TRANSFORMING GROWTH FACTOR-BETA-1 - AN AUTOCRINE REGULATOR OF ADRENOCORTICAL STEROIDOGENESIS

Transforming growth factor beta-1 (TGF-beta-1) is a member of a large family of structurally related regulatory polypeptides which comprises both functionally similar (TGF-beta-1, TGF-beta-2, TGF-beta-3, TGF-beta-4 and TGF-beta-5) and functionally distinct proteins. In the past few years, TGF-beta-1 has emerged as a multifunctional protein. One of its remarkable properties is its capacity to negatively modulate the differentiated, steroidogenic adrenocortical functions. We present here a review of the results from our recent work related to the effects of TGF-beta-1 on bovine adrenocortical cell (zona fasciculata-reticularis) functions. We identified the steroid 17-alpha-hydroxylase (P-450(17-alpha)) biosynthetic enzyme and the angiotensin II receptor as major targets whose expression are negatively regulated by TGF-beta-1 in these cells. We characterized TGF-beta-1 receptors at the surface of adrenocortical cells (mainly type I and type III receptors) and observed that their number is increased under ACTH treatment. Furthermore, we could detect the presence of immunoreactive TGF-beta-1 in the bovine adrenal cortex whereas it was undetectable in the adrenal medulla and in the capsule. We also observed that adrenocortical cells secrete TGF-beta-1 under a latent form together with large amounts of alpha-2-macroglobulin, a protease inhibitor known to be implied in the latency of TGF-beta in serum. Taken together, these observations led us to a working hypothesis, proposing TGF-beta-1 as an autocrine and/or paracrine regulator of adrenocortical steroidogenic functions. This concept points out the physiological activation of the latent TGF-beta-1 complex as the important limiting step controlling its action in the adrenal cortex.