An a2-Macroglobulin Receptor-dependent Mechanism for the Plasma Clearance of Transforming Growth Factor-ji1 in Mice

Radioiodinated transforming growth factor-,61 (TGF-,i1) bound to the plasma proteinase inhibitor, a2-macroglobulin (a2M), as determined by chromatography on Superose-6 and native polyacrylamide gel electrophoresis. When a2M confor-mational 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 predomi-nantly 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-methyl-amine were equivalent to those observed with '"I-a2M-methyl-amine 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-TGF-j01-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 func-tion as a concerted system to regulate TGF-ftl activity and the activity of related factors in vivo. (J. Clin. Invest. 1991. 87:39-44.) Key words: growth factor * proteinase * receptorv hepatocyte * live