Insulin-like growth factor-binding protein-3 proteolysis is induced after elective surgery

The insulin-like growth factors (IGFs) are bound to several binding proteins (IGFBPs) that appear to regulate IGF transport, receptor binding, and action. The concentrations of these peptides are altered by catabolic conditions. To determine if IGF-I and IGFBP levels change after surgery, sera were obtained from 16 patients before and after cholecystectomy. Immunoreactive IGF-I measured in plasma samples from which IGFBPs had been extracted did not change postoperatively. In contrast, IGF-I determined in unextracted samples increased roughly 3-fold postoperatively, presumably due to changes in IGFBPs. Two days postoperatively, IGFBP-3 levels, determined by ligand blot, averaged 36% of preoperative values, whereas levels of IGFBP-2 and a 24,000 mol wt IGFBP did not change significantly. Similarly, by immunoblot, intact IGFBP-3 was decreased 84.2 +/- 20.2%, and a 31,000 mol wt IGFBP-3 fragment increased 57.5 +/- 47.4% postoperatively. Coincubation of postoperative, but not preoperative, sera with control sera resulted in a significant decrease in IGFBP-3 and production of proteolytic fragments. IGFBP-3 proteolytic activity in postoperative sera was markedly inhibited by antipain, Na-p-tosyl-L-lysine chloromethyl ketone, phenylmethylsulfonylfluoride, aprotinin, o-phenanthroline, and EDTA, but not by leupeptin or N-tosyl-L-phenylalanine chloromethyl ketone. This pattern of inhibition is consistent with a metal-dependent trypsin-like serine protease. We speculate that proteolysis of IGFBP-3 may alter tissue uptake of IGF-I and thereby help to counteract the catabolic state caused by surgery.