Effects of human mononuclear cell factor on cultured rheumatoid synovial cells: Interactions of prostaglandin E 2 and cyclic adenosine 3′,5′-monophosphate

Abstract

1. 1. Adherent synovial cells from patients with rheumatoid arthritis produce large amounts of collagenase (EC 3.4.24.3) and prostaglandin E 2 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 E 2 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 E 2 into the incubation medium is associated with an increase in cyclic AMP levels. With continued exposure to exogenous prostaglandin E 2 or with prolonged incubation with mononuclear cell factor (stimulation of endogenous prostaglandin E 2), the cyclic AMP response to exogenous prostaglandin E 2 is suppressed. Incubation with indomethacin prevents the development of the refractory state by blocking endogenous prostaglandin E 2 production and maintains the ability of the cells to increase cyclic AMP levels in response to exogenous prostaglandin E 2. Preincubation with mononuclear cell factor plus indomethacin results in augmented sensitivity to exogenous prostaglandin E 2-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 E 2 levels or secondarily to prostaglandin E 2-induced increases in cyclic AMP levels. Mitogenic properties of mononuclear cell factor are revealed by blocking endogenous prostaglandin E 2 production with indomethacin. 4. 4. Cell products and drugs thus markedly affect prostaglandin production by synovial cells. The changes in endogenous prostaglandin E 2 levels and the associated alterations in cyclic AMP response may provide mechanisms for modulating other effects of such substances on synovial target cells.