Transforming growth factors-beta s: a multifunctional cytokine family. Implication in the regulation of adrenocortical cell endocrine functions.

Knowledge of the structure of the first recognized transforming growth factor-beta (TGF-beta 1) has led to the identification of more than two dozen structurally related peptides which appear of crucial importance in the regulation of cell proliferation, cell differentiation and embryogenesis. TGF-beta 1 and its close homologs (TGF-beta 2-5) are multifunctional peptides whose effects on cell functions are dependent upon the cell type, the environment and the presence of other growth factors. TGF-beta 1 is produced and secreted as a latent macromolecular complex. One of the major steps in the control of TGF-beta activity may thus be its release (activation) from its latent form upon the effect of local factors. Adrenocortical cells may be taken as an example in which autocrine production of TGF-beta may be a component of a negative regulatory loop in balance with the positive effect of a systemic hormone (ACTH) in controlling the expression of the cell steroidogenic differentiated functions. In this system, latent TGF-beta can be activated by an ACTH-induced secreted protein (CISP), a member of the thrombospondin family. This points to the importance of the functional interaction between TGF-beta s and extracellular matrix components in the local regulation of cell activities.

Alpha 2-macroglobulin: a binding protein for transforming growth factor-beta and various cytokines.

alpha 2-Macroglobulin (alpha 2M) is a large plasma glycoprotein that has long been known as an irreversible inhibitor of a variety of proteinases. More recently, it has been reported that numerous growth factors, cytokines and hormones bind to alpha 2M through diverse mechanisms. We review here a series of observations from our laboratory that support the concept that alpha 2M is a carrier protein for transforming growth factor-beta (TGF-beta) and allows this factor to act as an autocrine regulator of adrenocortical steroidogenic functions. alpha 2M was found to by synthesized and secreted by primary cultures of bovine adrenocortical cells in fairly large amounts (1 microgram/10(6) cells/24 h). TGF-beta is also secreted by this cell type, although under a latent form. Two distinct latent TGF-beta complexes have been characterized in adrenocortical cell conditioned medium, one of which is a complex between alpha 2M and TGF-beta. Although alpha 2M prevents the binding of TGF-beta to its membrane receptors, long-term incubation of alpha 2M with adrenocortical cells results in inhibition of cortisol production similar to that observed in the presence of TGF-beta alone. Taken together, these observations suggest that adrenocortical cells can release active TGF-beta from its latent complex with alpha 2M through an unknown mechanism. alpha 2M can therefore be considered as a TGF-beta carrier protein.

Thrombospondins selectively activate one of the two latent forms of transforming growth factor-beta present in adrenocortical cell-conditioned medium.

Transforming growth factor-beta (TGF beta) has been shown previously to be a potent inhibitor of bovine adrenocortical cell steroidogenic functions. However, it is present in the culture medium of these cells in a latent form. In this study, we analyzed in detail the biochemical composition of this latent TGF beta. Two distinct complexes could be separated chromatographically by gel filtration on Sephacryl S-300, and their composition was studied using immunochemical methods. The results indicate that one form (peak I) is a complex between alpha 2-macroglobulin (alpha 2M) and either the unprocessed TGF beta precursor or the mature form of TGF beta. In a major fraction of this complex, TGF beta is covalently linked to alpha 2 M, whereas in a minor fraction, it is noncovalently bound and, therefore, activatable. The second form of latent TGF beta (peak II) is a complex among latent TGF beta-binding protein (LTBP), latency-associated protein, and mature TGF beta and a complex between LTBP and unprocessed TGF beta. We investigated the ability of thrombospondins (TSP1 and TSP2) to activate these latent forms of TGF beta. TSP1 and TSP2 were equally potent at activating the LTBP-latency-associated protein-TGF beta complex in the absence of cell contact, but were ineffective on the alpha 2M-TGF beta complex. Therefore, TGF beta may act as an autocrine regulator of adrenocortical steroidogenic functions. Its activity appears to be controlled by TSPs, the local production of which is regulated by systemic ACTH.

Growth factors and pericellular components as a local signalling relay in the action of systemic hormones.

Recent years have shown that peptidic signals, originally identified as growth factors, may represent a local signalling system involved in the regulation of cell function under the dependence of systemic hormones. As an example, (i) adrenocortical cells are highly sensitive to transforming growth factor-beta (TGF beta) which is a powerful inhibitor of their differentiated functions; (ii) adrenocortical cells produce and secrete TGF beta, which is present in the adrenal cortex in situ; (iii) adrenocorticotropin (ACTH), which is the best known positive effector of adrenocortical functions induces an up-regulation of TGF beta receptors in adrenocortical cells. Altogether, these observations suggest that TGF beta may be a local signalling system acting in balance with the systemic hormone ACTH to eventually tune the ability of adrenocortical cells to produce corticosteroids.