Mononuclear cell modulation of connective tissue function. Suppression of fibroblast growth by stimulation of endogenous prostaglandin production

Abstract

The role of immune cell products in modulating connective tissue metabolism was investigated. Supernates of both unstimulated and phytohemagglutinin-stimulated human mononuclear cell cultures suppressed fibroblast proliferation (up to 90%) and concomitantly stimulated fibroblast prostaglandin E (PGE) synthesis (20- to 70-fold). The growth suppression was, at least in part, a secondary result of the increased fibroblast PGE synthesis; growth suppression (a) paralleled the increased fibroblast PGE synthesis, (b) was reversed by addition of inhibitors of prostaglandin synthesis (indomethacin, meclofenamate, and eicosatetraynoic acid), and (c) was reproduced by addition of exogenous PGE2 to fibroblast cultures. The prostaglandin-stimulatory, growth-suppressive activity was a product of non-T-lymphocyte, adherent cells and was present within 6 h of mononuclear cells and was present within 6 h of mononuclear cell culture. The activity was heat (56°C) and trypsin sensitive, nondialyzable, and appeared in the 12,000-20,000 mol wt fractions on Sephadex G-100 chromatography. The activity in supernates of mononuclear cell cultures was was removed by incubation with fibroblasts but not by similar incubation wtih peripheral blood mononuclear cells. Mononuclear cells release a factor(s) which modulates fibroblast proliferation by altering prostaglandin metabolism.