Table 1.

A2M interaction with cytokines and growth factors.

Binding partner	Proposed interaction	Biological significance and impact on cytokine/growth factor activity	ref.
FGF1	binds to A2M and increasingly to A2M**	–	(39)
FGF2	non-covalent contact with A2M**, slowly converts into a covalent interaction	complex forms in human plasma reduced binding to FGF-receptors (BHK-21 cells) reduced ability to stimulate plasminogen activator production (bovine epithelial cells) A2M** inhibits FGF-2–dependent fetal bovine heart endothelial cell proliferation does not affect FGF-2–induced vascular tubule formation on Matrigel or collagen matrix	(39–41)
FGF-4	binds A2M, increased binding to A2M**	-	(39)
FGF-6	binds A2M, increased binding to A2M**	-	(39)
IFN-γ	covalent binding to A2M** and protease-A2M*	no impact on antiproliferative activity (bladder tumor cell line) no influence on induction of MHC class II	(42)
IL-1β	covalent binding to A2M** and trypsin-A2M* increased binding to MAC	complex found in human plasma IL-1β/A2M retains IL-1-like activity (mouse thymocytes)	(43–45)
IL-2	binds oxidized A2M	–	(46)
IL-4	binds A2M and preferentially A2M**	–	(44)
IL-6	binds A2M** and MAC better binding to oxidized A2M	complex found in human plasma IL-6 receptor binding intact Stimulation of IL-6-dependent hybridoma cells remains intact protects IL-6 from proteolysis	(44, 46, 47)
IL-8	non-covalent binding to A2M**	IL-8/A2M isolated from lungs of ARDS patients no effect on neutrophil chemotaxis protects IL-8 from proteolysis	(48)
IL-18	binds mostly to MAC	–	(44)
NGF-β	non-covalent with A2M**, slowly converts into a covalent interaction binds less to oxidized A2M binds A2M between AA 614-797	–	(40, 46, 49)
PDGF	non-covalent binding to A2M**, slowly converts into a covalent interaction binds less to oxidized A2M 2 x PDGF per A2M all isoforms bind native A2M and A2M** binds to the growth factor binding site	complex found in human plasma retains mitogenic activity not detected by anti-PDGF antisera blocks receptor binding clearance of PDGF-BB/A2M** from mouse plasma through uptake via LRP-1 fusion protein containing the A2M binding site blocks binding to PDGF-β receptor (NIH 3T3 cells)	(17, 40, 49–54)
TGF-β1	non-covalent contact with A2M**, slowly converts into a covalent interaction binds less to oxidized A2M binds to the growth factor binding site	complex found in human plasma TGF-β/A2M is the ‘latent’ TGF-β form in plasma A2M impedes binding to cell surface receptors Fast clearance of TGF-β1/A2M* and TGF-β1/A2M** complexes from mouse plasma through liver uptake TGF-β and A2M** synergistically promote SMC proliferation (cultured rat aorta cells) protein with A2M binding site neutralizes TGF-β1 activity (endothelial cell proliferation assays)	(38, 51, 55–60)
TGF-β2	non-covalent contact with A2M**, slowly converts into a covalent interaction binds equally well A2M and A2M** binds less to oxidized A2M binds A2M between AA 614-797	A2M inhibits binding to cell surface receptors reduces the anti-proliferative activity of TGF-β1 protein containing the A2M binding site neutralizes TGF-β2 activity in endothelial cell proliferation assays (fetal bovine heart cells)	(40, 56)
TNF-α	non-covalent contact with A2M**, slowly converts into a covalent interaction binds to plasmin-A2M* and less to native A2M, trypsin-A2M* or thrombin-A2M* Increased binding to MAC and oxidized A2M	TNF-α binding to MAC suppresses inflammation by inhibition of MAPK p38 phosphorylation TNF-α retains cytotoxic effects on fibroblasts (L929 murine fibroblasts) no effect on antiproliferative activity (bladder tumor cell line)	(40, 42, 44, 46, 61)
VEGF	covalent binding does not bind at growth factor binding site binds the interior of A2M** and the exterior of native and protease-activated A2M*	reduced binding to VEGF receptor VEGF/A2M** complexes are internalized and degraded by macrophages (LRP-1-mediated) A2M does not impact VEGF-induced cell proliferation or Ca2+ increases (HUVECs).	(62, 63)

A2M*, protease-activated A2M; A2M**, A2M activated through reaction with low molecular-weight primary amines; AA, amino acid; ARDS, adult respiratory distress syndrome; FGF, fibroblast growth factor; HUVECs, Human umbilical vein endothelial cells; IFN, interferon; IL, interleukin; MAC, A2M activated for cytokine binding; NGF, nerve growth factor; PDGF, platelet-derived growth factor; SMC, smooth muscle cell; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.