Interferon-γ mediates suppression of erythropoiesis but not reduced red cell survival following CpG-ODN administration in vivo
Received 10 March 2006; received in revised form 14 June 2006; accepted 21 June 2006.
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
Naïve and erythropoietin (EPO)-treated mice were injected for 2 days with 100 μg 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-γ, but not IL-12, TNF-α, IFN-α, IL-1α, or IL-1β, 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-γ neutralization confirmed that IFN-γ 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-γ was found to be the major factor mediating erythropoietic suppression but not decreased RBC survival.
aCentre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
bCentre for Host-Parasite Interactions, Institute of Parasitology, McGill University, Montreal, Quebec, Canada
cDivision of Hematology, Department of Medicine, University of Washington, Seattle, Wash., USA
Offprint requests to: Mary M. Stevenson Ph.D., Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Rm. L11-409, 1650 Cedar Ave, Montreal, Quebec, Canada H3G 1A4
ABSTRACT