Mechanism of the upregulation of erythropoietin-induced uptake clearance by the spleen.
Repeated administration of recombinant human erythropoietin (rhEPO) causes upregulation of receptor-mediated tissue uptake by the spleen (Kato, M., H. Kamiyama, A. Okazaki, K. Kumaki, Y. Kato, and Y. Sugiyama. J. Pharmacol. Exp. Ther. 283: 520-527, 1997). To discover whether such upregulation is due to an increase in target cells, the numbers of colony-forming unit erythroids (CFU-E) and burst-forming unit erythroids (BFU-E), the precursor of CFU-E, were measured in the spleen after rhEPO treatment. The uptake clearance of 125I-labeled rhEPO by the spleen was almost proportional to the number of CFU-E, suggesting that the upregulation is due to an increased number of CFU-E. When growth cells were metabolically labeled with [3H]thymidine in vivo, the radioactivity in bone marrow fell significantly after rhEPO treatment, whereas that in the spleen increased significantly. A cell-fractionation study using Percoll revealed that the radioactivity in the BFU-E fraction of splenic cells increased initially after rhEPO treatment, followed by an increase in radioactivity in the CFU-E fraction with a concomitant reduction in radioactivity in the BFU-E fraction. These results demonstrate that EPO stimulates the migration of BFU-E from bone marrow to spleen, followed by its differentiation into CFU-E in the spleen. In conclusion, the upregulation observed in the spleen is due to its stimulatory effect on the migration of BFU-E.
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002452:Cell Count; D002454:Cell Differentiation; D002465:Cell Movement; D003114:Colony-Forming Units Assay; D015672:Erythroid Precursor Cells / Q000166:cytology*; D004921:Erythropoietin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000502:physiology*; D011994:Recombinant Proteins; D013154:Spleen / Q000378:metabolism*; D014316:Tritium; D015854:Up-Regulation