THROMBOSPONDINS SELECTIVELY ACTIVATE ONE OF THE 2 LATENT FORMS OF TRANSFORMING GROWTH-FACTOR-BETA PRESENT IN ADRENOCORTICAL CELL-CONDITIONED MEDIUM

Transforming growth factor-beta (TGF beta) has been shown previously t o be a potent inhibitor of bovine adrenocortical cell steroidogenic fu nctions. However, it is present in the culture medium of these cells i n a latent form. In this study, we analyzed in detail the biochemical composition of this latent TGF beta. Two distinct complexes could be s eparated chromatographically by gel filtration on Sephacryl S-300, and their composition was studied using immunochemical methods. The resul ts indicate that one form (peak I) is a complex between alpha(2)-macro globulin (<alpha(2)M) 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-bindi ng 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 fo rms of TGF beta. TSP1 and TSP2 were equally potent at activating the L TBP-latency-associated protein-TGF beta complex in the absence of cell contact, but were ineffective on the alpha(2)M-TGF beta complex. Ther efore, TGF beta may act as an autocrine regulator of adrenocortical st eroidogenic functions. Its activity appears to be controlled by TSPs, the local production of which is regulated by systemic ACTH.