INTERLEUKIN-4, BUT NOT INTERLEUKIN-10, REGULATES THE PRODUCTION OF INFLAMMATION MEDIATORS BY RHEUMATOID SYNOVIOCYTES

Rheumatoid synovitis is characterized by increased activation and proliferation of synoviocytes, which are an important source of cytokines, The role of Interleukin 4 (IL-4) and IL-10 on the production of mediators of inflammation by rheumatoid synoviocytes was studied herein, While IL-4 weakly affected the spontaneous PGE2 production, it strongly inhibited its production when cells were stimulated,vith IL-1 beta and TNF-alpha. IL-4 decreased by 60% to 80% the spontaneous and the IL-1 beta or TNF-alpha induced synthesis of GM-CSF. In contrast, IL-4 enhanced the spontaneous (2.6-fold), and to a lower extent (1.3-1.8-fold), the cytokine stimulated production of IL-6, This induction was not due to a passive release of presynthesized IL-6, since IL-4 increased the level of IL-6 mRNA expression induced by IL-1 beta. The D50 was 5 U/ml of IL-4 for both the stimulation of IL-6 synthesis and the inhibition of GM-CSF production, Kinetic studies of the action of IL-4 revealed a rapid and sustained inhibition of GM-CSF production, and a late increase of IL-6 secretion, By contrast, IL-10 had no effect on the production of either IL-6 or GM-CSF by synoviocytes. Thus, by inhibiting synoviocyte proliferation and inhibiting their secretion of PGE2 and GM-CSF, IL-4 displays on synoviocytes a series of biological effects which complements its anti-inflammatory properties on monocytes.