Role of the kidney in metabolic change of interleukin-2.
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.
Ohnishi
H
H
Department of Diagnostic Immunology Research and Biochemistry, Roswell Park Memorial Institute, Buffalo, N.Y.
Chao
J T
JT
Lin
K K
KK
Lee
H
H
Chu
T M
TM
D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism / Q000493:pharmacokinetics*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010436:Pepstatins / Q000494:pharmacology; D012083:Renin / Q000378:metabolism; D014018:Tissue Distribution
D007376:Interleukin-2; D010436:Pepstatins; C014195:Streptomyces pepsin inhibitor; D012083:Renin; D002402:Cathepsin D; C031375:pepstatin