REGULATION OF FIBROBLAST PROCOLLAGEN PRODUCTION - TRANSFORMING GROWTH FACTOR-BETA(1) INDUCES PROSTAGLANDIN E(2) BUT NOT PROCOLLAGEN SYNTHESIS VIA A PERTUSSIS-TOXIN-SENSITIVE G-PROTEIN

Transforming growth factor-beta(1) (TGF beta(1)) initiates a series of signalling events resulting in diverse cellular responses including stimulation of extracellular matrix protein production. In this study we have investigated the role of pertussis toxin-sensitive G-proteins in mediating the effects of TGF beta(1) on fibroblast procollagen metabolism. TGF beta(1) stimulated human fetal lung fibroblast procollagen synthesis and production in a dose-dependent manner which was maximal at 0.5 ng/ml. TGF beta(1) also decreased the proportion of newly synthesized procollagen degraded intracellularly. Pertussis toxin, a G-protein inhibitor, further stimulated TGF beta(1)-induced procollagen synthesis and production, but alone it had no effect on fibroblast procollagen metabolism. Addition of indomethacin also potentiated the TGF beta(1)-induced increase in procollagen synthesis and production. The effects of pertussis toxin and indomethacin were not additive. Pertussis toxin and indomethacin did not affect the proportion of newly synthesized procollagen degraded intracellularly, either alone or in combination, by control cells. The TGF beta(1)-induced decrease in intracellular procollagen degradation was maintained but not further affected by pertussis toxin or indomethacin. TGF beta(1) increased prostaglandin E(2) (PGE(2)) compared with PGE(2) production by control cells. Addition of pertussis toxin or indomethacin blocked the TGF beta(1)-induced increase in PGE(2) production. The TGF beta(1)-induced increase in PGE(2) preceded the increase in procollagen production. These results demonstrate that TGF beta(1)-induced procollagen synthesis by lung fibroblasts is modulated by production of PGE(2). Pertussis toxin and indomethacin block the production of PGE(2) and enhance the effect of TGF beta(1) on procollagen synthesis. From these data we conclude that the effects of TGF beta(1) on PGE(2) production but not procollagen synthesis are mediated via a receptor linked to a pertussis toxin-sensitive G-protein.