EFFECTS OF HUMAN MONONUCLEAR CELL FACTOR ON CULTURED RHEUMATOID SYNOVIAL-CELLS - INTERACTIONS OF PROSTAGLANDIN-E2 AND CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE

1. 1. Adherent synovial cells from patients with rheumatoid arthritis produce large amounts of collagenase (EC 3.4.24.3) and prostaglandin E2 in culture, and these substances may play a crucial role in the degradation of joint structures in rheumatoid arthritis. A soluble factor isolated from cultured peripheral blood mononuclear cells increases the level of collagenase and prostaglandin E2 production by synovial cells up to several hundred-fold. 2. 2. In synovial cells exposed to mononuclear cell factor the first detectable release of prostaglandin E2 into the incubation medium is associated with an increase in cyclic AMP levels. With continued exposure to exogenous prostaglandin E2 or with prolonged incubation with mononuclear cell factor (stimulation of endogenous prostaglandin E2), the cyclic AMP response to exogenous prostaglandin E2 is suppressed. Incubation with indomethacin prevents the development of the refractory state by blocking endogenous prostaglandin E2 production and maintains the ability of the cells to increase cyclic AMP levels in response to exogenous prostaglandin E2. Preincubation with mononuclear cell factor plus indomethacin results in augmented sensitivity to exogenous prostaglandin E2-induced increases in cyclic AMP levels which is greater than that observed in cells preincubated with indomethacin alone. 3. 3. Exposure of synovial cells to mononuclear cell factor also results in depression of cell proliferation. These effects may be due directly to increases in endogenous prostaglandin E2 levels or secondarily to prostaglandin E2-induced increases in cyclic AMP levels. Mitogenic properties of mononuclear cell factor are revealed by blocking endogenous prostaglandin E2 production with indomethacin. 4. 4. Cell products and drugs thus markedly affect prostaglandin production by synovial cells. The changes in endogenous prostaglandin E2 levels and the associated alterations in cyclic AMP response may provide mechanisms for modulating other effects of such substances on synovial target cells. © 1979.