ENHANCING EFFECT OF IL-17 ON IL-1-INDUCED IL-6 AND LEUKEMIA INHIBITORY FACTOR PRODUCTION BY RHEUMATOID-ARTHRITIS SYNOVIOCYTES AND ITS REGULATION BY TH2 CYTOKINES

IL-17 is a cytokine produced by CD4 T cells that activates the product ion of inflammatory mediators by synoviocytes. To study the contributi on of soluble factors in the interaction between T cells and synoviocy tes in rheumatoid arthritis (RA), we looked at the effect of IL-17 on these cells in the presence of cytokines classified as pro (IL-1)- and anti-inflammatory (IL-4, IL-13, IL-10), Both human rIL-I beta and rIL -17 induced IL-6 and leukemia inhibitory factor (LIF) production by sy novial fibroblasts in a dose-dependent manner. After 7 days of culture , optimal concentrations of IL-1 beta increased 1L-6 (33-fold) and LIF (10-fold) production by synoviocytes, while IL-17 showed a lesser eff ect on IL-6 (17-fold) and LIF (4-fold) production. Using low concentra tions of IL-17 and IL-1 beta in combination, a synergistic effect was observed on the production of IL-6, whereas an additive effect was obs erved for LIF production. Production of biologically active IL-17 was demonstrated in RA synovium supernatants with the use of a blocking an ti-IL-17 Ab. Both IL-4 and IL-13 had a modest stimulatory effect on IL -1- and IL-17-induced production of IL-6, but inhibited that of LIF, I n contrast, IL-10 had a limited inhibitory effect on IL-6 production a nd no effect on that of LIF, These findings indicate that low levels o f cytokines produced by monocytes (IL-l) and T cells (IL-17) can act t ogether on synoviocytes, Thus, some RA synovium T cells producing IL-1 9 can activate mesenchymal cells leading to an increased proinflammato ry pattern sensitive to Th2 cytokine regulation.