α ₂-Macroglobulin: A Binding Protein for Transforming Growth Factor-β and Various Cytokines

Abstract

α₂-Macroglobulin (α₂M) 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 α₂M through diverse mechanisms. We review here a series of observations from our laboratory that support the concept that α₂M is a carrier protein for transforming growth factor-β (TGF-β) and allows this factor to act as an autocrine regulator of adrenocortical steroidogenic functions. α₂M was found to be synthesized and secreted by primary cultures of bovine adrenocortical cells in fairly large amounts (1 μg/l0⁶ cells/24 h). TGF-β is also secreted by this cell type, although under a latent form. Two distinct latent TGF-β complexes have been characterized in adrenocortical cell conditioned medium, one of which is a complex between α₂M and TGF-β. Although α₂M prevents the binding of TGF-β to its membrane receptors, long-term incubation of α₂M with adrenocortical cells results in inhibition of cortisol production similar to that observed in the presence of TGF-β alone. Taken together, these observations suggest that adrenocortical cells can release active TGF-β from its latent complex with α₂M through an unknown mechanism. α₂M can therefore be considered as a TGF-β carrier protein.