Type beta transforming growth factor affects adrenocortical cell-differentiated functions

Type beta transforming growth factor (TGF-beta) had no detectable effect on mitogenic activities of bovine adrenocortical cells in culture. However, the presence of TGF-beta (1 ng/ml) in the medium resulted in a striking alteration of adrenocortical cell steroidogenic activities, maximally expressed after 18-20 h of treatment. TGF-treated cells exhibited a basal as well as an adrenocorticotropin-stimulated cortisol production inhibition by an average 50-60%, while cAMP accumulation in response to the hormone was not modified. Detailed study of the adrenocortical steroid biosynthetic pathway by high performance liquid chromatography analysis and supply of representative steroid substrates revealed a drastic loss (average 50%) of the steroid 17 alpha-hydroxylase activity following TGF treatment. TGF-beta thus appeared as a potent negative modulator of adrenocortical 17 alpha-hydroxylase activity. This TGF-induced loss in the activity of a key steroidogenic enzyme resulted in a shift of the adrenocortical cell secretion pattern at the expense of the 17 alpha-hydroxysteroid end products. This 17 alpha-hydroxylation alteration was also expressed when TGF-treated cells were challenged by angiotensin II. However, in this case, an additional lesion was suggested by a 70-90% inhibition in angiotensin II-activated cortisol production. This could be explained by the observation that TGF-beta exposure induced an average 50% decrease in the adrenocortical cell angiotensin II receptor number without any detectable change in receptor affinity (Ka approximately 10(9) M-1). In addition, a parallel alteration in the angiotensin II-activated phosphoinositide breakdown was observed in TGF-treated cells, indicating that TGF-beta appears as a negative effector of the adrenocortical cell transmembrane signaling system in the case of angiotensin II. It is concluded that, in vitro, TGF-beta is a potent modulator of differentiated adrenocortical cell functions, in which at least two major negatively regulated specific targets were characterized. The mechanism(s) of action and the possible physiological significance of TGF-beta in the control of the development and the differentiated functions of the adrenocortical gland in vivo remain to be established.