title: Shared and distinct functions of the transcription factors IRF4 and IRF8 in myeloid cell development.
abstract: Interferon regulatory factor (IRF) 8 and IRF4 are structurally-related, hematopoietic cell-specific transcription factors that cooperatively regulate the differentiation of dendritic cells and B cells. Whilst in myeloid cells IRF8 is known to modulate growth and differentiation, the role of IRF4 is poorly understood. In this study, we show that IRF4 has activities similar to IRF8 in regulating myeloid cell development. The ectopic expression of IRF4 in myeloid progenitor cells in vitro inhibits cell growth, promotes macrophages, but hinders granulocytic cell differentiation. We also show that IRF4 binds to and activates transcription through the IRF-Ets composite sequence (IECS). Furthermore, we demonstrate that Irf8⁻/⁻Irf4⁻/⁻ mice exhibit a more severe chronic myeloid leukemia (CML)-like disease than Irf8⁻/⁻ mice, involving a disproportionate expansion of granulocytes at the expense of monocytes/macrophages. Irf4⁻/⁻ mice, however, display no obvious abnormality in myeloid cell development, presumably because IRF4 is expressed at a much lower level than IRF8 in granulocyte-macrophage progenitors. Our results also suggest that IRF8 and IRF4 have not only common but also specific activities in myeloid cells. Since the expression of both the IRF8 and IRF4 genes is downregulated in CML patients, these results may add to our understanding of CML pathogenesis.
authors: Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Michio
authors: M
authors: Yamamoto
authors: Takayuki
authors: T
authors: Kato
authors: Chie
authors: C
authors: Hotta
authors: Akira
authors: A
authors: Nishiyama
authors: Daisuke
authors: D
authors: Kurotaki
authors: Masahiro
authors: M
authors: Yoshinari
authors: Masamichi
authors: M
authors: Takami
authors: Motohide
authors: M
authors: Ichino
authors: Masatoshi
authors: M
authors: Nakazawa
authors: Toshifumi
authors: T
authors: Matsuyama
authors: Ryutaro
authors: R
authors: Kamijo
authors: Seiichi
authors: S
authors: Kitagawa
authors: Keiko
authors: K
authors: Ozato
authors: Tomohiko
authors: T
authors: Tamura
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D004247:DNA; D050835:Interferon Regulatory Factors; D012333:RNA, Messenger; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4