Multiple mechanisms are necessary to spatially and temporally restrict and direct the effects of potent mediators of inflammation, immune reactions and tissue repair. Recent studies implicate alpha 2-macroglobulin (alpha 2M) as a protein that regulates the distribution and activity of many cytokines, including transforming growth factors-beta (TGFs-beta), tumor necrosis factor-alpha (TNF-alpha), platelet derived growth factor (PDGF), interleukin-6 (IL-6), nerve growth factor (NGF), fibroblast growth factor (b-FGF), and interleukin-1 beta (IL-1 beta). Some cytokines, including PDGF, NGF, and IL-6 bind preferentially to the native secreted form of alpha 2M, whereas the TGF-beta s, TNF-alpha and IL-1 beta bind preferentially to forms of alpha 2M that have been modified by proteinases such as plasmin. Cytokines bound to native alpha 2M retain much of their biologic activity in various bioassays, whereas cytokines bound to "activated" alpha 2Ms have decreased activity in some cell systems. Because native alpha 2M in circulation can escape into extravascular fluid during tissue injury and inflammation, alpha 2M is a putative cytokine carrier, especially in the presence of heparin or specific cytokine receptors that can displace non-covalently bound cytokines from native alpha 2M. However, proteinase or chemically modified alpha 2Ms become activated for receptor-mediated endocytosis (RME) when they undergo conformational alterations that expose a latent alpha 2M receptor-recognition domain. Circulating activated alpha 2Ms, together with bound cytokines, are rapidly removed by hepatic alpha 2M-receptors (alpha 2M-R) but also bind to other cells expressing alpha 2M-R. This suggests that diseases resulting from an apparent change in the production of one or several different cytokines might represent changes in either the production of alpha 2M "cytokine scavengers" or their alpha 2M-receptor-mediated clearance/targeting mechanisms. The sequence identity between the LDL-receptor related protein and the alpha 2M receptor (115) provides a theoretical basis for interference with cytokine clearance by association of competing lipoprotein ligands with this cytokine clearance pathway. Furthermore, activated alpha 2Ms or augmentation of alpha 2M-receptor-dependent cytokine clearance might be novel strategies for preventing the harmful systemic or local effects of excess cytokines such as TGF-beta s and TNF-alpha in vivo.