Transforming Growth Factor-β Inhibits Steroid 17α-Hydroxylase Cytochrome P-450 Expression in Ovine Adrenocortical Cells*

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Abstract
The maintenance of optimal steroidogenesis in adrenocortical cells primarily depends on the chronic action of ACTH to promote the synthesis of the various steroid-metabolizing cytochrome P-450 enzymes. In the steroidogenic pathway, 17.alpha.-hydroxylase cytochrome P-450 (P-45017.alpha.) is a key enzyme controlling the formation of cortisol and androgens. Recently, we demonstrated that transforming growth factor-.beta. (TGF-.beta.) is a potent inhibitor of steroid production in ovine adrenocortical cells. In the present study we used a polyclonal antibody to P45017.alpha. to determine adrenal cell P-45017.alpha. enzyme content by Western analysis. In addition, we used a cDNA probe encoding for bovine P-45017.alpha. mRNA to determine levels of P-45017.alpha. mRNA in sheep ovarian adrenocortical cells in primary culture. When cells were cultured in a serum-free medium in the presence of ACTH for 48 h, P-45017.alpha. activity, enzyme content, and mRNA levels of P-45017.alpha. increased by 3- to more than 10-fold. TGF-.beta. decreased the basal level and completely blocked the stimulatory action of ACTH on P-45017.alpha. enzyme activity. The effects of TGF.beta. on P-45017.alpha. enzyme content and mRNA levels were manifested in a dose-dependent manner, with maximal inhibition observed using 1 ng/ml TGF.beta.. Importantly, the inhibitory effects of TGF.beta. on P-45017.alpha. were not overcome by (Bu)2cAMP. These findings indicate that TGF.beta. is a potent negative regulator of P-450, and the inhibitory action appears to be at the level of P-45017.alpha. gene expression. The ability of TGF.beta. to suppress the postive stimulatory action of ACTH suggests that the TGF.beta. could play a role in determining the pathway of steriodogenesis and, thereby, the specific steroids secreted by adrenocortical cells.

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