HGNC Approved Gene Symbol: IRF2
Cytogenetic location: 4q35.1 Genomic coordinates (GRCh38): 4:184,387,729-184,474,550 (from NCBI)
Interferon regulatory factor-1 (IRF1; 147575), a transcriptional activator, and IRF2, its antagonistic repressor, are regulators of type I interferon and interferon-inducible genes. The IRF1 gene is itself interferon-inducible and hence may be one of the target genes critical for interferon action (Harada et al., 1993).
Harada et al. (1993) found that when the IRF2 gene was overexpressed in NIH 3T3 cells, the cells became transformed and displayed enhanced tumorigenicity in nude mice. This transformed phenotype was reversed by concomitant expression of the IRF1 gene. Thus, restrained cell growth depends on a balance between these 2 mutually antagonistic transcription factors.
Harada et al. (1994) determined the structures of the human IRF1 and IRF2 genes and further characterized their promoters. Comparison of exon-intron organization of the 2 genes demonstrated a common evolutionary structure, notably within the exons encoding the N-terminal portions of the 2 factors. The 5-prime regulatory regions of both genes contain highly GC-rich sequences and consensus binding sequences for several known transcription factors, including NF-kappa-B. One IRF binding site was found within the IRF2 promoter, and expression of the IRF2 gene was affected by both transient and stable IRF1 expression.
Using fluorescence in situ hybridization, Harada et al. (1994) assigned the IRF2 gene to 4q35.1.
Nishio et al. (2001) screened for mutations in the 5-prime flanking and coding regions of IRF2 in patients with atopic dermatitis (see 603165). They found 5 novel variants and conducted a transmission disequilibrium test in families identified through patients with atopic dermatitis. The data suggested that the IRF2 gene may play a role in the development of atopic dermatitis in Japanese.
Hida et al. (2000) observed that Irf2 -/- mice exhibited progressive cutaneous inflammation accompanied by hair loss and ulcer formation. Histopathologic analysis demonstrated epidermal thickening with proliferating keratinocytes expressing Icam1/Cd54 (147840), features similar to those found in psoriasis. In addition, however, there was a disorganized muscle layer and prominent fibrosis. In the basal dermis, infiltrating Cd8 (see 186910)-positive rather than Cd4 (186940)-positive T cells were involved in the development of disease. In vitro analysis showed that the Cd8 T cells exhibited prolonged activation and proliferation with high expression of Cd44 (107269) and Ly6c. RT-PCR and Northern blot analysis detected spontaneous expression of Ifna (147660) and Ifnb (147640), as well as overexpression of IFN-inducible genes, i.e., Oas (see 603351), Irf7 (605047), Ip10 (SCYB10; 147310), and Mig (SCYB9; 601704), in the Irf2 -/- mice. Inactivation of the Ifna/Ifnb pathways by mutating Ifnar1 (107450) or Irf9 resulted in the absence of skin disease in Irf2 -/- mice.
Ko et al. (2002) noted that Irf1 -/- mice are deficient in Inos (163730), Il12b (161561), Cd8-positive T cells, and natural killer (NK) cells, whereas Irf2 -/- mice are deficient in NK cells and have dysregulated Il12b induction. Icsbp (601565) -/- mice are deficient in Il12b, Irf2, and reactive oxygen intermediates (ROIs). All 3 are inducible by gamma-interferon (Ifng; 147570) and have varying susceptibility to different intracellular bacterial and protozoan pathogens. Ko et al. (2002) determined that Irf1 -/- mice are highly susceptible to fatal liver damage from Brucella abortus, the causative agent of brucellosis, which manifests as arthritis, endocarditis, and meningitis in humans. In contrast, Irf2 -/- mice are highly resistant to Brucella, whereas Icsbp -/- mice maintain a plateau of infection similar to that seen in Il12b -/- mice. The authors concluded that IL12, reactive nitrogen intermediates, and ROIs are probably crucial immune components in resistance to Brucella infection.
Using flow cytometry, Taki et al. (2005) examined NK-cell development in mice deficient in either Irf2 or Il15 (600554). They found that Il15 was essential for early expansion of NK cells in bone marrow. In contrast, Irf2 was required to prevent NK-cell apoptosis and keep immature NK cells alive, thus promoting NK-cell maturation and their supply to peripheral blood.
Li et al. (2016) found that intraperitoneal infection of Irf2 -/- mice with a normally noninvasive strain of Sindbis virus (SINV) resulted in uncontrolled virus replication, neuronal cell death, and failure to recruit protective immune cells into brain. Wildtype mice produced Ifna only briefly early after infection, but Irf2 -/- mice persistently produced Ifna and other inflammatory cytokines, accompanied by increased permeability of the blood brain barrier. Immunohistochemical analysis demonstrated reduced B-cell numbers, but similar T-cell, macrophage, and cytotoxic cell numbers, in brains of Irf2 -/- mice compared with wildtype. Adoptive transfer of antibodies to SINV were not protective in Irf2 -/- mice. Li et al. (2016) proposed that proper localization of B cells and local production of antibodies in the central nervous system are required for protection from encephalitis.
Harada, H., Kitagawa, M., Tanaka, N., Yamamoto, H., Harada, K., Ishihara, M., Taniguchi, T. Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 259: 971-974, 1993. [PubMed: 8438157] [Full Text: https://doi.org/10.1126/science.8438157]
Harada, H., Takahashi, E.-I., Itoh, S., Harada, K., Hori, T.-A., Taniguchi, T. Structure and regulation of the human interferon regulatory factor 1 (IRF-1) and IRF-2 genes: implications for a gene network in the interferon system. Molec. Cell. Biol. 14: 1500-1509, 1994. [PubMed: 7507207] [Full Text: https://doi.org/10.1128/mcb.14.2.1500-1509.1994]
Hida, S., Ogasawara, K., Sato, K., Abe, M., Takayanagi, H., Yokochi, T., Sato, T., Hirose, S., Shirai, T., Taki, S., Taniguchi, T. CD8+ T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-alpha/beta signaling. Immunity 13: 643-655, 2000. [PubMed: 11114377] [Full Text: https://doi.org/10.1016/s1074-7613(00)00064-9]
Ko, J., Gendron-Fitzpatrick, A., Splitter, G. A. Susceptibility of IFN regulatory factor-1 and IFN consensus sequence binding protein-deficient mice to brucellosis. J. Immun. 168: 2433-2440, 2002. [PubMed: 11859135] [Full Text: https://doi.org/10.4049/jimmunol.168.5.2433]
Li, M. M. H., Bozzacco, L., Hoffmann, H.-H., Breton, G., Loschko, J., Xiao, J. W., Monette, S., Rice, C. M., MacDonald, M. R. Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion. J. Exp. Med. 213: 2931-2947, 2016. [PubMed: 27899441] [Full Text: https://doi.org/10.1084/jem.20160303]
Nishio, Y., Noguchi, E., Ito, S., Ichikawa, E., Umebayashi, Y., Otsuka, F., Arinami, T. Mutation and association analysis of the interferon regulatory factor 2 gene (IRF2) with atopic dermatitis. J. Hum. Genet. 46: 664-667, 2001. [PubMed: 11721886] [Full Text: https://doi.org/10.1007/s100380170018]
Taki, S., Nakajima, S., Ichikawa, E., Saito, T., Hida, S. IFN regulatory factor-2 deficiency revealed a novel checkpoint critical for the generation of peripheral NK cells. J. Immun. 174: 6005-6012, 2005. [PubMed: 15879093] [Full Text: https://doi.org/10.4049/jimmunol.174.10.6005]