Hepatic catabolism of intravenously administered pro-macrophage-stimulating protein in mice

We injected 125I-pro-macrophage-stimulating protein (pro-MSP) intravenously into normal mice to determine its clearance from the circulation and to test for conversion of pro-MSP to the biologically active heterodimer in the absence of inflammation or tissue injury. Pro-MSP was cleared from the circulation with a half-life of approximately 100 min. This rapid clearance was not peculiar to 125I-pro-MSP, since clearance rates of unlabeled pro-MSP and of 125I-bovine serum albumin were comparable. The liver was the major locus of radioactivity 10-20 min after the intravenous injection of 125I-pro-MSP. By 90 min, over 60% of total recovered radioactivity was in the small intestine. Reflecting gastrointestinal transit, counts decreased in the small intestine and appeared in the colon by 180 min. Essentially all counts in urine and feces obtained at later times were soluble in trichloracetic acid. These findings reflected rapid hepatic proteolysis of pro-MSP to fragments undetectable by antibody to pro-MSP; within 20 min after intravenous administration, immunoprecipitable counts were only 22% of the total liver extract radioactivity. Comparison of sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radioautography data for immunoprecipitated plasma and liver extract revealed no evidence for hepatic conversion of pro-MSP to MSP. Thus, the hepatic catabolic pathway of pro-MSP is degradative and does not yield mature MSP. The results support our view that MSP is not released into the circulation but is generated at specific extravascular loci by pro-MSP convertases.