TRANSFORMING GROWTH FACTOR-BETA-1 IS A NEGATIVE REGULATOR OF STEROID 17-ALPHA-HYDROXYLASE EXPRESSION IN BOVINE ADRENOCORTICAL-CELLS

Transforming growth factor beta-1 (TGF-beta-1) has been shown previously to induce striking alterations of bovine adrenocortical cell steroidogenic functions. One of the major lesions was characterized as a loss of steroid-17-alpha-hydroxylase activity, a key step in the biosynthetic pathway leading to active corticosteroid hormones. The mechanism of this negative effect of TGF-beta-1 on adrenocortical differentiated functions was investigated. It was observed that: 1) bovine adrenocortical 17-alpha-hydroxylase activity rapidly decreased in cells exposed to TGF-beta-1, in a time (10-20 h)-dependent manner; 2) immunoblotting of the corresponding cytochrome P-450(17)-alpha showed that the loss of activity was superimposable to the decrease of the cellular protein content; 3) the cell content in 17-alpha-hydroxylase messenger RNA sharply dropped under TGF-beta-1 treatment (70-75% loss within 3-4 h) as determined by Northern blot analysis; 4) TGF-beta-1 inhibited as well the induction of P-450(17)-alpha normally observed under adrenocorticotropin treatment; and 5) these TGF-beta-1 effects were selectively directed toward P-450(17)-alpha expression, whereas another major steroidogenic cytochrome, i.e. P-450scc. was not affected. These observations showed that TGF-beta-1 is a potent negative modulator of 17-alpha-hydroxylase expression in bovine adrenocortical cells, very possibly at the transcriptional level. TGF-beta-1 (whose gene is expressed in these cells) may thus be examined as a possible autocrine inhibitory factor implied in the regulation of adrenocortical differentiated functions, in balance with ACTH, which represents the major positive signal in this system.