IN-VIVO EFFECTS OF INTERLEUKIN-11 AND STEM-CELL FACTOR IN COMBINATIONWITH ERYTHROPOIETIN IN THE REGULATION OF ERYTHROPOIESIS

In this study we evaluated the in vivo effects of interleukin-11 (IL-1 1) and stem cell factor (SCF), in combination with erythropoietin (EPO ) on murine erythropoiesis. Mice were treated for 7d with IL-11, SCF a nd EPO, each at three dose levels, In total, 27 different dose combina tions were tested, IL-11 as well as SCF could only marginally stimulat e erythroid progenitor cell numbers, but IL-11 in combination with SCF was able to increase BFU-E and CFU-E numbers 4-fold, in the absence o f exogenous EPO, This resulted in an increased reticulocyte count. In contrast with the stimulatory effect on immature erythroid cell stages , IL-11 treatment induced a mild anaemia, which probably resulted from a plasma volume expansion. The additional treatment with EPO resulted in strong synergistic effects on CFU-E numbers, The combination of hi gh-dose IL-11 and high-dose SCF was able to increase the overall effic iency of EPO-induced erythroid amplification, which was reflected by a left-shift of the in vivo EPO dose-response curve. The stimulating ef fects of IL-11 and SCF were further demonstrated when the effects on t he reticulocyte count of a single high-dose EPO injection were assesse d in normal and SCF+IL-11 treated mice. Whereas a single EPO dose incr eased the reticulocyte count by a factor of 3, IL-11+SCF pretreatment increased this to a factor of 7. This study shows that in vivo SCF and IL-11 are important modulators of red blood cell production. First, t hese factors probably increase the input from the stem cell compartmen t into the erythroid lineage, where subsequently EPO is required for f urther amplification. Additionally, however, IL-11 and SCF increase th e overall efficiency of EPO-induced amplification, probably due to a s timulatory effect on late-stage erythroid cells and to a redistributio n of cells from marrow to spleen.