Cytokine binding and clearance properties of proteinase-activated alpha-2-macroglobulins.
LaMarre J, Wollenberg GK, Gonias SL,
Hayes MA. Cytokine binding and clearance properties of proteinase-activated
alpha 2-macroglobulins. Lab Invest. 1991 Jul;65(1):3-14.
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 extra vascular 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.
External Link: PMID:
1712874