REGULATION OF FIBROBLAST PROCOLLAGEN PRODUCTION - TRANSFORMING GROWTHFACTOR-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 s timulation of extracellular matrix protein production. In this study w e have investigated the role of pertussis toxin-sensitive G-proteins i n mediating the effects of TGF beta(1) on fibroblast procollagen metab olism. 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 synth esized procollagen degraded intracellularly. Pertussis toxin, a G-prot ein inhibitor, further stimulated TGF beta(1)-induced procollagen synt hesis and production, but alone it had no effect on fibroblast procoll agen metabolism. Addition of indomethacin also potentiated the TGF bet a(1)-induced increase in procollagen synthesis and production. The eff ects of pertussis toxin and indomethacin were not additive. Pertussis toxin and indomethacin did not affect the proportion of newly synthesi zed procollagen degraded intracellularly, either alone or in combinati on, by control cells. The TGF beta(1)-induced decrease in intracellula r procollagen degradation was maintained but not further affected by p ertussis 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 in crease in PGE(2) production. The TGF beta(1)-induced increase in PGE(2 ) preceded the increase in procollagen production. These results demon strate that TGF beta(1)-induced procollagen synthesis by lung fibrobla sts is modulated by production of PGE(2). Pertussis toxin and indometh acin block the production of PGE(2) and enhance the effect of TGF beta (1) on procollagen synthesis. From these data we conclude that the eff ects of TGF beta(1) on PGE(2) production but not procollagen synthesis are mediated via a receptor linked to a pertussis toxin-sensitive G-p rotein.