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.

Regulation of myelopoiesis by the transcription factor IRF8

“…Nevertheless, IRF8 appears to be involved in tissue-resident Mϕ development as well. The number of bone marrow resident Mϕs in Irf8 −/− mice is significantly lower [28]. Even though Irf8 −/− mice display only a modest decrease in splenic red pulp Mϕs, the loss of both IRF8 and structurally related IRF4 causes a significant decrease in these cells.…”

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

“…However, neutrophilic differentiation is inhibited by the ectopic expression of IRF4 or IRF8, possibly as a result of altered PU.1 expression (Yamamoto et al, 2011;Becker et al, 2012). Presumably because of the lower expression level, IRF4 −/− mice, but not IRF8 −/− mice, exhibit no obvious abnormality in the development of myeloid cells compared with their wild-type controls (Yamamoto et al, 2011). Additionally, IRF8 shows a potent ability to inhibit myeloid cell growth and to promote apoptosis potentially by regulating several key genes, for example Bcl2l1, Nf1 and Bax (Huang et al, 2007;Yang et al, 2011;Scheller et al, 2013).…”

“…Although IRF4 is expressed at a much lower level than IRF8 in granulocyte-macrophage progenitors, both of these IRFs strongly promote the differentiation of CMPs to macrophages. However, neutrophilic differentiation is inhibited by the ectopic expression of IRF4 or IRF8, possibly as a result of altered PU.1 expression (Yamamoto et al, 2011;Becker et al, 2012). Presumably because of the lower expression level, IRF4 −/− mice, but not IRF8 −/− mice, exhibit no obvious abnormality in the development of myeloid cells compared with their wild-type controls (Yamamoto et al, 2011).…”

Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias

“…Indeed, multiple studies have recently demonstrated that deletion of IRF4 in mice leads to the development of B-cell leukemia. [12][13][14][26][27][28][29] …”