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 proliferation of synoviocytes. This is consistent with the active production of factors such as platelet-derived growth factor (PDGF) and IL-1 by the synovitis, 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-1 beta stimulated rheumatoid arthritis synoviocyte proliferation in a dose-dependent manner and through its 130 kDa receptor. This antiproliferative effect of IL-4 directly correlated with a blockade of the synoviocyte cell cycle at the G0 + G1 phases. We also observed that IL-4 induced striking morphologic changes in IL-1 beta or PDGF-stimulated synoviocytes, including increased volume and granulosity. These changes led to major perturbations of the cell monolayer, associated with a marked decrease of synoviocyte viability. Taken together, these data indicate that IL-4 inhibits growth factor-induced proliferation of synoviocytes by interfering with the cell cycle, and by decreasing cell survival.
Dechanet
J
J
Schering-Plough Laboratory for Immunological Research, Dardilly, France.
Briolay
J
J
Rissoan
M C
MC
Chomarat
P
P
Galizzi
J P
JP
Banchereau
J
J
Miossec
P
P
D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000502:physiology; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology*
D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D015847:Interleukin-4