Human Alpha-2-Macroglobulin (?2M) is a glycoprotein of 725 kDa encoded by a gene that spans approximately 48 kb and consists of 36 exons. The protein is found in serum at concentrations of 2-4 mg/ml. It consists of two identical subunits which themselves are made up of two peptide chains covalently linked by disulfide bonds. ?2M is one of the acute phase proteins. Its gene promoter contains an IL6RE response element and its expression is enhanced by IL6 by a factor of up to several 100-fold through the action of the human transcription factor NF-IL6. Native ?2M does not bind to a receptor. However, it undergoes a conformational change upon reaction with either small primary amines such as methylamine or with protein ligands to form activated ?2M . As a result, a receptor recognition site is exposed on each subunit of the molecule enabling it to bind to its receptors on macrophages. ?2M is a natural inhibitor of several serum proteases such as cathepsin, chymotrypsin, collagenase, elastase, Kallikreins, plasmin, factor Xa, thrombin, and trypsin, which it inhibits by irreversible complex formation. Bound proteases retain residual biological activity and preferentially react with low molecular weight substrates. Plasma levels of ?2M are reduced in patients with sepsis and have been described to be associated with fatal outcome in some studies. The interactions between ?2M and cytokines are thought to modulate the expression of acute phase proteins in liver hepatocytes. ?2M inhibits the growth of several tumors in vitro and in vivo (rat). The conditioned medium of astroglial cells contains ?2M, and this protein has been shown to promote the outgrowth of neuritis. The main fraction of TGF-beta in the V.8: Human plasma alpha-2-macrogobulin serum is complexed with ?2M appears to be biologically active on adrenocortical cells.