Heparan sulfate proteoglycan on endothelium efficiently 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 cells in the synovium of patients with rheumatoid arthritis (RA). Methods Endothelial cells were purified from RA synovium. Expression of heparan sulfate, chemokines, and adhesion molecules on the endothelium was assessed by immunohistochemical analysis or flow cytometry. The effects of chemokines and heparan sulfate on T cell adhesion to RA endothelium were estimated with relevant antibodies and signaling inhibitors. Production of chemokines from synovial T cells was detected by Northern blotting and enzyme‐linked immunosorbent assay. Results The endothelium in RA synovium highly expressed HSPG. The soluble form of chemokines, macrophage inflammatory protein 1β (MIP‐1β), induced T cell adhesion to the endothelial cells. When MIP‐1α and MIP‐1β were immobilized on RA endothelial cells, a more efficient integrin‐mediated 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‐1α antibody, or anti‐MIP‐1β antibody, indicating that these chemokines were bound to heparan sulfate on the cells. T cell adhesion was also inhibited by pertussis toxin, wortmannin, and cytochalasin B. MIP‐1α and MIP‐1β were found on vessels in RA synovium in vivo, which were spontaneously produced from T cells purified from RA synovium. Conclusion Endothelial cells in RA synovium characteristically express HSPG, which is involved in T cell integrin triggering by “posting” chemokines, which are produced by synovial 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.