TY - JOUR
T1 - Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis
AU - Libregts, Sten F.
AU - Gutiérrez, Laura
AU - de Bruin, Alexander M.
AU - Wensveen, Felix M.
AU - Papadopoulos, Petros
AU - van Ijcken, Wilfred
AU - Ozgür, Zeliha
AU - Philipsen, Sjaak
AU - Nolte, Martijn A.
PY - 2011
Y1 - 2011
N2 - Anemia of chronic disease is a complication accompanying many inflammatory diseases. The proinflammatory cytokine IFN-γ 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-γ-producing effector T cells, leading to a progressive anemia. We demonstrate that the anemia in these mice is fully dependent on IFN-γ and that this cytokine reduces both the life span and the formation of red blood cells. Molecular analysis revealed that IFN-γ 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-γ 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-γ-induced inhibition of erythropoiesis. These findings reveal a molecular mechanism by which chronic exposure to IFN-γ induces anemia
AB - Anemia of chronic disease is a complication accompanying many inflammatory diseases. The proinflammatory cytokine IFN-γ 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-γ-producing effector T cells, leading to a progressive anemia. We demonstrate that the anemia in these mice is fully dependent on IFN-γ and that this cytokine reduces both the life span and the formation of red blood cells. Molecular analysis revealed that IFN-γ 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-γ 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-γ-induced inhibition of erythropoiesis. These findings reveal a molecular mechanism by which chronic exposure to IFN-γ induces anemia
U2 - https://doi.org/10.1182/blood-2010-10-315218
DO - https://doi.org/10.1182/blood-2010-10-315218
M3 - Article
C2 - 21725055
SN - 0006-4971
VL - 118
SP - 2578
EP - 2588
JO - Blood
JF - Blood
IS - 9
ER -