TSG-6, a new protein ligand for CXCL8, modulates the activity of this pro-inflammatory chemokine (54.12)

Abstract

Abstract TSG-6, a 35 kDa secreted protein, is expressed during inflammation (e.g. in the cartilage/synovium of arthritis patients) and delays the onset/reduces the severity of joint damage in models of inflammatory arthritis. For example, TSG-6-/- mice with proteoglycan-induced arthritis exhibit elevated neutrophil invasion and protease activity in the paw joints compared to controls. The aim of this study is to investigate potential mechanisms for the anti-inflammatory and chondroprotective effects of TSG-6, focusing on its interaction with CXCL8. This chemokine is known to promote neutrophil migration and to induce matrix metalloproteinase (MMP) secretion by endothelial cells. Using plate-based assays and surface plasmon resonance we have demonstrated that TSG-6 binds to CXCL8 in a pH-dependent manner and that TSG-6 can inhibit the interaction of CXCL8 with heparin. Since the sequestration of CXCL8 by endothelial glycosaminoglycans (e.g. heparan sulphate) contributes to its pro-migratory activity, this might represent one mechanism through which TSG-6 limits neutrophil extravasation. We have also shown, using gelatin zymography, that TSG-6 can block the CXCL8-mediated production of active MMPs by endothelial cells. MMPs have been implicated in the destruction of articular cartilage in arthritis, where they occur at elevated levels (e.g. in RA synovial fluids). Inhibition of the expression and/or activation of MMPs could, therefore, contribute to TSG-6’s chondroprotective effect.