INTERLEUKIN-4 BUT NOT INTERLEUKIN-10 INHIBITS THE PRODUCTION OF LEUKEMIA INHIBITORY FACTOR BY RHEUMATOID SYNOVIUM AND SYNOVIOCYTES

The expression of the proinflammatory cytokine leukemia inhibitory fac tor (LIF) has been reported in the cartilage and synovium of rheumatoi d arthritis (RA) patients. Here, we show that high levels of LIF were constitutively produced by cultures of synovium pieces. Low levels of LIF were produced spontaneously by isolated synoviocytes, but interleu kin (IL)-1 beta caused a fourfold enhancement of this secretion. The a nti-inflammatory cytokine IL-4 reduced the production of LIF by synovi um pieces by 75%, as observed earlier with IL-6, IL-1 beta and tumor n ecrosis factor (TNF)-alpha. IL-4 had a direct effect since it inhibite d LIF production by unstimulated and IL-1 beta- or TNF-alpha-stimulate d synoviocytes. Conversely, IL-4 enhanced the production of IL-6, whic h shares with LIF biological activities and receptor components. The i nhibitory effect of IL-4 was dose dependent and was reversed using a b locking anti-IL-4 receptor antibody. Similar inhibitory action of IL-4 on LIF production was observed on synovium pieces from patients with osteoarthritis and on normal synoviocytes. IL-10, another anti-inflamm atory cytokine acting on monocytes, had no effect on LIF production by either synovium pieces or isolated synoviocytes. Thus, the production of LIF by synovium tissue was inhibited by IL-4 through both a direct effect on synoviocytes and an indirect effect by inhibition of the pr oduction of LIF-inducing cytokines.