Interferon Regulatory Factor Family Research Articles

IRF6 Is Involved in the Regulation of Cell Proliferation and Transformation in MCF10A Cells Downstream of Notch Signaling.

IRF6, a member of Interferon Regulatory Factors (IRF) family, is involved in orofacial and epidermal development. In breast cancer cell lines ectopic expression of IRF6 reduces cell numbers suggesting a role as negative regulator of cell cycle. IRF6 is a direct target of canonical Notch signaling in keratinocyte differentiation. Notch is involved in luminal cell fate determination and stem cell regulation in the normal breast and is implicated as an oncogene in breast cancer. Notch activation is sufficient to induce proliferation and transformation in non-tumorigenic breast epithelial cell line, MCF10A. ΔNp63, which is downregulated by Notch activation in the breast, regulates IRF6 expression in keratinocytes. In this report, we investigate Notch-IRF6 and ΔNp63-IRF6 interactions in MCF10A and MDA MB 231 cells. We observed that in these cells, IRF6 expression is partially regulated by canonical Notch signaling and ΔNp63 downregulation. Furthermore, we demonstrate that IRF6 abrogation impairs Notch-induced proliferation and transformation in MCF10A cells. Thus, we confirm the previous findings by showing a tissue independent regulation of IRF6 by Notch signaling, and extend them by proposing a context dependent role for IRF6, which acts as a positive regulator of proliferation and transformation in MCF10A cells downstream of Notch signaling.

Upregulation of Interferon Regulatory Factor 6 Promotes Neuronal Apoptosis After Traumatic Brain Injury in Adult Rats.

The interferon regulatory factor (IRF) family was first discovered as a set of transcriptional regulators of the type I interferon system in 1988. In mammals, the IRF family includes nine members that play important roles in the immune system, oncogenesis, and apoptosis. However, the distribution and the function of IRF6 in the central nervous system are limited. In this study, we established an adult rat traumatic brain injury (TBI) model. Compared to the sham brain cortex, Western blot and immunohistochemistry showed significant upregulation of IRF6 in the ipsilateral brain cortex after TBI. Immunofluorescence double-labeling showed that IRF6 completely co-localized with neurons, not astrocytes or oligodendrocytes. Furthermore, we detected that the neuronal apoptosis marker active caspase-3 co-localized with IRF6 in neurons. Additionally, IRF6 knockdown in PC12 cells in vitro resulted in a decrease in active caspase-3 expression and an increase in Bcl-2 and p-Akt expression. We conclude that IRF6 might promote neuronal apoptosis by inhibiting Akt phosphorylation after TBI.

Neddylation is required for herpes simplex virus type I (HSV-1)-induced early phase interferon-beta production.

Type I interferons such as interferon-beta (IFN-β) play essential roles in the host innate immune response to herpes simplex virus type I (HSV-1) infection. The transcription of type I interferon genes is controlled by nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB (IκB), which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBα. However, the role of neddylation in type I interferon expression remains unknown. Here, we report that neddylation inhibition with MLN4924 or upon UBA3 deficiency led to accumulation of phosphorylated IκBα, impaired IκBα degradation, and impaired NF-κB nuclear translocation in the early phase of HSV-1 infection even though phosphorylation and nuclear translocation of IRF3 were not affected. The blockade of NF-κB nuclear translocation by neddylation inhibition becomes less efficient at the later time points of HSV-1 infection. Consequently, HSV-1-induced early phase IFN-β production significantly decreased upon MLN4924 treatment and UBA3 deficiency. NF-κB inhibitor JSH-23 mimicked the effects of neddylation inhibition in the early phase of HSV-1 infection. Moreover, the effects of neddylation inhibition on HSV-1-induced early phase IFN-β production diminished in the presence of NF-κB inhibitor JSH-23. Thus, neddylation contributes to HSV-1-induced early phase IFN-β production through, at least partially, promoting NF-κB activation.

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

The family of interferon regulatory factors (IRFs) consists of nine members (IRF1-IRF9) in mammals. They act as transcription factors for the interferons and thus exert essential regulatory functions in the immune system and in oncogenesis. Recent clinical and experimental studies have identified critically important roles of the IRFs in cardiovascular diseases, arising from their participation in divergent and overlapping molecular programmes beyond the immune response. Here we review the current knowledge of the regulatory effects and mechanisms of IRFs on the immune system. The role of IRFs and their potential molecular mechanisms as novel stress sensors and mediators of cardiovascular diseases are highlighted.

Characterization and expression analyses of five interferon regulatory factor transcripts (Irf4a, Irf4b, Irf7, Irf8, Irf10) in Atlantic cod (Gadus morhua)

The interferon regulatory factor (IRF) family of genes encodes a group of transcription factors that have important roles not only in regulating the expression of Type I interferons (IFNs) and other genes in the IFN pathway, but also in growth, development and the regulation of oncogenesis. In this study, several IRF family members (Irf4a, Irf4b, Irf7, Irf8, Irf10) in Atlantic cod (Gadus morhua) were characterized at the cDNA and putative amino acid levels, allowing for phylogenetic analysis of these proteins in teleost fish, as well as the development of gene-specific primers used in RT-PCR and quantitative PCR (QPCR) analyses. Two Atlantic cod Irf10 splice variants were identified and their presence confirmed by sequencing of the Irf10 genomic region. RT-PCR showed that Irf7, Irf8 and both Irf10 transcripts were expressed in all 15 cod tissues tested, while Irf4a and Irf4b were absent in some tissues. QPCR analysis of spleen expression expanded upon this, and upon previous work. All IRF transcripts in the study were responsive to stimulation by the viral mimic poly(I:C), and all except Irf4a were responsive to exposure to formalin-killed Aeromonas salmonicida (ASAL). These IRF genes, thus, are likely important in the cod immune response to both viral and bacterial infections. Increased temperature (10 °C to 16 °C) was also observed to modulate the antibacterial responses of all IRF transcripts, and the antiviral responses of Irf4b and Irf10-v2. This research supports earlier studies which reported that elevated temperature modulates the expression of many immune genes in Atlantic cod.

Novel Types of Small RNA Exhibit Sequence- and Target-dependent Angiogenesis Suppression Without Activation of Toll-like Receptor 3 in an Age-related Macular Degeneration (AMD) Mouse Model.

RNA interference (RNAi) has become a powerful tool for suppressing gene expression in vitro and in vivo. A great deal of evidence has demonstrated the potential for the use of synthetic small interfering RNAs (siRNAs) as therapeutic agents. However, the application of siRNA to clinical medicine is still limited, mainly due to sequence-independent suppression of angiogenesis mediated by Toll-like receptor 3 (TLR3). Here, we describe novel types of synthetic RNA, named nkRNA and PnkRNA, that exhibit sequence-specific gene silencing through RNAi without activating TLRs or RIG-I–like receptor signaling. In addition, we confirmed the therapeutic effect for the novel types of RNA in an animal model of age-related macular degeneration (AMD) without retinal degeneration. These data indicate that nkRNA and PnkRNA are of great potential utility as therapies against blinding choroidal neovascularization due to AMD.

Understanding Transcription Factor Regulation by Integrating Gene Expression and DNase I Hypersensitive Sites.

Transcription factors are proteins that bind to DNA sequences to regulate gene transcription. The transcription factor binding sites are short DNA sequences (5–20 bp long) specifically bound by one or more transcription factors. The identification of transcription factor binding sites and prediction of their function continue to be challenging problems in computational biology. In this study, by integrating the DNase I hypersensitive sites with known position weight matrices in the TRANSFAC database, the transcription factor binding sites in gene regulatory region are identified. Based on the global gene expression patterns in cervical cancer HeLaS3 cell and HelaS3-ifnα4h cell (interferon treatment on HeLaS3 cell for 4 hours), we present a model-based computational approach to predict a set of transcription factors that potentially cause such differential gene expression. Significantly, 6 out 10 predicted functional factors, including IRF, IRF-2, IRF-9, IRF-1 and IRF-3, ICSBP, belong to interferon regulatory factor family and upregulate the gene expression levels responding to the interferon treatment. Another factor, ISGF-3, is also a transcriptional activator induced by interferon alpha. Using the different transcription factor binding sites selected criteria, the prediction result of our model is consistent. Our model demonstrated the potential to computationally identify the functional transcription factors in gene regulation.

Abstract 4996: Interferon consensus sequence binding protein (ICSBP) promotes epithelial to mesenchymal transition (EMT)-like phenomena, cell motility, and invasion via TGF-β signaling in U2OS cells

Abstract Interferon consensus sequence binding protein (ICSBP) is a transcription factor induced by interferon gamma (IFN-γ) and a member of the interferon regulatory factor (IRF) family. ICSBP is predominantly expressed in hematopoietic cells and regulates the immune response and cell growth and differentiation. However, little is known about its function in non-hematopoietic cells. Here we show a novel function for ICSBP in epithelial to mesenchymal transition (EMT)-like phenomena (ELP), cell motility, and invasion in human osteosarcoma cell lines, including U2OS cells. IFN-γ treatment induced ICSBP expression and EMT-like morphological change in U2OS cells, which were suppressed by ICSBP knock-down. To further investigate the role of ICSBP in ELP, we established a stable U2OS cell line that overexpresses ICSBP. ICSBP expression caused U2OS cells to have a more elongated shape and an increased vimentin and fibronectin expression. ICSBP expression also promoted adhesiveness, motility, and invasiveness of U2OS cells. ICSBP up-regulated transforming growth factor (TGF)-β receptors and activated TGF-β signaling cascades, which were responsible for ELP as well as increased cell motility and invasion. In addition, ICSBP-induced TGF-β receptor activation resulted in the up-regulation of Snail. Knock-down of Snail attenuated the ICSBP-induced augmentation of cell motility and invasion. Up-regulation of Snail, ELP, and increased invasion by ICSBP expression were also observed in other osteosarcoma cell lines, such as Saos-2 and 143B. Furthermore, ICSBP and TGF- β receptor I were expressed in 45/54 (84%) and 47/54 (87%) of human osteosarcoma tissues, respectively, and showed significant correlation (r= 0.47, p= 0.0007) with respect to their expression levels. Taken altogether, these data demonstrate a novel function for ICSBP in ELP, cell motility, and invasion through the TGF-β and Snail signaling pathways Citation Format: Jee Young Sung, Seog-Yun Park, June Hyuk Kim, Hyun Guy Kang, Jong Hyung Yoon, Yoon Sook Na, Yong-Nyun Kim, Byung-Kiu Park. Interferon consensus sequence binding protein (ICSBP) promotes epithelial to mesenchymal transition (EMT)-like phenomena, cell motility, and invasion via TGF-β signaling in U2OS cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4996. doi:10.1158/1538-7445.AM2014-4996

A reporter mouse reveals lineage-specific and heterogeneous expression of IRF8 during lymphoid and myeloid cell differentiation.

The IFN regulatory factor family member 8 (IRF8) regulates differentiation of lymphoid and myeloid lineage cells by promoting or suppressing lineage-specific genes. How IRF8 promotes hematopoietic progenitors to commit to one lineage while preventing the development of alternative lineages is not known. In this study, we report an IRF8-EGFP fusion protein reporter mouse that revealed previously unrecognized patterns of IRF8 expression. Differentiation of hematopoietic stem cells into oligopotent progenitors is associated with progressive increases in IRF8-EGFP expression. However, significant induction of IRF8-EGFP is found in granulocyte-myeloid progenitors and the common lymphoid progenitors but not the megakaryocytic-erythroid progenitors. Surprisingly, IRF8-EGFP identifies three subsets of the seemingly homogeneous granulocyte-myeloid progenitors with an intermediate level of expression of EGFP defining bipotent progenitors that differentiation into either EGFP(hi) monocytic progenitors or EGFP(lo) granulocytic progenitors. Also surprisingly, IRF8-EGFP revealed a highly heterogeneous pre-pro-B population with a fluorescence intensity ranging from background to 4 orders above background. Interestingly, IRF8-EGFP readily distinguishes true B cell committed (EGFP(int)) from those that are noncommitted. Moreover, dendritic cell progenitors expressed extremely high levels of IRF8-EGFP. Taken together, the IRF8-EGFP reporter revealed previously unrecognized subsets with distinct developmental potentials in phenotypically well-defined oligopotent progenitors, providing new insights into the dynamic heterogeneity of developing hematopoietic progenitors.

TRIpartite motif 21 (TRIM21) differentially regulates the stability of interferon regulatory factor 5 (IRF5) isoforms.

IRF5 is a member of the Interferon Regulatory Factor (IRF) family of transcription factors activated downstream of the Toll-Like receptors (TLRs). Polymorphisms in IRF5 have been shown to be associated with the autoimmune disease Systemic Lupus Erythematosus (SLE) and other autoimmune conditions, suggesting a central role for IRF5 in the regulation of the immune response. Four different IRF5 isoforms originate due to alternative splicing and to the presence or absence of a 30 nucleotide insertion in IRF5 exon 6. Since the polymorphic region disturbs a PEST domain, a region associated with protein degradation, we hypothesized that the isoforms bearing the insertion might have increased stability, thus explaining the association of individual IRF5 isoforms with SLE. As the E3 ubiquitin ligase TRIpartite Motif 21 (TRIM21) has been shown to regulate the stability and hence activity of members of the IRF family, we investigated whether IRF5 is subjected to regulation by TRIM21 and whether dysregulation of this mechanism could explain the association of IRF5 with SLE. Our results show that IRF5 is degraded following TLR7 activation and that TRIM21 is involved in this process. Comparison of the individual IRF5 variants demonstrates that isoforms generated by alternative splicing are resistant to TRIM21-mediated degradation following TLR7 stimulation, thus providing a functional link between isoforms expression and stability/activity which contributes to explain the association of IRF5 with SLE.

Interferon Regulatory Factor 6 Differentially Regulates Toll-like Receptor 2-dependent Chemokine Gene Expression in Epithelial Cells

Epidermal and mucosal epithelial cells are integral to host defense. They not only act as a physical barrier but also utilize pattern recognition receptors, such as the Toll-like receptors (TLRs), to detect and respond to pathogens. Members of the interferon regulatory factor (IRF) family of transcription factors are key components of TLR signaling as they impart specificity to downstream responses. Although IRF6 is a critical regulator of epithelial cell proliferation and differentiation, its role in TLR signaling has not previously been addressed. We show here that IRF6 is activated by IRAK1 as well as by MyD88 but not by TRIF or TBK1. Co-immunoprecipitation experiments further demonstrated that IRF6 can interact with IRAK1. Gene silencing in epithelial cells along with gene promoter reporter assays showed that IRAK1 mediates TLR2-inducible CCL5 gene expression at least in part by promoting IRF6 activation. Conversely, IRAK1 regulated CXCL8 gene expression independently of IRF6, thus identifying a molecular mechanism by which TLR2 signaling differentially regulates the expression of specific chemokines in epithelial cells. Bioinformatics analysis and mutagenesis-based experiments identified Ser-413 and Ser-424 as key regulatory sites in IRF6. Phosphomimetic mutation of these residues resulted in greatly enhanced IRF6 dimerization and trans-activator function. Collectively, our findings suggest that, in addition to its importance for epithelial barrier function, IRF6 also contributes to host defense by providing specificity to the regulation of inflammatory chemokine expression by TLR2 in epithelial cells.

IRF5-mediated signaling and implications for SLE

Transcription of the type I IFN genes is regulated by members of the Interferon Regulatory Factor (IRF) family of transcription factors, composed in humans of 9 distinct proteins. In addition to IRF3 and IRF7, the transcription factor IRF5 has been shown to be involved in type I IFN production and interestingly, polymorphisms of the IRF5 gene in humans can result in risk or protective haplotypes with regard to SLE susceptibility. In addition to regulation of type I IFN expression, IRF5 is involved in other signaling pathways, including IgG switching in B cells, macrophage polarization and apoptosis, and its role in SLE pathogenesis may therefore not be limited to dysregulated control of IFN expression. In this review we will comprehensively discuss the role of IRF5 in immune-mediated responses and its potential multifaceted role in conferring SLE susceptibility.

THU0518 Dicam Attenuates Macrophage Differentiation via Suppression of Integrin αVβ3-Dependent Akt-Foxo3a-Irf7 Pathway

BackgroundDICAM, a dual Ig domain containing adhesion molecule, is involved in cell-cell adhesion through a direct interaction with αVβ3 integrin. In our previous study showing the inhibitory role in osteoclastogenesis,...

Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease

The interferon-regulatory factor (IRF) family comprises nine members in mammals. Although this transcription factor family was originally thought to function primarily in the immune system, contributing to both the innate immune response and the development of immune cells, recent advances have revealed that IRFs plays critical roles in other biological processes, such as metabolism. Accordingly, abnormalities in the expression and/or function of IRFs have increasingly been linked to disease. Herein, we provide an update on the recent progress regarding the regulation of immune responses and immune cell development associated with IRFs. Additionally, we discuss the relationships between IRFs and immunity, metabolism, and disease, with a particular focus on the role of IRFs as stress sensors. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.

Interferon consensus sequence-binding protein (ICSBP) promotes epithelial-to-mesenchymal transition (EMT)-like phenomena, cell-motility, and invasion via TGF-β signaling in U2OS cells.

Interferon consensus sequence-binding protein (ICSBP) is a transcription factor induced by interferon gamma (IFN-γ) and a member of the interferon regulatory factor (IRF) family. ICSBP is predominantly expressed in hematopoietic cells and regulates the immune response and cell growth and differentiation. However, little is known about its function in non-hematopoietic cells. Here we show a novel function for ICSBP in epithelial-to-mesenchymal transition (EMT)-like phenomena (ELP), cell motility, and invasion in human osteosarcoma cell lines, including U2OS cells. IFN-γ treatment induced ICSBP expression and EMT-like morphological change in U2OS cells, which were suppressed by ICSBP knockdown. To further investigate the role of ICSBP in ELP, we established a stable U2OS cell line that overexpresses ICSBP. ICSBP expression caused U2OS cells to have a more elongated shape and an increased vimentin and fibronectin expression. ICSBP expression also promoted adhesiveness, motility, and invasiveness of U2OS cells. ICSBP upregulated transforming growth factor (TGF)-β receptors and activated TGF-β signaling cascades, which were responsible for ELP as well as increased cell motility and invasion. In addition, ICSBP-induced TGF-β receptor activation resulted in the upregulation of Snail. Knockdown of Snail attenuated the ICSBP-induced augmentation of cell motility and invasion. Upregulation of Snail, ELP, and increased invasion by ICSBP expression were also observed in other osteosarcoma cell lines, such as Saos-2 and 143B. Furthermore, ICSBP and TGF-β receptor I were expressed in 45/54 (84%) and 47/54 (87%) of human osteosarcoma tissues, respectively, and showed significant correlation (r=0.47, P=0.0007) with respect to their expression levels. Taken altogether, these data demonstrate a novel function for ICSBP in ELP, cell motility, and invasion through the TGF-β and Snail signaling pathways.

A160: Role of Interleukin‐1 in Abnormal Monocyte Phenotype in Systemic Onset Juvenile Idiopathic Arthritis

Background/Purpose:Monocytes phenotype changes in different microenvironments: the proinflammatory M1, regulatory M2, and M2‐like phenotypes are each regulated by specific transcriptional factors (TFs). We have observed altered phenotypes in blood monocytes in systemic onset juvenile idiopathic arthritis (sJIA), including a decreased M1 cells, an increased mixed M1/M2 cells, and reduced secretion of IL‐1, despite an increased IL‐1b response to LPS (PMID 22281427). Here, we investigate whether these monocyte phenotypes are affected by IL‐1 blockade. We analyzed monocytes from RAPPORT (RAndomized Placebo Phase study Of Rilonacept in the Treatment of sJIA) patients to determine levels of TFs involved in monocyte polarization and expression of genes related to IL‐1 secretion, before and after treatment with Rilonacept, an IL‐1 trap.Methods:Subjects on the Rilonacept arm received active drug from week 0 for a total of 24 weeks; subjects on the placebo arm received placebo for 4 weeks, then Rilonacept for 20 weeks. Blood samples were obtained at week 0, 2, 4, 14 and 24. We used real time PCR to measure M1 associated genes: Interferon Regulatory factor (IRF) family IRF5, STAT1; M2 associated genes IRF4, STAT6, Kruppel‐Like Factor 4 (KLF4) and peroxisome proliferator‐activated receptor‐γ (PPAR‐γ); IL‐1 secretion related genes: RAB39, RAB27A, RAB27B, P2RX7, and IL‐1β. All TFs levels were normalized by the average levels of 3 housekeeping genes.Results:30 non‐paired RNA samples from 15 subjects were tested. Samples from subjects treated with Rilonacept for ≥10 weeks (Late RAPPORT) showed decreased expression of M2 genes, especially KLF4, compared to those untreated or treated for <10 weeks (Early RAPPORT) (Fig ), except for PPAR‐γ. Samples collected when there was clinical improvement also showed reduced KLF4 (Fig .). The expression of TFs following IL‐1 inhibition in sJIA patients is distinct from normal controls. Levels of IL‐1 secretion related genes, except for RAB27B, also were reduced in “Late RAPPORT” samples (Fig .).imageimageimageConclusion:IL‐1 blockade in sJIA is likely associated with changes in the activation profile and expression of IL‐1 secretion related genes in circulating monocytes. Monocytes phenotypes in treated subjects are not “normal” and likely reflect changes associated with compensated inflammation.

HIV-2 Vpx Protein Interacts with Interferon Regulatory Factor 5 (IRF5) and Inhibits Its Function

Interferon regulatory factor (IRF) family members have been implicated as critical transcription factors that function in immune responses, hematopoietic differentiation, and cell growth regulation. Activation of IRF5 results in the production of pro-inflammatory cytokines such as TNFα, IL6, and IL12, as well as type I interferons. In this study, we demonstrate that HIV-2 Vpx interacts with IRF5, and Vpx inhibits IRF5-mediated transactivation. Expression of Vpx in THP-1 cells reduced mRNA levels and protein production of Toll-like receptor-dependent IL6, IL12p40, and TNFα induced by lipopolysaccharide, R848, and ODN2216. Chromatin immunoprecipitation assays show that Vpx expression results in decreased promoter binding activity of IRF5. This study provides new insights into mechanisms employed by HIV-2 to counteract innate immune defenses against viral infection.

IRF4 is a novel mediator for neuronal survival in ischaemic stroke

Neuroprotection following ischaemic stroke is driven by the interplay between regulatory transcription factors and endogenous protective factors. IRF4, a member of the interferon regulatory factor (IRF) family, is implicated in the survival of tumour cells. However, its role in the survival of normal cells including neurons remains elusive. Using genetic approaches, we established a central role for IRF4 in protection against ischaemia/reperfusion (I/R)-induced neuronal death. IRF4 was expressed in neurons, and induced by ischaemic stroke. Neuron-specific IRF4 transgenic (IRF4-TG) mice exhibited reduced infarct lesions, and this effect was reversed in IRF4-knockout mice. Notably, we revealed that IRF4 rescues neurons from I/R-induced death both in vivo and in vitro. Integrative transcriptional and cell survival analyses showed that IRF4 functions mechanistically as a transcription activator of serum response factor (SRF) crucial to salvage neurons during stroke. Indeed, the expression of SRF and SRF-dependent molecules was significantly upregulated upon IRF4 overexpression and conversely inhibited upon IRF4 ablation. Similar results were observed in oxygen glucose deprivation (OGD)-treated primary cortical neurons. Furthermore, we identified the IRF4-binding site in the promoter region of the SRF gene essential for its transcription. To verify the IRF4–SRF axis in vivo, we generated neuron-specific SRF knockout mice, in which SRF exerted profound cerebroprotective effects similar to those of IRF4. More importantly, the phenotype observed in IRF4-TG mice was completely reversed by SRF ablation. Thus, we have shown that the IRF4–SRF axis is a novel signalling pathway critical for neuronal survival in the setting of ischaemic stroke.

Transcriptional control of dendritic cell differentiation.

Dendritic cells (DCs) are professional antigen presenting cells involved critically not only in provoking innate immune responses but also in establishing adaptive immune responses. Dendritic cells are heterogenous and divided into several subsets, including plasmactyoid DCs (pDCs) and several types of conventional DCs (cDCs), which show subset-specific functions. Plasmactyoid DCs are featured by their ability to produce large amounts of type I interferons (IFNs) in response to nucleic acid sensors, TLR7 and TLR9 and involved in anti-viral immunity and pathogenesis of certain autoimmune disorders such as psoriasis. Conventional DCs include the DC subsets with high crosspresentation activity, which contributes to anti-viral and anti-tumor immunity. These subsets are generated from hematopoietic stem cells (HSCs) via several intermediate progenitors and the development is regulated by the transcriptional mechanisms in which subset-specific transcription factors play major roles. We have recently found that an Ets family transcription factor, SPI-B, which is abundantly expressed in pDCs among DC subsets, plays critical roles in functions and late stage development of pDCs. SPI-B functions in cooperation with other transcription factors, especially, interferon regulatory factor (IRF) family members. Here we review the transcription factor-based molecular mechanisms for generation and functions of DCs, mainly by focusing on the roles of SPI-B and its relatives.

HIV and Interferon Regulatory Factor 1: A Story of Manipulation and Control

Members of the interferon regulatory factor (IRF) family control the expression of numerous proteins, many of which are central to regulating host immune responses. IRF1 is one of the central mediators of the innate and adaptive immune responses required for antigen processing and presentation, Th1/Th2 differentiation, and natural killer (NK) cell and macrophage function. Many viruses have evolved mechanisms to target the IRF1 pathway in order to promote viral pathogenesis. During early HIV infection, IRF1 acts as a double-edged sword, critical for driving viral replication as well as eliciting antiviral responses. In this review, we describe the strategies that HIV-1 has evolved to modulate IRF1 in order to enhance viral replication and to disarm the host immune system. IRF1 has been shown to be an important factor in natural protection against HIV in highly exposed seronegative (HESN) individuals and is crucial in regulating the initial stages of HIV replication and HIV disease progression, as well as the establishment of latency. An understanding of how the protective effects of IRF1 responses are controlled in HESN individuals, naturally resistant to HIV infection, may provide important clues on how to regain control of HIV and tip the balance of immunity in favor of the host, or provide new opportunities to eliminate HIV in its host altogether.