title: Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis.
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.
authors: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Sten F
authors: SF
authors: Libregts
authors: Laura
authors: L
authors: Gutiérrez
authors: Alexander M
authors: AM
authors: de Bruin
authors: Felix M
authors: FM
authors: Wensveen
authors: Petros
authors: P
authors: Papadopoulos
authors: Wilfred
authors: W
authors: van Ijcken
authors: Zeliha
authors: Z
authors: Ozgür
authors: Sjaak
authors: S
authors: Philipsen
authors: Martijn A
authors: MA
authors: Nolte
mesh_terms: D000740:Anemia / Q000209:etiology*; D000818:Animals; D053282:CD27 Ligand / Q000235:genetics / Q000502:physiology; D002908:Chronic Disease; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D004905:Erythrocyte Aging / Q000187:drug effects*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects*; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D053282:CD27 Ligand; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C505771:CD70 protein, human; C494257:IRF1 protein, human; C494258:Irf1 protein, mouse