but also by binding and therefore masking the availability of GAGs. Along with previous work, these findings suggest that TSG-6 functions as a pluripotent regulator of chemokines by modulating chemokine:GAG interactions, which may be a major mechanism by which TSG-6 produces its anti-inflammatory effects in vivo.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dyer, Dr Douglas
• Authors: Dyer, D. P., Salanga, C. L., Johns, S. C., Valdambrini, E., Fuster, M. M., Milner, C. M., Day, A. J., and Handel, T. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Biological Chemistry
• Publisher: American Society for Biochemistry and Molecular Biology, Inc.
• ISSN: 0021-9258
• ISSN (Online): 1083-351X
• Copyright Holders: Copyright © 2016 American Society for Biochemistry and Molecular Biology, Inc.
• First Published: First published in Journal of Biological Chemistry 291:12627-12640
• Publisher Policy: Reproduced under a Creative Commons License