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.
Highlights
Cell differentiation requires appropriate changes in gene expression patterns, which are tightly regulated by cell typespecific transcription factors
We have previously shown that the introduction of Interferon Regulatory Factor 8 (IRF8) into Irf8-/- myeloid progenitor cell lines such as Tot2 causes their differentiation into mature macrophages concomitant with a cell cycle arrest at the G0/G1 phase
These results indicate that the transduction of IRF4 or IRF8 cells results in their differentiation into bona fide macrophages
Summary
Cell differentiation requires appropriate changes in gene expression patterns, which are tightly regulated by cell typespecific transcription factors. Myeloid progenitor cells, defined as granulocytemacrophage progenitors (GMPs) [2], give rise to granulocytes (such as neutrophils) or monocytes/macrophages. A number of transcription factors including PU., C/EBPs and Interferon Regulatory Factor 8 (IRF8) have been shown to regulate this process. We have shown previously that IRF8, a hematopoietic cell-specific factor belonging to the IRF family, directs macrophage differentiation whilst it inhibits myeloid cell growth and neutrophil differentiation [4,5]. Conservation of IRF8’s function between mice and humans has been proven by a recent study demonstrating that a loss-offunction mutation in the human IRF8 gene results in a very high neutrophil count and an absence of circulating monocytes and dendritic cells [12]
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