Human Immunology 75 (2014) 1110–1114
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Review
The regulation role of interferon regulatory factor-1 gene and clinical relevance Lei Dou a, Hui-Fang Liang a, David A. Geller b, Yi-Fa Chen a,⇑,1, Xiao-Ping Chen a,1 a b
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
a r t i c l e
i n f o
Article history: Received 11 December 2013 Accepted 27 September 2014 Available online 13 October 2014 Keywords: IRF-1 Infection Injury Oncogenesis Immune system Interaction
a b s t r a c t IRF-1, a kind of transcription factors, is expressed constitutively in all cells types except early embryonal cells. By virtue of its interaction with specific DNA sequence, IRF-1 regulates the transcription of a set of target genes which play essential roles in various physiological and pathological processes, including viral infection, tumor immune surveillance, pro-inflammatory injury, development of immunity system. What’s more, IRF-1 also interacts with other transcription factors to regulate the specific genes transcription in the nucleus. In immunity system, IRF-1 is suggested to provide a link between innate and adoptive immune system. Although IRF-1 has been demonstrated with essential role in human immunity, the comprehensive understanding of the role of IRF-1 has been restrained because of extensive target genes, Here, we review the clinical relevance of IRF-1 and underlying mechanism based on the latest researches. Ó 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IRF-1 in anti-infection immune responses . . . . . . . . . . . . . . . . IRF-1 in tumor immune surveillance . . . . . . . . . . . . . . . . . . . . IRF-1 in pro-inflammatory injury . . . . . . . . . . . . . . . . . . . . . . . IRF-1 in development of immune system and autoimmunity. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Interferon regulatory factor (IRF)-1, the first member of the interferon (IFN) regulatory factor family, was originally identified as a key regulator of type I interferon (a/b). IRF-1 messenger RNA (mRNA) is expressed constitutively in cell cycle-dependent accumulation at a low base level in all cells types except early embryonal cells, but IRF-1 protein has a short half-life of 30 min [1]. IRF-1 levels are markedly regulated at the transcriptional level in response to various stimuli such as IFNs (type I and type II), double-stranded RNA, cytokines, and hormones. The DNA-binging domains (DBDs) of IRF-1 are located in the first 115 amino acids ⇑ Corresponding author. 1
Yi-Fa Chen and Xiao-Ping Chen are co-communicating authors.
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of the amino-terminal region characterized by a series of five well-conserved tryptophan-rich repeats. The DBD forms a helixturn-helix domain and recognizes a DNA sequence similar to the IFN-stimulated response element (A/GNGAAANNGAAACT) [2,3]. IRF-1 may bind DNA either as a monomer or as a dimer [4]. By virtue of its affinity of specific DNA sequence, IRF-1 was described to participate in transcription of various IRF-1-induced genes [5]. Besides that, IRF-1 also contains a carboxy(C)-terminal IRF-association domain (IAD), which is less well-conserved and facilitates heterodimerization between family members, interaction with transcription factors and cofactors [6]. Other functional domains also contribute to a balanced activity of IRF-1 as shown in Fig. 1. IRF-1 contains two potential sequences which might act as nuclear location signal (NLS), RKERKSK and KSKTKRK, which is required and is sufficient to translocate IRF-1
http://dx.doi.org/10.1016/j.humimm.2014.09.015 0198-8859/Ó 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
L. Dou et al. / Human Immunology 75 (2014) 1110–1114
from the site of synthesis in the cytoplasm to the nucleus [7]. A Cterminal fragment of IRF-1 has no activator function by itself but acts as a strong enhancer of activator sequences. The N-terminal 60 amino acids of IRF-1 strongly inhibit its transcriptional activity as a repression domain [8]. By the activities of all these functional domains, IRF-1 is suggested to provide a link between innate and adoptive immune system and plays a critical role in various physiological and pathological aspects, including viral infection, oncogenesis, proinflammatory injury, development of immune system and autoimmunity. This review focuses on the regulation role of IRF-1 in some specific topics. Improved understanding the role of IRF-1 that led to some pathological processes may aid development of novel therapeutic strategies. 2. IRF-1 in anti-infection immune responses Type I IFN (IFN-a/b), one of the most important target genes of IRF-1, provides a crucial mechanism of anti-infection response [9]. As the discovery of pattern recognition receptors (PRRs), IRFs gained much attention as essential regulators of anti-infection response. PRRs recognize various pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS) and viral nuclear acids [10]. Two classes of PRR have been defined: the transmembrane PRRs, namely Toll-like receptors (TLRs); and the cytosolic PRRs, including IFN-inducible double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), nucleotide-binging oligomerization domination (NOD) proteins, and retinoic-acidinducible gene 1 (RIG-1) [10,11]. Our understanding of how IRF-1 function as an important mediator to elicits immune response by activating these PRRs to tune the immune response for clearance of specific pathogen has progressed remarkably in the past few years. IRF-1 was the first member of IRFs family that was discovered to activate promoters in type I IFN genes. It has long been known that most virus can elicit the induction of type I IFN gene in most cell types by the activation of cytosolic PRRs [12,13], such as Newcastle disease virus (NDV; a negative-sense single-stranded RNA virus), vesicular stomatitis virus (VSV; a negative-sense ssRNA virus) and encephalomyocarditis virus (EMCV; a positive-sense ssRNA virus). IRF-1 was the first member of IRFs family that was discovered to activate promoters in type I IFN genes. However, NDV can induce mRNA that encodes type I IFN in a normal manner in IRF1/ mouse embryonic fibroblasts (MEFs), indicating that IRF-1 is not essential for the induction of type I IFN genes by the
repression domain
NLS
regulaon domain
DBD wwwww repression DNA binding
Transcripon inducon of target genes
acvaon
enhancement
heterodimerizaon interacon with other factors
Fig. 1. Schematic diagram of IRF-1 structure and domains. The upper part depicts the organization of the human IRF-1 gene. The horizontal bars in the lower part reflects the functions that have been assigned to known domains. Repression, activation, and enhancement relate to the transcriptional modulation properties of protein domains.
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virus-activated cytosolic pathway [14]. However, it is demonstrated that hepatitis C virus RNA replication may disrupt IRF-1 activation by targeting the double-stranded RNA (dsRNA)-dependent protein kinase R, suggesting that PKR, as an cytosolic PAMP, may initiates a dsRNA-induced-signaling cascade that result in the activity of IRF-1 [15]. Similarly, IRF-1 also involved in the TLRs mediated anti-viral immune responses. TLRs were thought to induce type I IFN responses by activating IRF-3 and IRF7 [9]. Until recently, an elegant series of experiments by Schmitz et al. demonstrates that the TLR9/MyD88/IRF1/IFN-beta pathway contributes to anti-viral resistance in vitro and in vivo and also reveals an unexpected link between TLR-9 and IFN-gamma signaling pathways [16]. The subsequent experiment by Negishi et al. also explored the TLR-9-mediated IFN-beta responses in mDC recruitment and activation of IRF1 through MyD88 [17]. They found that when TLR-9 signaling occurs together with IFN-gamma engagement, IRF-1 is not only induced but also activated and translocated rapidly into the nucleus to mediate efficient induction of IFN-beta, inducible nitric oxide synthase (iNOS) and IL-12p35. Although the direct interaction between the adaptor molecule MyD88 and the transcription factor IRF-1 has been demonstrate, the underlying mechanism of how MyD88 activates IRF-1 remains unclear. Besides that, interaction between IRF-1 and NF-KappaB plays an important role in the induction of several promoters, including the inducible nitric oxide synthase (iNOS) promoter [18,19]. IRF-1 binding sites were identified in the promoter of the iNOS gene, and IRF-1 is essential for iNOS induction. iNOS is relevant for production of NO, which is one of the principal mechanisms as defense against bacteria, tumor cells, protozoa, helminths, and fungi. Interferon (IFN)-gamma and Herpes simplex virus/tumor necrosis factor-alpha synergistically induce nitric oxide synthase in macrophages through cooperative action of nuclear factor-kappa B and IFN regulatory factor-1 [20]. Nitric oxide blocks human rhinovirus 16 (HRV-16)-mediated activation and nuclear translocation of both NF-kappaB and IRF-1. However, the ability of HRV16 to induce epithelial expression of IRF-1 is dependent, at least in part, on viral activation of NF-kappaB [21].
3. IRF-1 in tumor immune surveillance Accumulating evidences have indicated the contribution of IRF1 to tumor immune surveillance in human. IRF-1 inactivation by deletion of its one or more exons (exon skipping) has demonstrated in many hematological malignancies, including acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS) [22]. The loss of one IRF-1 allele has been reported in esophageal and gastric cancers and the frequent loss of heterozygosity of IRF-1 gene was also demonstrated in sporadic breast cancer [23– 26]. But unlike the classic tumor suppressor genes, loss of IRF-1 alleles alone rarely induces tumor development, however, IRF-1 deficiency significantly increase the incidence of developing tumors in combination with other genetic alterations, such as the expression of a c-Ha-Ras transgene, nullizygosity of the transformation-related protein 53 gene (Trp53) [27]. The mechanisms by which IRF-1 mediates tumor suppression are not well understood. There is a consensus that IRF-1 activates a set of target genes associated with regulation of the cell cycle, apoptosis and the immune response to involve in the susceptibility and progression of tumor. A direct antitumor growth effect and enhanced immune cell recognition of the tumor have been investigated using murine hepatocarcinoma cells expressing IRF-1/ human estrogen receptor fusion protein [28]. Several IRF-1 target genes that exert growth-inhibitory and promote apoptosis effects were listed in Table 1.
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Table 1 IRF-1 target genes associate with tumor immune surveillance. Target gene
Role
Reference
2 ,5 -Oligo (A) synthetase
Cell growth inhibition
[29]
p21WAF1/CIP1
Cell cycle-dependent Kinase inhibitor Tumor suppressor gene Anti-proliferation Inhibition of cell transformation Apoptosis Apoptosis Apoptosis Apoptosis DNA repair N/A Metabolic process Anti-proliferation Cell adhesion Signal transduction
[27]
0
0
p53 Protein kinase R Lysyl oxidase Caspase-1 Caspase-7 Caspase-8 PUMA BRIP1 BARD1 HPGD PLAGL1 RASSF5 AKAP12
[30] [31] [32] [35] [41] [36] [33] [39] [39] [39] [39] [39] [39]
The function of IRF-1 in cell cycle regulation has been studied extensively and its tumor suppressive activity may be explained, at least in part. IRF-1 induces the transcription of 20 ,50 -oligo (A) synthetase, whose product activates the mRNA-degrading enzyme RNase L and may cause cell growth inhibition [29]. A series of antiproliferation gene transcription was also mediated by IRF-1, including the cell cycle-dependent Kinase inhibitor p21WAF1/ CIP1 and tumor suppressor protein p53 [27,30], which lead to a G1 cell cycle arrest. Double-stranded RNA-dependent protein kinase R (PKR) plays an important role in the regulation of proliferation and exerts antigrowth activities by IRF-1 [31]. Lysyl oxidase, as a potential down stream mediator for the tumor suppression activity of IRF-1, may lower the biosynthetic capacity of the cell by enhanced degradation of rate-limiting precursor [32]. While aberrant expression of lysyl oxidase may lead to oncogenesis. IRF-1 is also associated with apoptosis induced by DNA damage or other stimuli. DNA damage-induced apoptosis in mitogenically activated mature T lymphocytes is dependent on IRF-1 but independent of p53. In addition, IRF-1 induces apoptosis by the intrinsic pathway, independent of the extrinsic pathway, by upregulation of p53 unregulated modulator (PUMA) [33]. However, in thymocytes, apoptosis is dependent on p53 but not on IRF-1. Thus, IRF-1 and p53 regulate DNA damage-induced apoptosis cooperatively and independently, depending on the type and differentiation stage of the cell [34]. Caspases are unique proteases that play essential roles in an activation cascade downstream in the apoptosis mechanism. It is demonstrated that IRF-1 directly mediates the IFN-gamma induced apoptosis via the activation of caspase-1 gene expression in IFN-gamma sensitive ovarian cancer and other cancer cells [35]. Furthermore, IRF-1 is involved in induction of caspase-8 expression and apoptosis initiated by IFNgamma [36]. Further studies have identified additional IRF-1 target genes recently. The tumor suppressor activity of IRF-1 has been associated with down-regulation of cyclin D1 [37] and surviving [38]. A ChIP–chip approach performed by Frontini et al. demonstrate the mRNA and protein levels of the DNA repair protein BRIP1 [Fanconi anemia gene J (FANC J)] are up-regulated after IRF1 overexpression, which reveals a novel role for IRF-1 in the regulation of the DNA inter-strand crosslink damage response [35]. The association between IRF-1 and BRIP1 further validates the importance of IRF-1 as a tumor susceptibility gene. In addition, five other target genes, hydroxyprostaglandin (HPGD), pleiomorphic adenoma gene-like 1 (PLAGL1), Ras association domain family 5 (RASSF5), a kinase anchor protein 12 (AKAP12) and deleted in colorectal can-
cer (DCC) have been reported to play the antitumor activity as IRF1 target genes [39]. Except various downstream target genes, Janus kinase and signal transducer and activator of transcription (JAK–STAT) pathway involves in the IRF-1 mediated tumor growth regulation at the transcriptional level. STAT1 is known to function upstream of IRF-1 and regulates IRF-1 promoter expression [40,41]. IFN-alpha and IFN-gamma fail to induce IRF-1 in cells that lack signal transducer and activator of transcription 1. This mechanism is currently hypothesized to involve IRF-1 up-regulation in response to IFN induction through STAT1 [42,43]. Newly synthesized IRF-1 may in turn activate expression of STAT1, resulting in positive feedback regulation of IRF-1 expression. Noon-song et al. carried out chromatin immunoprecipitation (ChIP) followed by PCR in IFN-gamma treated human amnion epithelial (WISH) cells and showed association of pJAK1, pJAK2, IFNGR1, and STAT1 on the same DNA sequence of the IRF-1 gene promoter [44]. Furthermore, accumulating evidence indicates the interaction of 2 IRFs in tumor initiation and progression [45–47]. Structures and chromosomal locations of human IRF-1 and IRF-2 genes are suggested the functional relationship between them [48]. Expression of the IRF-2 gene is affected by both transient and stable IRF-1 expression. Loss of IRF-1 expression and over-expression of IRF-2 were associated with malignant phenotype in melanoma, breast cancer, hepatic cellular cancer and esophageal carcinoma. The relative level of IRF-2 to IRF-1 (IRF-2/IRF-1 ratio) seems a more accurate indicator for development and progression of malignancies compared with IRF-1 or IRF-2 alone [46]. Recently, the mechanism of autophagy and its role in anticancer therapy draw more attentions. Autophagy induced by type I IFN in multiple cancer cell lines has been evidenced by autophagic markers, such as, the conversion of microtubule-associated protein 1 light chain 3 beta (MAP1LC3B/LC3-I) to LC3-II and the formation of autophagosomes [49]. In addition, JAK–STAT and PI3K–AKT– mTOR pathways also involve in type I IFN induced autophagy [50]. The regulation role of IRF-1 in the IFN-r induced autophagy has been evidenced in certain hepatocellular carcinoma cells [51].
4. IRF-1 in pro-inflammatory injury Previous studies have demonstrated that IRF-1 involved in injury in many clinical setting, including ischemia–reperfusion injury (IR), transplantation, shock. In liver warm IR model, IRF-1 knockout mice are protected from organ injury after IR and that over-expression of IRF-1 results in liver damage even in the absence of ischemia [52]. It is also proposed that reactive oxygen species (ROS)-induced renal tubular expression of IRF-1 exacerbates damage in acute kidney injury (AKI) [53]. The critical role of IRF-1 in liver transplantation has been identified in previous studies by IRF-1 knockout or over-expression in donor graft [54,55]. These observations imply a correlation between the IRF1 gene and poor outcome after IR. Over-expression of IRF-1 in donor graft further prove IRF-1 is an important regulator of IR injury after transplantation. Bae et al. provides the evidence that Nardostachys jatamansi (NJ, one kind of herb) inhibits endotoxic shock by inhibiting the production of IL-1b, IL-6, TNF-a, and IFNa/b through the inhibition of mitogen-activated protein kinase (MAPKs) activation and IRF induction [56]. Production of reactive oxygen species (ROS), upregulation of inducible nitric oxide synthase (iNOS), activation of c-Jun NH2-terminal kinase (JNK), upregulation of proinflammatory cytokines, and neutrophil accumulation have all been identified as contributing events to the inflammation-associated injury [57,58]. IRF-1 is an important mediator of the effects of signal transducer and activator of transcription 1 (STAT1) on ROS production in liver injury
L. Dou et al. / Human Immunology 75 (2014) 1110–1114
induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN) [59]. IRF-1 is also a necessary and sufficient transcription factor mediating pro-inflammatory genes expression secondary to IR injury, including iNOS [60]. JNK activation has also been found in the IR injury [61] and hemorrhagic shock [62]. Both a reduction in JNK activation in IRF-1 knockout mice following IR and abundant JNK activation following over-expression of IRF-1 in vivo suggest IRF-1 accounts for MAPK activation following IR. By all these mechanism, IRF-1 may contribute to the inflammation-associated injury. It is also interesting that IRF-2 acts a competitive inhibitor to compete with IRF-1 for DNA binding sites. It was demonstrated that endogenous intra-hepatic IRF-2 is protective and over-expression of IRF-2 diminishes induction of IRF1-dependant genes and decreases subsequent liver injury [63]. IRF-2 over-expression may represent a novel therapeutic strategy by decreasing IRF-1 dependant injury.
5. IRF-1 in development of immune system and autoimmunity In addition to the functions ascribe to IRF-1 in regulation of expression of various genes whose products are central to immunological response, previous studies have revealed roles for IRF-1 in the development of various immune cells, including NK cells, mature CD8+ T cells and differentiation of Th1 cells. IRF-1 affects the development and function of NK cells. Analysis of the spleen and liver of IRF1/ mice demonstrates a reduction in NK cell counts and function. It was demonstrated that the lack of IRF-1 affects the radiation-resistant cells in bone marrow that constitute the microenvironment required for NK-cell development, but not the NK-cell progenitors [64]. However, IRF-1/ bonemarrow cells can generate functional NK cells when cultured with the cytokine interleukin-15, which is transcriptionally regulated by IRF-1 and is essential for NK cell development [65]. IRF1/ mouse have reduced numbers of mature CD8 positive cells within the thymus and peripheral lymphatic organs. Expression of low molecular weight protein-2 (LMP2), antigen processing-1 (AP1) and major histocompatibility complex 1 (MHC1) are decreased on IRF1/ thymic stromal cells [14,66]. However, IRF1/ stromal cells can fully support development of CD8+ thymocytes. The defect in CD8+ T cell development does not reside in the thymic environment but is instead due to a thymocyte-intrinsic defect during differentiation from immature to mature CD8+ T cells. It is evidence that IRF1 is crucial for gene expression in developing thymocytes required for lineage commitment and selection of CD8 positive thymocytes [67]. Moreover, IRF-1 promotes the differentiation of Th1 cells [68]. T cells from IRF1-/- mice fail to mount Th1 responses, and, instead, CD4 positive cells exclusively undergo Th2 differentiation. IRF-1 deficiency affect the production of the p40 subunit of interleukin-12 (IL-12p40) by macrophages and the responsiveness of CD4+ T cells to IL-12, which is essential for Th1 differentiation [69]. Moreover, IRF-1 regulates the expression of genes encoding iNOS induced by IFN-gamma. iNOS catalyzes the production of nitric oxide, a short-lived volatile gas important in the effector phase of the Th1 response [70]. In essence, IRF-1 is indispensable for the differentiation of Th1. Coordinated activation and differentiation of various immunity cell types contribute to effective immune response, but abnormalities of IRF-1 regulation of these processes underlie the pathogenesis of many autoimmune disorders. It has demonstrated that IRF1 plays an important role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalitis, including oligodendrocyte injury and inflammatory demyelination [71]. Giannouli et al. also found that absence of IRF-1 transcript factor appear to
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protect against the development of autoimmunity in myelodysplasia [72]. These evidences suggest the potential therapeutic value of IRF-1 in autoimmunity disease.
6. Conclusion This review summarize the contribution of IRF-1 involving in various physiological and pathological aspects, including viral infection, tumor immune surveillance, pro-inflammatory injury, development of immune system and autoimmune disease. What’ more, it also introduces the mechanism underlying IRF-1 mediated reaction and the interactions with other transcription factors. In one side, it is helpful to clarify the regulation role of IRF-1 in some specific clinical settings. In the other side, it is useful to aid the development of novel therapeutic strategy based on IRF-1 target genes. References [1] Watanabe N, Sakakibara J, Hovanessian AG, Taniguchi T, Fujita T. Activation of IFN-beta element by IRF-1 requires a posttranslational event in addition to IRF1 synthesis. Nucleic Acids Res 1991;19(16):4421–8. [2] Fujita T, Sakakibara J, Sudo Y, Miyamoto M, Kimura Y, Taniguchi T. Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-beta gene regulatory elements. EMBO J 1988;7(11):3397–405. [3] Miyamoto M, Fujita T, Kimura Y, et al. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell 1988;54(6):903–13. [4] Kirchhoff S, Schaper F, Oumard A, Hauser H. In vivo formation of IRF-1 homodimers. Biochimie 1998;80(9):659–64. [5] Escalante CR, Yie J, Thanos D, Aggarwal AK. Structure of IRF-1 with bound DNA reveals determinants of interferon regulation. Nature 1998;391(6662):103–6. [6] Schaper F, Kirchhoff S, Posern G, et al. Functional domains of interferon regulatory factor I (IRF-1). Biochem J 1998;335(1):147–57. [7] Pine R, Decker T, Kessler DS, Levy DE, Darnell JE. Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Mol Cell Biol 1990;10(6):2448–57. [8] Kirchhoff S, Oumard A, Nourbakhsh M, Levi BZ, Hauser H. Interplay between repressing and activating domains defines the transcriptional activity of IRF-1. Eur J Biochem/FEBS 2000;267(23):6753–61. [9] Colonna M. TLR pathways and IFN-regulatory factors: to each its own. Eur J Immunol 2007;37(2):306–9. [10] Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124(4):783–801. [11] Janeway Jr CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20(2):197–216. [12] Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004;5(7):730–7. [13] Yoneyama M, Kikuchi M, Matsumoto K, et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 2005;175(5):2851–8. [14] Matsuyama T, Kimura T, Kitagawa M, et al. Targeted disruption of IRF-1 or IRF2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell 1993;75(1):83–97. [15] Pflugheber J, Fredericksen B, Sumpter Jr R, et al. Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc Natl Acad Sci U S A 2002;99(7):4650–5. [16] Schmitz F, Heit A, Guggemoos S, et al. Interferon-regulatory-factor 1 controls Toll-like receptor 9-mediated IFN-beta production in myeloid dendritic cells. Eur J Immunol 2007;37(2):315–27. [17] Negishi H, Fujita Y, Yanai H, et al. Evidence for licensing of IFN-gammainduced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc Natl Acad Sci U S A 2006;103(41):15136–41. [18] Spink J, Evans T. Binding of the transcription factor interferon regulatory factor-1 to the inducible nitric-oxide synthase promoter. J Biol Chem 1997;272(39):24417–25. [19] Morris KR, Lutz RD, Choi HS, Kamitani T, Chmura K, Chan ED. Role of the NFkappaB signaling pathway and kappaB cis-regulatory elements on the IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of nitric oxide. Infect Immun 2003;71(3):1442–52. [20] Paludan SR, Malmgaard L, Ellermann-Eriksen S, Bosca L, Mogensen SC. Interferon (IFN)-gamma and Herpes simplex virus/tumor necrosis factoralpha synergistically induce nitric oxide synthase 2 in macrophages through cooperative action of nuclear factor-kappa B and IFN regulatory factor-1. Eur Cytokine Netw 2001;12(2):297–308.
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Formation of STAT1–STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha. J Biol Chem 1996;271(10):5790–4. [41] Sanceau J, Hiscott J, Delattre O, Wietzerbin J. IFN-beta induces serine phosphorylation of STAT-1 in Ewing’s sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. Oncogene 2000;19(30):3372–83. [42] Gysemans C, Callewaert H, Overbergh L, Mathieu C. Cytokine signalling in the beta-cell: a dual role for IFN gamma. Biochem Soc Trans 2008;36(3):328–33. [43] Wan L, Cao D, Zeng J, Ziemba A, Pizzorno G. Activation of STAT1, IRF-1, and NFkappaB is required for the induction of uridine phosphorylase by tumor necrosis factor-alpha and interferon-gamma. Nucleosides Nucleotides Nucleic Acids 2010;29(4–6):488–503. [44] Noon-Song EN, Ahmed CM, Dabelic R, Canton J, Johnson HM. Controlling nuclear JAKs and STATs for specific gene activation by IFN gamma. Biochem Biophys Res Commun 2011;410(3):648–53. 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Contents lists available at ScienceDirect
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Review
The regulation role of interferon regulatory factor-1 gene and clinical relevance Lei Dou a, Hui-Fang Liang a, David A. Geller b, Yi-Fa Chen a,⇑,1, Xiao-Ping Chen a,1 a b
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
a r t i c l e
i n f o
Article history: Received 11 December 2013 Accepted 27 September 2014 Available online 13 October 2014 Keywords: IRF-1 Infection Injury Oncogenesis Immune system Interaction
a b s t r a c t IRF-1, a kind of transcription factors, is expressed constitutively in all cells types except early embryonal cells. By virtue of its interaction with specific DNA sequence, IRF-1 regulates the transcription of a set of target genes which play essential roles in various physiological and pathological processes, including viral infection, tumor immune surveillance, pro-inflammatory injury, development of immunity system. What’s more, IRF-1 also interacts with other transcription factors to regulate the specific genes transcription in the nucleus. In immunity system, IRF-1 is suggested to provide a link between innate and adoptive immune system. Although IRF-1 has been demonstrated with essential role in human immunity, the comprehensive understanding of the role of IRF-1 has been restrained because of extensive target genes, Here, we review the clinical relevance of IRF-1 and underlying mechanism based on the latest researches. Ó 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IRF-1 in anti-infection immune responses . . . . . . . . . . . . . . . . IRF-1 in tumor immune surveillance . . . . . . . . . . . . . . . . . . . . IRF-1 in pro-inflammatory injury . . . . . . . . . . . . . . . . . . . . . . . IRF-1 in development of immune system and autoimmunity. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Interferon regulatory factor (IRF)-1, the first member of the interferon (IFN) regulatory factor family, was originally identified as a key regulator of type I interferon (a/b). IRF-1 messenger RNA (mRNA) is expressed constitutively in cell cycle-dependent accumulation at a low base level in all cells types except early embryonal cells, but IRF-1 protein has a short half-life of 30 min [1]. IRF-1 levels are markedly regulated at the transcriptional level in response to various stimuli such as IFNs (type I and type II), double-stranded RNA, cytokines, and hormones. The DNA-binging domains (DBDs) of IRF-1 are located in the first 115 amino acids ⇑ Corresponding author. 1
Yi-Fa Chen and Xiao-Ping Chen are co-communicating authors.
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of the amino-terminal region characterized by a series of five well-conserved tryptophan-rich repeats. The DBD forms a helixturn-helix domain and recognizes a DNA sequence similar to the IFN-stimulated response element (A/GNGAAANNGAAACT) [2,3]. IRF-1 may bind DNA either as a monomer or as a dimer [4]. By virtue of its affinity of specific DNA sequence, IRF-1 was described to participate in transcription of various IRF-1-induced genes [5]. Besides that, IRF-1 also contains a carboxy(C)-terminal IRF-association domain (IAD), which is less well-conserved and facilitates heterodimerization between family members, interaction with transcription factors and cofactors [6]. Other functional domains also contribute to a balanced activity of IRF-1 as shown in Fig. 1. IRF-1 contains two potential sequences which might act as nuclear location signal (NLS), RKERKSK and KSKTKRK, which is required and is sufficient to translocate IRF-1
http://dx.doi.org/10.1016/j.humimm.2014.09.015 0198-8859/Ó 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
L. Dou et al. / Human Immunology 75 (2014) 1110–1114
from the site of synthesis in the cytoplasm to the nucleus [7]. A Cterminal fragment of IRF-1 has no activator function by itself but acts as a strong enhancer of activator sequences. The N-terminal 60 amino acids of IRF-1 strongly inhibit its transcriptional activity as a repression domain [8]. By the activities of all these functional domains, IRF-1 is suggested to provide a link between innate and adoptive immune system and plays a critical role in various physiological and pathological aspects, including viral infection, oncogenesis, proinflammatory injury, development of immune system and autoimmunity. This review focuses on the regulation role of IRF-1 in some specific topics. Improved understanding the role of IRF-1 that led to some pathological processes may aid development of novel therapeutic strategies. 2. IRF-1 in anti-infection immune responses Type I IFN (IFN-a/b), one of the most important target genes of IRF-1, provides a crucial mechanism of anti-infection response [9]. As the discovery of pattern recognition receptors (PRRs), IRFs gained much attention as essential regulators of anti-infection response. PRRs recognize various pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS) and viral nuclear acids [10]. Two classes of PRR have been defined: the transmembrane PRRs, namely Toll-like receptors (TLRs); and the cytosolic PRRs, including IFN-inducible double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), nucleotide-binging oligomerization domination (NOD) proteins, and retinoic-acidinducible gene 1 (RIG-1) [10,11]. Our understanding of how IRF-1 function as an important mediator to elicits immune response by activating these PRRs to tune the immune response for clearance of specific pathogen has progressed remarkably in the past few years. IRF-1 was the first member of IRFs family that was discovered to activate promoters in type I IFN genes. It has long been known that most virus can elicit the induction of type I IFN gene in most cell types by the activation of cytosolic PRRs [12,13], such as Newcastle disease virus (NDV; a negative-sense single-stranded RNA virus), vesicular stomatitis virus (VSV; a negative-sense ssRNA virus) and encephalomyocarditis virus (EMCV; a positive-sense ssRNA virus). IRF-1 was the first member of IRFs family that was discovered to activate promoters in type I IFN genes. However, NDV can induce mRNA that encodes type I IFN in a normal manner in IRF1/ mouse embryonic fibroblasts (MEFs), indicating that IRF-1 is not essential for the induction of type I IFN genes by the
repression domain
NLS
regulaon domain
DBD wwwww repression DNA binding
Transcripon inducon of target genes
acvaon
enhancement
heterodimerizaon interacon with other factors
Fig. 1. Schematic diagram of IRF-1 structure and domains. The upper part depicts the organization of the human IRF-1 gene. The horizontal bars in the lower part reflects the functions that have been assigned to known domains. Repression, activation, and enhancement relate to the transcriptional modulation properties of protein domains.
1111
virus-activated cytosolic pathway [14]. However, it is demonstrated that hepatitis C virus RNA replication may disrupt IRF-1 activation by targeting the double-stranded RNA (dsRNA)-dependent protein kinase R, suggesting that PKR, as an cytosolic PAMP, may initiates a dsRNA-induced-signaling cascade that result in the activity of IRF-1 [15]. Similarly, IRF-1 also involved in the TLRs mediated anti-viral immune responses. TLRs were thought to induce type I IFN responses by activating IRF-3 and IRF7 [9]. Until recently, an elegant series of experiments by Schmitz et al. demonstrates that the TLR9/MyD88/IRF1/IFN-beta pathway contributes to anti-viral resistance in vitro and in vivo and also reveals an unexpected link between TLR-9 and IFN-gamma signaling pathways [16]. The subsequent experiment by Negishi et al. also explored the TLR-9-mediated IFN-beta responses in mDC recruitment and activation of IRF1 through MyD88 [17]. They found that when TLR-9 signaling occurs together with IFN-gamma engagement, IRF-1 is not only induced but also activated and translocated rapidly into the nucleus to mediate efficient induction of IFN-beta, inducible nitric oxide synthase (iNOS) and IL-12p35. Although the direct interaction between the adaptor molecule MyD88 and the transcription factor IRF-1 has been demonstrate, the underlying mechanism of how MyD88 activates IRF-1 remains unclear. Besides that, interaction between IRF-1 and NF-KappaB plays an important role in the induction of several promoters, including the inducible nitric oxide synthase (iNOS) promoter [18,19]. IRF-1 binding sites were identified in the promoter of the iNOS gene, and IRF-1 is essential for iNOS induction. iNOS is relevant for production of NO, which is one of the principal mechanisms as defense against bacteria, tumor cells, protozoa, helminths, and fungi. Interferon (IFN)-gamma and Herpes simplex virus/tumor necrosis factor-alpha synergistically induce nitric oxide synthase in macrophages through cooperative action of nuclear factor-kappa B and IFN regulatory factor-1 [20]. Nitric oxide blocks human rhinovirus 16 (HRV-16)-mediated activation and nuclear translocation of both NF-kappaB and IRF-1. However, the ability of HRV16 to induce epithelial expression of IRF-1 is dependent, at least in part, on viral activation of NF-kappaB [21].
3. IRF-1 in tumor immune surveillance Accumulating evidences have indicated the contribution of IRF1 to tumor immune surveillance in human. IRF-1 inactivation by deletion of its one or more exons (exon skipping) has demonstrated in many hematological malignancies, including acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS) [22]. The loss of one IRF-1 allele has been reported in esophageal and gastric cancers and the frequent loss of heterozygosity of IRF-1 gene was also demonstrated in sporadic breast cancer [23– 26]. But unlike the classic tumor suppressor genes, loss of IRF-1 alleles alone rarely induces tumor development, however, IRF-1 deficiency significantly increase the incidence of developing tumors in combination with other genetic alterations, such as the expression of a c-Ha-Ras transgene, nullizygosity of the transformation-related protein 53 gene (Trp53) [27]. The mechanisms by which IRF-1 mediates tumor suppression are not well understood. There is a consensus that IRF-1 activates a set of target genes associated with regulation of the cell cycle, apoptosis and the immune response to involve in the susceptibility and progression of tumor. A direct antitumor growth effect and enhanced immune cell recognition of the tumor have been investigated using murine hepatocarcinoma cells expressing IRF-1/ human estrogen receptor fusion protein [28]. Several IRF-1 target genes that exert growth-inhibitory and promote apoptosis effects were listed in Table 1.
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Table 1 IRF-1 target genes associate with tumor immune surveillance. Target gene
Role
Reference
2 ,5 -Oligo (A) synthetase
Cell growth inhibition
[29]
p21WAF1/CIP1
Cell cycle-dependent Kinase inhibitor Tumor suppressor gene Anti-proliferation Inhibition of cell transformation Apoptosis Apoptosis Apoptosis Apoptosis DNA repair N/A Metabolic process Anti-proliferation Cell adhesion Signal transduction
[27]
0
0
p53 Protein kinase R Lysyl oxidase Caspase-1 Caspase-7 Caspase-8 PUMA BRIP1 BARD1 HPGD PLAGL1 RASSF5 AKAP12
[30] [31] [32] [35] [41] [36] [33] [39] [39] [39] [39] [39] [39]
The function of IRF-1 in cell cycle regulation has been studied extensively and its tumor suppressive activity may be explained, at least in part. IRF-1 induces the transcription of 20 ,50 -oligo (A) synthetase, whose product activates the mRNA-degrading enzyme RNase L and may cause cell growth inhibition [29]. A series of antiproliferation gene transcription was also mediated by IRF-1, including the cell cycle-dependent Kinase inhibitor p21WAF1/ CIP1 and tumor suppressor protein p53 [27,30], which lead to a G1 cell cycle arrest. Double-stranded RNA-dependent protein kinase R (PKR) plays an important role in the regulation of proliferation and exerts antigrowth activities by IRF-1 [31]. Lysyl oxidase, as a potential down stream mediator for the tumor suppression activity of IRF-1, may lower the biosynthetic capacity of the cell by enhanced degradation of rate-limiting precursor [32]. While aberrant expression of lysyl oxidase may lead to oncogenesis. IRF-1 is also associated with apoptosis induced by DNA damage or other stimuli. DNA damage-induced apoptosis in mitogenically activated mature T lymphocytes is dependent on IRF-1 but independent of p53. In addition, IRF-1 induces apoptosis by the intrinsic pathway, independent of the extrinsic pathway, by upregulation of p53 unregulated modulator (PUMA) [33]. However, in thymocytes, apoptosis is dependent on p53 but not on IRF-1. Thus, IRF-1 and p53 regulate DNA damage-induced apoptosis cooperatively and independently, depending on the type and differentiation stage of the cell [34]. Caspases are unique proteases that play essential roles in an activation cascade downstream in the apoptosis mechanism. It is demonstrated that IRF-1 directly mediates the IFN-gamma induced apoptosis via the activation of caspase-1 gene expression in IFN-gamma sensitive ovarian cancer and other cancer cells [35]. Furthermore, IRF-1 is involved in induction of caspase-8 expression and apoptosis initiated by IFNgamma [36]. Further studies have identified additional IRF-1 target genes recently. The tumor suppressor activity of IRF-1 has been associated with down-regulation of cyclin D1 [37] and surviving [38]. A ChIP–chip approach performed by Frontini et al. demonstrate the mRNA and protein levels of the DNA repair protein BRIP1 [Fanconi anemia gene J (FANC J)] are up-regulated after IRF1 overexpression, which reveals a novel role for IRF-1 in the regulation of the DNA inter-strand crosslink damage response [35]. The association between IRF-1 and BRIP1 further validates the importance of IRF-1 as a tumor susceptibility gene. In addition, five other target genes, hydroxyprostaglandin (HPGD), pleiomorphic adenoma gene-like 1 (PLAGL1), Ras association domain family 5 (RASSF5), a kinase anchor protein 12 (AKAP12) and deleted in colorectal can-
cer (DCC) have been reported to play the antitumor activity as IRF1 target genes [39]. Except various downstream target genes, Janus kinase and signal transducer and activator of transcription (JAK–STAT) pathway involves in the IRF-1 mediated tumor growth regulation at the transcriptional level. STAT1 is known to function upstream of IRF-1 and regulates IRF-1 promoter expression [40,41]. IFN-alpha and IFN-gamma fail to induce IRF-1 in cells that lack signal transducer and activator of transcription 1. This mechanism is currently hypothesized to involve IRF-1 up-regulation in response to IFN induction through STAT1 [42,43]. Newly synthesized IRF-1 may in turn activate expression of STAT1, resulting in positive feedback regulation of IRF-1 expression. Noon-song et al. carried out chromatin immunoprecipitation (ChIP) followed by PCR in IFN-gamma treated human amnion epithelial (WISH) cells and showed association of pJAK1, pJAK2, IFNGR1, and STAT1 on the same DNA sequence of the IRF-1 gene promoter [44]. Furthermore, accumulating evidence indicates the interaction of 2 IRFs in tumor initiation and progression [45–47]. Structures and chromosomal locations of human IRF-1 and IRF-2 genes are suggested the functional relationship between them [48]. Expression of the IRF-2 gene is affected by both transient and stable IRF-1 expression. Loss of IRF-1 expression and over-expression of IRF-2 were associated with malignant phenotype in melanoma, breast cancer, hepatic cellular cancer and esophageal carcinoma. The relative level of IRF-2 to IRF-1 (IRF-2/IRF-1 ratio) seems a more accurate indicator for development and progression of malignancies compared with IRF-1 or IRF-2 alone [46]. Recently, the mechanism of autophagy and its role in anticancer therapy draw more attentions. Autophagy induced by type I IFN in multiple cancer cell lines has been evidenced by autophagic markers, such as, the conversion of microtubule-associated protein 1 light chain 3 beta (MAP1LC3B/LC3-I) to LC3-II and the formation of autophagosomes [49]. In addition, JAK–STAT and PI3K–AKT– mTOR pathways also involve in type I IFN induced autophagy [50]. The regulation role of IRF-1 in the IFN-r induced autophagy has been evidenced in certain hepatocellular carcinoma cells [51].
4. IRF-1 in pro-inflammatory injury Previous studies have demonstrated that IRF-1 involved in injury in many clinical setting, including ischemia–reperfusion injury (IR), transplantation, shock. In liver warm IR model, IRF-1 knockout mice are protected from organ injury after IR and that over-expression of IRF-1 results in liver damage even in the absence of ischemia [52]. It is also proposed that reactive oxygen species (ROS)-induced renal tubular expression of IRF-1 exacerbates damage in acute kidney injury (AKI) [53]. The critical role of IRF-1 in liver transplantation has been identified in previous studies by IRF-1 knockout or over-expression in donor graft [54,55]. These observations imply a correlation between the IRF1 gene and poor outcome after IR. Over-expression of IRF-1 in donor graft further prove IRF-1 is an important regulator of IR injury after transplantation. Bae et al. provides the evidence that Nardostachys jatamansi (NJ, one kind of herb) inhibits endotoxic shock by inhibiting the production of IL-1b, IL-6, TNF-a, and IFNa/b through the inhibition of mitogen-activated protein kinase (MAPKs) activation and IRF induction [56]. Production of reactive oxygen species (ROS), upregulation of inducible nitric oxide synthase (iNOS), activation of c-Jun NH2-terminal kinase (JNK), upregulation of proinflammatory cytokines, and neutrophil accumulation have all been identified as contributing events to the inflammation-associated injury [57,58]. IRF-1 is an important mediator of the effects of signal transducer and activator of transcription 1 (STAT1) on ROS production in liver injury
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induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN) [59]. IRF-1 is also a necessary and sufficient transcription factor mediating pro-inflammatory genes expression secondary to IR injury, including iNOS [60]. JNK activation has also been found in the IR injury [61] and hemorrhagic shock [62]. Both a reduction in JNK activation in IRF-1 knockout mice following IR and abundant JNK activation following over-expression of IRF-1 in vivo suggest IRF-1 accounts for MAPK activation following IR. By all these mechanism, IRF-1 may contribute to the inflammation-associated injury. It is also interesting that IRF-2 acts a competitive inhibitor to compete with IRF-1 for DNA binding sites. It was demonstrated that endogenous intra-hepatic IRF-2 is protective and over-expression of IRF-2 diminishes induction of IRF1-dependant genes and decreases subsequent liver injury [63]. IRF-2 over-expression may represent a novel therapeutic strategy by decreasing IRF-1 dependant injury.
5. IRF-1 in development of immune system and autoimmunity In addition to the functions ascribe to IRF-1 in regulation of expression of various genes whose products are central to immunological response, previous studies have revealed roles for IRF-1 in the development of various immune cells, including NK cells, mature CD8+ T cells and differentiation of Th1 cells. IRF-1 affects the development and function of NK cells. Analysis of the spleen and liver of IRF1/ mice demonstrates a reduction in NK cell counts and function. It was demonstrated that the lack of IRF-1 affects the radiation-resistant cells in bone marrow that constitute the microenvironment required for NK-cell development, but not the NK-cell progenitors [64]. However, IRF-1/ bonemarrow cells can generate functional NK cells when cultured with the cytokine interleukin-15, which is transcriptionally regulated by IRF-1 and is essential for NK cell development [65]. IRF1/ mouse have reduced numbers of mature CD8 positive cells within the thymus and peripheral lymphatic organs. Expression of low molecular weight protein-2 (LMP2), antigen processing-1 (AP1) and major histocompatibility complex 1 (MHC1) are decreased on IRF1/ thymic stromal cells [14,66]. However, IRF1/ stromal cells can fully support development of CD8+ thymocytes. The defect in CD8+ T cell development does not reside in the thymic environment but is instead due to a thymocyte-intrinsic defect during differentiation from immature to mature CD8+ T cells. It is evidence that IRF1 is crucial for gene expression in developing thymocytes required for lineage commitment and selection of CD8 positive thymocytes [67]. Moreover, IRF-1 promotes the differentiation of Th1 cells [68]. T cells from IRF1-/- mice fail to mount Th1 responses, and, instead, CD4 positive cells exclusively undergo Th2 differentiation. IRF-1 deficiency affect the production of the p40 subunit of interleukin-12 (IL-12p40) by macrophages and the responsiveness of CD4+ T cells to IL-12, which is essential for Th1 differentiation [69]. Moreover, IRF-1 regulates the expression of genes encoding iNOS induced by IFN-gamma. iNOS catalyzes the production of nitric oxide, a short-lived volatile gas important in the effector phase of the Th1 response [70]. In essence, IRF-1 is indispensable for the differentiation of Th1. Coordinated activation and differentiation of various immunity cell types contribute to effective immune response, but abnormalities of IRF-1 regulation of these processes underlie the pathogenesis of many autoimmune disorders. It has demonstrated that IRF1 plays an important role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalitis, including oligodendrocyte injury and inflammatory demyelination [71]. Giannouli et al. also found that absence of IRF-1 transcript factor appear to
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protect against the development of autoimmunity in myelodysplasia [72]. These evidences suggest the potential therapeutic value of IRF-1 in autoimmunity disease.
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