IL-4 INHIBITS GROWTH FACTOR-STIMULATED RHEUMATOID SYNOVIOCYTE PROLIFERATION BY BLOCKING THE EARLY PHASES OF THE CELL-CYCLE

A major feature of rheumatoid arthritis is an uncontrolled proliferati on of synoviocytes. This is consistent with the active production of f actors such as platelet-derived growth factor (PDGF) and IL-1 by the s ynovitis, which act in vivo as well as in vitro as potent synoviocyte growth factors. We have previously shown that IL-4 is able to inhibit growth factor production in an ex vivo model of synovitis. Herein, we show that IL-4 strongly inhibited PDGF and IL-1beta stimulated rheumat oid arthritis synoviocyte proliferation in a dose-dependent manner and through its 130 kDa receptor. This antiproliferative effect of IL-4 d irectly correlated with a blockade of the synoviocyte cell cycle at th e G0 + G1 phases. We also observed that IL-4 induced striking morpholo gic changes in IL-1beta or PDGF-stimulated synoviocytes, including inc reased volume and granulosity. These changes led to major perturbation s of the cell monolayer, associated with a marked decrease of synovioc yte viability. Taken together, these data indicate that IL-4 inhibits growth factor-induced proliferation of synoviocytes by interfering wit h the cell cycle, and by decreasing cell survival.