alpha(2)-Macroglobulin: A binding protein for transforming growth factor-beta and various cytokines

alpha(2)-Macroglobulin (alpha(2)M) 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(2)M through diverse mechanisms. We review here a series of observations from our laboratory that support the concept that alpha(2)M 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(2)M was found to be synthesized and secreted by primary cultures of bovine adrenocortical cells in fairly large amounts (1 mu g/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(2)M and TGF-beta. Although alpha(2)M prevents the binding of TGF-beta to its membrane receptors, long-term incubation of alpha(2)M 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(2)M through an unknown mechanism. alpha(2)M can therefore be considered as a TGF-beta carrier protein.