Journal
EXPERIMENTAL HEMATOLOGY
Volume 34, Issue 11, Pages 1451-1461Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2006.06.014
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Objective. Cytokines released during inflammatory processes have been proposed to play a central role in mediating mechanism(s) leading to anemia. Here, we used CpG-ODN to investigate the effects of a pro-inflammatory response on the pathophysiological processes leading to anemia. Methods. Naive and erythropoietin (EPO)-treated mice were injected for 2 days with 100 Pg CpG-ODN or control ODN and the effects on the course of red blood cell (RBC) and reticulocyte counts, RBC turnover, and EPO-stimulated maturation of erythroid cells were analyzed. To study the effect of CpG-ODN on erythroid cell maturation in vitro, we obtained primary EPO-responsive cells by treating mice with thiamphenicol (15 mg/g body weight). Results. CpG-ODN-treated mice developed anemia, which persisted for 5 days and was associated with a 50% reduction in EPO-stimulated differentiation of EPOR+ cells to TER119(+) erythroblasts. CpG-ODN-induced suppression required accessory cells, including antigen presenting cells, which activated other cells to produce pro-inflammatory cytokines. In vitro neutralization of IFN-gamma, but not IL-12, TNF-alpha, IFN-alpha, IL-1 alpha, or IL-1 beta, abrogated the erythropoietic suppression induced by CpG-ODN. The anemia observed in CpG-ODN-treated mice was also associated with reduced RBC survival in vivo, as demonstrated by a sevenfold to eightfold higher turnover of biotinylated RBC compared to control ODN-treated mice. In vivo IFN-gamma neutralization confirmed that IFN-gamma contributed to erythropoietic suppression but not reduced RBC survival. Conclusions. Together, these results demonstrate that CpG-ODN anemia is associated with suppressed erythropoiesis and decreased RBC survival. Importantly, CpG-ODN-induced IFN-gamma was found to be the major factor mediating erythropoietic suppression but not decreased RBC survival. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.
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