Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anemia / etiology*
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Animals
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CD27 Ligand / genetics
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CD27 Ligand / physiology
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Chronic Disease
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Colony-Forming Units Assay
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Disease Models, Animal*
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Erythrocyte Aging / drug effects*
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Erythroid Precursor Cells / cytology
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Erythroid Precursor Cells / drug effects*
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Erythropoiesis / drug effects*
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Interferon Regulatory Factor-1 / antagonists & inhibitors
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Interferon Regulatory Factor-1 / biosynthesis
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Interferon Regulatory Factor-1 / blood
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Interferon Regulatory Factor-1 / genetics
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Interferon Regulatory Factor-1 / physiology*
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Interferon-gamma / pharmacology*
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Macrophages / physiology
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Mice
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Mice, Inbred C57BL
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Phagocytosis
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / blood
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / physiology
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Specific Pathogen-Free Organisms
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / biosynthesis
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Trans-Activators / blood
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Trans-Activators / genetics
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Trans-Activators / physiology*
Substances
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CD27 Ligand
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CD70 protein, human
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IRF1 protein, human
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Interferon Regulatory Factor-1
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Irf1 protein, mouse
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Trans-Activators
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proto-oncogene protein Spi-1
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Interferon-gamma