An alpha 2-macroglobulin receptor-dependent mechanism for the plasma clearance of transforming growth factor-beta 1 in mice.

Abstract

Radioiodinated transforming growth factor-,61 i1) bound to the plasma proteinase inhibitor, a2-macroglobulin (a2M), as determined by chromatography on Superose-6 and native polyacrylamide gel electrophoresis. When a2M conformational change was induced with methylamine, 1"I-TGF-jfl binding significantly increased. Intravenously injected 125I_ TGF-il cleared from the circulation of mice rapidly at first; however, intravascular radioactivity stabilized near 20% of the initial level. At necropsy, radioactivity was recovered predominantly in the liver (65%); however, the density of radioactivity (disintegrations per minute/g organ wt) was highest in the lungs. Markedly different results were obtained with purified 125I-TGF-fll-a2M-methylamine complex. Clearance of the complex occurred as a first-order process with a t11 of 4 min.Greater than 90% ofthe radioactivity was recovered in the liver.The clearance and distribution of 125I-TGF-81-a2M-methylamine were equivalent to those observed with '"I-a2M-methylamine and '"I-a2M-trypsin. The latter two radioligands clear via specific a2M receptors in the liver. Large molar excesses of a2M-trypsin or a2M-methylamine competed with 125I-TGFj01-a2M-methylamine for plasma clearance. Native a2M, which does not bind to the a2M receptor, did not compete. The receptor binding domain of a2M-methylamine was blocked by chemical modification or enzyme treatment. The resulting a2M preparations still bound 125I-TGF-fll; however, the complexes did not clear when injected intravenously in mice. The studies presented here demonstrate that a2M can mediate the plasma clearance of a growth factor via the a2M receptor system. We propose that a2M, the a2M receptor, and proteinases may function as a concerted system to regulate TGF-ftl activity and the activity of related factors in vivo. (J. Clin. Invest. 1991.

Expression of differentially expressed nucleolar transforming growth factor‐β1 target (DENTT) in adult mouse tissues

“…Serum stimulation of AtT20 cells also increased DENTT production by 4 hr that peaked at 2.5-fold above DENTT basal levels by 8 hr, and then decreased, whereas only a modest increase in DENTT protein occurred in GH3 or ␣T3-1 cells. Because serum has been shown to contain proteins that can associate and bind TGF-␤1 like ␣2-macroglobulin (LaMarre et al, 1991), our studies suggest that there may be other factors in serum in addition to TGF-␤1 that may also be able to regulate DENTT expression. By using the activin/TGF-␤ -responsive p3TP-Lux Luciferase reporter (Carcamo et al, 1994) that has been shown to be responsive in AtT20, GH3, and ␣T3-1 cells (Yamashita et al, 1995;Bilezikjian et al, 2001), our transient transfection studies showed that DENTT expression significantly increases the level of p3TP-Lux reporter transcription in AtT20 cells but not in GH3 or ␣T3-1 cells.…”

Hepcidin Bound to α2-Macroglobulin Reduces Ferroportin-1 Expression and Enhances Its Activity at Reducing Serum Iron Levels

“…4) and the marked dependence of hepcidin binding to ␣ 2 M/␣ 2 M-MA on pH (Fig. 5, C and D (10,50). Lrp1 is the major receptor responsible for clearance of activated-␣ 2 M from the circulation (18).…”

Effects of TGF-β on the immune system: implications for cancer immunotherapy

“…Administration of activated ␣ 2 M or augmentation of the clearance of the TGF-␤-␣ 2 M complex might be strategies for decreasing TGF-␤ levels. However, it has to be considered that not only TGF-␤, but also many other cytokines such as TNF-␣ and IL-6 bind to ␣ 2 M. 142 What the potential adverse effects are of neutralizing these other cytokines remains to be investigated. Furthermore, it is important to determine whether the ␣ 2 M receptor can be easily saturated, because in this case the ␣ 2 M-TGF-␤ complexes will persist in the circulation.…”