Cutting Edge: IRF8 Regulates Bax Transcription In Vivo in Primary Myeloid Cells

Abstract

A prominent phenotype of IRF8 knock out (IRF8 KO) mice is the uncontrolled expansion of immature myeloid cells. The molecular mechanism underlying this myeloproliferative syndrome is still elusive. In this study, we observed that Bax expression level is low in bone marrow (BM) preginitor cells and increased dramatically in primary myeloid cells in wt mice. In contrast, Bax expression level remained at low level in primary myeloid cells in IRF8 KO mice. However, in vitro IRF8 KO BM-differentiated myeloid cells expressed Bax at a level as high as that in wt myeloid cells. Furthermore, we demonstrated that IRF8 specifically binds to the Bax promoter region in primary myeloid cells. Functional analysis indicated that IRF8 deficiency results in increased resistance of the primary myeloid cells to Fas-mediated apoptosis. Our findings thus determine that IRF8 directly regulates Bax transcription in vivo but no in vitro during myeloid cell lineage differentiation.

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

“…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). It was also reported that IRF1 stimulates cell differentiation and mediates the N-ras-induced growth suppression of myeloid cells (Passioura et al, 2005;Schmitz et al, 2007).…”

Pak2 regulates myeloid-derived suppressor cell development in mice

“…43 Downregulation of IRF8 and Bax expression in Pak2-deficient MDSCs is consistent with the finding in MDSCs from tumor-bearing mice 43 and the report that IRF8-KO CD11b 1 primary myeloid cells display lower Bax expression level than WT cells. 23 On the other hand, Pak2-deficient MDSCs, while having reduced IRF8 expression ( Figure 6C-D), had a comparable level of Bcl-xL expression when compared with WT CD11b high Gr1 high PMNs ( Figure 5E). The discrepancy in Bcl-xL expression between Pak2-and IRF8-deficient MDSCs suggests that Pak2 may also regulate transcription factors other than IRF8, which downregulate Bcl-xL expression, thus offsetting the impact of IRF8 on Bcl-xL expression.…”

“…Our data are in line with the reported decreased sensitivity of IRF8-deficient MDSCs to spontaneous and Fasmediated apoptosis. 23,43 Collectively, our data demonstrate that loss of Pak2 function results in deregulated intrinsic and extrinsic anti-and pro apoptotic pathways, thus conferring apoptosis resistance to MDSCs.…”

“…Spontaneous late apoptosis (Annexin V 1 /PI 1 ) of spleen MDSCs in mice with Pak2-KO and WT BM was examined. As myeloid cell turnover is regulated by the Fas-FasL apoptosis pathway, 22,23 we also examined the responsiveness of Pak2-KO MDSCs to FasL-induced apoptosis. Splenic MDSCs from mice with Pak2-KO BM exhibited a near 40% and 60% reduction in spontaneous and Fas-FasL-mediated apoptosis as compared with WT CD11b high Gr1 high cells, respectively, indicating that Pak2-KO MDSCs are less sensitive to both spontaneous and FasL-induced apoptosis ( Figure 5A; representative flow shown in supplemental Figure 4A).…”

“…It mediates myeloid cell apoptosis through upregulation of Bcl-xL 43 and downregulation of Bax 23,43 and Bcl-2. 47 Respectively decreased and increased levels of Bax and Bcl-xL expression were observed in IRF8-deficient MDSCs from tumor-bearing mice than in myeloid cells with the same phenotypes from tumor-free mice.…”