IFN Regulatory Factor 8 Mediates Apoptosis in Nonhemopoietic Tumor Cells via Regulation of Fas Expression

Abstract

IRF8 is a transcription factor that was originally identified in myeloid cells. Mice with a null mutation of IRF8 exhibit uncontrolled expansion of myeloid cells that progress into a phenotype resembling human chronic myelogenous leukemia (CML). In human patients with CML, IRF8 transcript levels are frequently diminished. Here, we report that disruption of IRF8 function diminished Fas‐mediated apoptosis in solid tumor cells. Furthermore, it was found that constitutively expressed IRF8 is associated with the Fas promoter to activate Fas transcription. In addition, disruption of constitutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFNγ‐initiated induction of STAT1 phosphorylation. Interestingly, the constitutively expressed IRF8 was also essential for TNF‐α‐sensitization of Fas‐mediated apoptosis since disruption of IRF8 function also inhibited TNFα‐sensitized and Fas‐mediated apoptosis. Analysis of IRF8‐deficient dendritic cells (DC) generated from IRF8 null mice revealed that Fas expression level is also down‐regulated as compared to the wild type mice. In addition, IRF8‐deficient DCs also exhibited higher level of FLIPs protein as compared to the control wt DCs. Taken together, our data suggest that IRF8 is an essential regulator of Fas‐mediated apoptosis and that IRF8 mediates apoptosis through regulation of Fas and FLIP.

Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

“…A previous study has shown that Bcl-xL expression is regulated by IRF8 in myeloid leukemia cell lines (43), and our previous study has shown that Bax and Fas are transcriptionally regulated by IRF8 in myeloid cells and in nonhematopoietic cells (40,44). We, therefore, reasoned that altered expression of Fas, Bax, and Bcl-xL might be due to altered IRF8 expression in MDSCs.…”

Epigenetic disruption of interferon-γ response through silencing the tumor suppressor interferon regulatory factor 8 in nasopharyngeal, esophageal and multiple other carcinomas

“…For examples, IRF8 forms a complex with PU.1 to activate the transcription of p15 INK4B /CDKN2B, a bona fide TSG, in murine myeloid cells in response to IFNaˆtreatment (Schmidt et al, 2004). IRF8 also induces the expression of multiple TSGs such as NF1 (Zhu et al, 2004;Tamura et al, 2005) and apoptotic genes such as FAS (Yang et al, 2007a, b), and represses the expression of the oncogenic BCR/ABL and antiapoptotic BCL2 (Tamura et al, 2003;Burchert et al, 2004).…”

ICSBP promoter methylation in myelodysplastic syndromes and acute myeloid leukaemia

“…12 To substantiate these findings, we investigated a cohort of 100 patients with myeloid malignancies that had been characterized cytogenetically (Supplementary Table S3 lead to a loss of wild-type function in in vitro and in vivo models. 5,6,16 We analysed these exons by direct sequencing in 68 patients from whom material was available (Supplementary Materials and Methods). We found unaltered sequences in almost all analysed patients.…”