title: TSG-6 inhibits neutrophil migration via direct interaction with the chemokine CXCL8.
abstract: TNF-stimulated gene/protein-6 (TSG-6) is expressed by many different cell types in response to proinflammatory cytokines and plays an important role in the protection of tissues from the damaging consequences of acute inflammation. Recently, TSG-6 was identified as being largely responsible for the beneficial effects of multipotent mesenchymal stem cells, for example in the treatment of animal models of myocardial infarction and corneal injury/allogenic transplant. The protective effect of TSG-6 is due in part to its inhibition of neutrophil migration, but the mechanisms underlying this activity remain unknown. In this study, we have shown that TSG-6 inhibits chemokine-stimulated transendothelial migration of neutrophils via a direct interaction (KD, ∼ 25 nM) between TSG-6 and the glycosaminoglycan binding site of CXCL8, which antagonizes the association of CXCL8 with heparin. Furthermore, we found that TSG-6 impairs the binding of CXCL8 to cell surface glycosaminoglycans and the transport of CXCL8 across an endothelial cell monolayer. In vivo this could limit the formation of haptotactic gradients on endothelial heparan sulfate proteoglycans and, hence, integrin-mediated tight adhesion and migration. We further observed that TSG-6 suppresses CXCL8-mediated chemotaxis of neutrophils; this lower potency effect might be important at sites where there is high local expression of TSG-6. Thus, we have identified TSG-6 as a CXCL8-binding protein, making it, to our knowledge, the first soluble mammalian chemokine-binding protein to be described to date. We have also revealed a potential mechanism whereby TSG-6 mediates its anti-inflammatory and protective effects. This could inform the development of new treatments for inflammation in the context of disease or following transplantation.
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom;
authors: Douglas P
authors: DP
authors: Dyer
authors: Jennifer M
authors: JM
authors: Thomson
authors: Aurelie
authors: A
authors: Hermant
authors: Thomas A
authors: TA
authors: Jowitt
authors: Tracy M
authors: TM
authors: Handel
authors: Amanda E I
authors: AE
authors: Proudfoot
authors: Anthony J
authors: AJ
authors: Day
authors: Caroline M
authors: CM
authors: Milner
mesh_terms: D064591:Allografts; D001665:Binding Sites; D001693:Biological Transport, Active / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002465:Cell Movement / Q000502:physiology*; D018922:HL-60 Cells; D006493:Heparin; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D033581:Stem Cell Transplantation
chemical_list: C508606:CXCL8 protein, human; D015815:Cell Adhesion Molecules; D016209:Interleukin-8; C072273:TNFAIP6 protein, human; D006493:Heparin