Mechanism of stimulation of prostaglandin synthesis by a factor from rheumatoid synovial tissue.

Rheumatoid synovial cell monolayers, with [1-14C]arachidonic acid ([1-14C]AA) incorporated into cell lipids, are stimulated by a factor (RSF) produced by explant cultures of rheumatoid synovial tissue to produce up to 50-fold increases in [1-14C]prostaglandin E2 and [1-14C]prostaglandin I2. In contrast, levels of free [1-14C]AA released from RSF-stimulated cells are generally lower than [1-14C]AA levels in cultures of untreated cells. These observations are inconsistent with a mechanism of prostaglandin stimulation consisting of an increase in phospholipase activity, because this mechanism would increase free AA levels as well as prostaglandins. A mechanism is proposed in which free AA is maintained at low steady-state levels by reacylation of free AA into phospholipids at a rate more rapid than its reaction with cyclooxygenase to form prostaglandins. In this mechanism, stimulation of the rate of the cyclooxygenase step by RSF accounts for increased prostaglandin synthesis as well as the decreased release of AA. On the basis of data previously reported by others, it is suggested that this mechanism may also be applicable to the stimulation of prostaglandin synthesis by several other agents. Preliminary characterization of the RSF indicates that it is a protein, and molecular seive chromatography indicates that its molecular weight is about 18,000. The production of RSF by rheumatoid synovial tissue is suppressed to undetectable levels by 1 microM dexamethasone.