Indomethacin suppresses the anti-proliferative effects of transforming growth factor-beta isoforms on fibroblast cell cultures

The transforming growth factor-beta (TGFbeta) family of mediators consists of five closely related isoforms, of which three are present in mammals. TGFbeta1 has been shown to exert a biphasic effect on the proliferation of several cell types, including fibroblasts, with stimulation at low concentrat...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Biochemical journal 1997-02, Vol.321 ( Pt 3) (3), p.639-643
Hauptverfasser: McAnulty, R J, Hernández-Rodriguez, N A, Mutsaers, S E, Coker, R K, Laurent, G J
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:The transforming growth factor-beta (TGFbeta) family of mediators consists of five closely related isoforms, of which three are present in mammals. TGFbeta1 has been shown to exert a biphasic effect on the proliferation of several cell types, including fibroblasts, with stimulation at low concentrations and inhibition at higher concentrations. The stimulatory effects are well characterized, but the mechanisms by which TGFbeta1 inhibits cell proliferation are incompletely understood. In the present study we have compared the effects of all three mammalian TGFbeta isoforms on human lung fibroblast proliferation, and have elucidated the role of the TGFbeta-induced synthesis of prostaglandin E2 (PGE2) in mediating their actions. All three isoforms stimulated fibroblast proliferation with maximal effects at 5 pg/ml (0.2 pM) and an order of potency of TGFbeta3 > TGFbeta2 > TGFbeta1. At higher concentrations, proliferation declined, and at 40 pg/ml and above all isoforms inhibited fibroblast proliferation. Again TGFbeta3 was the most potent, but there were no significant differences between the inhibitory effects of TGFbeta1 and TGFbeta2. Addition of indomethacin, an inhibitor of PGE2 synthesis, did not alter the proliferative activity of any of the TGFbeta isoforms, but completely overcame their inhibitory effects, restoring the stimulatory actions observed at lower TGFbeta concentrations. All TGFbeta isoforms stimulated PGE2 synthesis; TGFbeta3 was approximately twice as potent as TGFbeta1 and TGFbeta2, each of which had similar effects. These data suggest that the inhibition of fibroblast proliferation at higher concentrations of TGFbeta isoforms may be mediated by autocrine stimulation of PGE2 synthesis.
ISSN:0264-6021
1470-8728
DOI:10.1042/bj3210639