HEPARAN-SULFATE PROTEOGLYCAN ON ENDOTHELIUM EFFICIENCY INDUCES INTEGRIN-MEDIATED T-CELL ADHESION BY IMMOBILIZING CHEMOKINES IN PATIENTS WITH RHEUMATOID SYNOVITIS

Objective. To clarify the role of heparan sulfate proteoglycan (HSPG) and chemokines in integrin-mediated T cell adhesion to endothelial cel ls in the synovium of patients with rheumatoid arthritis (RA). Methods . Endothelial cells were purified from RA synovium. Expression of hepa ran sulfate, chemokines, and adhesion molecules on the endothelium was assessed by immunohistochemical analysis or now cytometry. The effect s of chemokines and heparan sulfate on T cell adhesion to RA endotheli um were estimated with relevant antibodies and signaling inhibitors. P roduction of chemokines from synovial T cells was detected by Northern blotting and enzyme-linked immunosorbent assay. Results. The endothel ium in RA synovium highly expressed HSPG. The soluble form of chemokin es, macrophage inflammatory protein 1 beta (MIP-1 beta), induced T cel l adhesion to the endothelial cells. When MIP-1 alpha and MIP-1 beta w ere immobilized on RA endothelial cells, a more efficient integrin-med iated adhesion of T cells was induced compared with their soluble form . The induced T cell adhesion was reduced by pretreatment with either heparitinase, anti-MIP-1 alpha antibody, or anti-MIP-1 beta antibody, indicating that these chemokines were bound to heparan sulfate on the cells. T cell adhesion was also inhibited by pertussis toxin, wortmann in, and cytochalasin B, MIP-1 alpha and MIP-1 beta were found on vesse ls in RA synovium in vivo, which were spontaneously produced from T ce lls purified from RA synovium. Conclusion. Endothelial cells in RA syn ovium characteristically express HSPG, which is involved in T cell int egrin triggering by ''posting'' chemokines, which are produced by syno vial T cells, and by ''relaying'' them to their receptors on T cells, which activate G protein-dependent phosphoinositide 3-kinase and actin -dependent integrin triggering.