Chronic IFN-gamma production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis

Anemia of chronic disease is a complication accompanying many inflammatory diseases. The proinflammatory cytokine IFN-gamma has been implicated in this form of anemia, but the underlying mechanism remains unclear. Here we describe a novel mouse model for anemia of chronic disease, in which enhanced CD27-mediated costimulation strongly increases the formation of IFN-gamma-producing effector T cells, leading to a progressive anemia. We demonstrate that the anemia in these mice is fully dependent on IFN-gamma and that this cytokine reduces both the life span and the formation of red blood cells. Molecular analysis revealed that IFN-gamma induces expression of the transcription factors of interferon regulatory factor-1 (IRF-1) and PU.1 in both murine and human erythroid precursors. We found that, on IFN-gamma stimulation, IRF-1 binds to the promoter of SPI.1 (PU.1) and induces PU.1 expression, leading to inhibition of erythropoiesis. Notably, down-regulation of either IRF-1 or PU.1 expression is sufficient to overcome IFN-gamma-induced inhibition of erythropoiesis. These findings reveal a molecular mechanism by which chronic exposure to IFN-gamma induces anemia. (Blood. 2011;118(9):2578-2588)