Rj. Mcanulty et al., INDOMETHACIN SUPPRESSES THE ANTIPROLIFERATIVE EFFECTS OF TRANSFORMINGGROWTH-FACTOR-BETA ISOFORMS ON FIBROBLAST CELL-CULTURES, Biochemical journal, 321, 1997, pp. 639-643
The transforming growth factor-beta (TGF beta) family of mediators con
sists of five closely related isoforms, of which three are present in
mammals. TGF beta(1) has been shown to exert a biphasic effect on the
proliferation of several cell types, including fibroblasts, with stimu
lation at low concentrations and inhibition at higher concentrations.
The stimulatory effects are well characterized, but the mechanisms by
which TGF beta(1) inhibits cell proliferation are incompletely underst
ood. In the present study we have compared the effects of all three ma
mmalian TGF beta isoforms on human lung fibroblasts proliferation, and
have elucidated the role of the TGF beta-induced synthesis of prostag
landin E(2) (PGE(2)) in mediating their actions. All three isoforms st
imulated fibroblast proliferation with maximal effects at 5 pg/ml (0.2
pM) and an order of potency of TGF beta(3) > TGF beta(2) > TGF beta(1
). At higher concentrations, proliferation declined, and at 40 pg/ml a
nd above all isoforms inhibited fibroblast proliferation. Again TGF be
ta(3) was the most potent, but there were no significant differences b
etween the inhibitory effects of TGF beta(1) and TGF beta(2). Addition
of indomethacin, an inhibitor of PGE(2) synthesis, did not alter the
proliferative activity of any of the TGF beta isoforms, but completely
overcame their inhibitory effects, restoring the stimulatory actions
observed at lower TGF beta concentrations. All TGF beta isoforms stimu
lated PGE(2) synthesis; TGF beta(3) was approximately twice as potent
as TGF beta(1) and TGF beta(2), each of which had similar effects. The
se data suggest that the inhibition of fibroblast proliferation at hig
her concentrations of TGF beta isoforms may be mediated by autocrine s
timulation of PGE(2) synthesis.