The metabolic change of human recombinant interleukin-2 (IL-2) was investigated by the use of 125I-labeled IL-2 (125I-IL-2). After intravenous injection into mice, the distribution of 125I-IL-2 in various organs revealed that the major portion of injected 125I-IL-2 was rapidly accumulated in the kidney. Simultaneous injection of an excess amount of cold IL-2 greatly reduced the distribution of 125I-IL-2 to the kidney, suggesting that the accumulation of 125I-IL-2 by the kidney was a specific reactivity between 125I-IL-2 and the kidney. The gel filtration profile of 125I-IL-2 in the serum specimens remained the same as that of the originally injected sample, and differed completely from that in the urine specimens, suggesting that 125I-IL-2 was metabolized in the kidney. To confirm this notion, 125I-IL-2 was incubated in vitro with kidney homogenate, which degraded 125I-IL-2 in acidic pH. After subcellular fractionation, the cytosol fraction of the kidney was shown to hydrolyze 125I-IL-2 with an optimal pH of 4. The reactivity of the kidney cytosol fraction with 125I-IL-2 was inhibitable by pepstatin, an acid protease inhibitor, but not by TLCK or TPCK. Additional experiments using a heat-treated kidney cytosol fraction plus cathepsin D, and pepstatin inhibition on the degradation of 125I-IL-2 by cathepsin D, a major acid protease in the kidney, resulted in the identification of this enzyme to be responsible for the degradation of 125I-IL-2. Overall, these results demonstrated that the kidney is the organ to metabolize IL-2 and that cathepsin D, a renal acid protease, is involved in the degradation of IL-2.

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