TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) INHIBITS TGF-ALPHA EXPRESSION IN BOVINE ANTERIOR PITUITARY-DERIVED CELLS

Transforming growth factor-beta-1 (TGF-beta-1) is a multifunctional regulator of cell growth and differentiation. We report here that TGF-beta-1 decreased the proliferation of nontransformed bovine anterior pituitary-derived cells grown in culture. We have previously demonstrated that these cells express both TGF-alpha and its receptor [the epidermal growth factor (EGF) receptor] and that expression can be stimulated by phorbol ester (TPA) and EGF. TGF-beta-1 treatment over a 2-day period decreased the proliferation of pituitary cells. This decreased growth rate was accompanied by a decrease in the TGF-alpha mRNA level. The effect of TGF-beta-1 on TGF-alpha mRNA down-regulation was both dose dependent (maximal effect observed at 1.0 ng/ml TGF-beta-1) and time dependent (minimum of 2-day treatment with TGF-beta-1 was required before a decrease in TGF-alpha mRNA was observed). Studies on TGF-alpha mRNA stability indicated that TGF-beta-1 did not alter the TGF-alpha mRNA half-life. Treatment of the TGF-beta-1 down-regulated cells with EGF resulted in the stimulation of TGF-alpha mRNA levels; thus, the TGF-beta-1-treated cells remained responsive to EGF. The decreased proliferation in response to TGF-beta-1 could be only partially reversed by simultaneous treatment of the cells with EGF (10(-9) M) and TGF-beta-1 (3.0 ng/ml). Qualitatively, the TGF-beta-1-induced reduction of TGF-alpha mRNA content was independent of cell density. TGF-beta-1 treatment of the anterior pituitary-derived cells also reduced the levels of c-myc and EGF receptor mRNA. These results represent the first demonstration of the down-regulation of TGF-alpha synthesis by a polypeptide growth factor and suggest that TGF-beta-1 may be a physiological regulator of TGF-alpha production in vivo.