Human synovial fibroblasts: the relationships between cyclic AMP, bradykinin, and prostaglandins

Abstract

Human synovial fibroblasts in culture respond to bradykinin (8×10⁻⁹ M) with an increment in intracellular cyclic AMP concentration. These bradykinin (BK) concentrations are comparable to levels of the nonapeptide found in pathological synovial effusions. The cyclic AMP response to BK is enhanced by a heat stable factor(s) in fetal calf serum (FCS) and by the addition of arachidonic acid (AA) to monolayer cultures incubated in serum-free media. Synovial fibroblasts initially treated with BK are refractory to rechallenge with this agent as measured by the absence of an increment in cyclic AMP. These BK refractory cells do respond with significant increment in cyclic AMP to challenge with prostaglandin E₁ (PGE₁). Cells that have become refractory to PGE₁ stimulation respond to BK. This suggests that a receptor or activator system different from the one for PGE₁ and PGE₂ exists for BK. When both BK and PGE₁ are incubated together with synovial fibroblasts, the cyclic AMP response elicited is more than additive as compared to the response of each hormone separately. Indomethacin (IM) inhibits the BK evoked cyclic AMP response unless cell cultures are pretreated with PGE₁. The PGE₁ analog, 7-oxa-13-prostynoic acid, is a better inhibitor of the cyclic AMP response induced by BK than by PGE₁. BK does not elicit a cyclic AMP response solely by elaborating PGE₁, yet the prostaglandin pathway and its products seem to have a role in the degree of the cyclic AMP response to BK challenge.