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.