Interferon-Regulatory Factor Transcription Factors Proteins

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Interferon-Regulatory Factor Transcription Factors Proteins

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Interferon-Regulatory Factor Transcription Factors Proteins Background

Interferon regulatory factors (IRFs) are a family of transcription factors that were first identified as regulators of virus-induced type I interferon (IFNA and B) gene expression. With the later discovery of other IFN families (type II and III), most of the IRFs, with the exception of IRF6 , have been implicated in their regulation. Subsequent findings revealed that IRFs play important roles in the regulation of both innate and adaptive immune responses. In particular, IRFs have been shown to be involved in the activation and differentiation of distinct immune cell populations, To date, ten IRFs have been discovered (IRF1-10) in vertebrates; however, some are rendered inactive or eliminated in mice and humans, such as IRF10 . A number of structural features within IRFs are well conserved.

The most studied pathway(s) that leads to IRF activation is through the TLRs. TLR signaling can be divided into two pathways: one dependents on the adapter protein MyD88 (myeloid differentiation primary response), and the other is MYD88-independent and requires the adapter protein TRIF (Toll/IL-1 receptor domain-containing adaptor inducing IFN-B). Depending on the IRF, one or both pathways may lead to activation, resulting in its binding to the promoters of target genes and modulation of immune responses. The steps leading to IRF activation and function can be broadly summarized into five major stages: (1) signal, (2) post-translational modification, (3) dimer formation, (4) nuclear translocation, (5) regulation of target gene expression.

With ongoing advances in the field of genome-wide association studies (GWAS), genetic variations in IRFs have been identified and associated with numerous autoimmune diseases. These genetic associations have opened up an expansive field of research focused on determining the role of IRFs in autoimmune disease pathogenesis. Autoimmune diseases are characterized by an attack on one’s “self”. The attack can be either specific to a particular organ, as is the case in inflammatory bowel disease (IBD), or systemic, as seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren’s Syndrome (SS). A number of genetic variants or single nucleotide polymorphisms (SNPs) within IRF genes have been detected at higher rates in patients with autoimmune diseases than matched healthy controls that enable an association with risk or protection from disease. Given the critical role of IRFs in IFN gene regulation, it was first postulated that genetic variants would contribute to elevated type I IFN expression that is now detected in multiple autoimmune diseases. Based on emerging data, however, researchers propose that IRF function (or dysfunction) in autoimmune diseases is more robust than just as regulators of the IFNs.

IRF1 regulates the transcription of genes that play essential roles in viral infection, tumor immune surveillance, pro-inflammatory injury, and immunity system development. IRF2 negatively regulates type I IFN responses and plays a role in the induction of Th1 differentiation. While not well replicated, association of IRF2 genetic variants with susceptibility to SLE has been shown, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2. IRF3 is constitutively expressed in all cell types and is primarily known for its regulation of type I IFNs in response to pathogens. Similar to IRF1, few replicative association studies have been performed to link IRF3 genetic variants to autoimmune diseases. The most studied has been IRF3 polymorphisms in SLE, yet little agreement has been reached. Distinct from other IRF family members, IRF4 expression is restricted to immune cells, and can either function as a transcriptional activator or repressor depending on its interacting partner. IRF4 is induced upon the activation of T and B cells. IRF5 has been demonstrated to play a key role in modulating innate and adaptive immune responses in numerous cell types, including dendritic cells, monocytes/macrophages, and B cells. IRF5 is regarded as the “master regulator of proinflammatory cytokines”. IRF7 expression is not restricted to immune cells but nor is it ubiquitously expressed. It is best known as a master regulator of type I IFN gene expression and IFN-dependent innate immune responses. IRF8 is a key transcription factor for myeloid cell differentiation. With regard to autoimmune diseases, two genetic variants in the IRF8 gene have been associated with BD in Han Chinese.

MS is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by an autoimmune inflammatory reaction against CNS myelin. IRF1 signaling in microglial cells has been shown to be involved in the pathogenesis of MS. IRF1 SNPs have been associated with progressive MS and IRF1-regulated genes, such as MHC class I (MHCI), TNF receptor (TNFR) and caspase 1, have been shown to be elevated in MS patients. In glial cells, IRF1 was found to cooperate with NFkB for the regulation of MHCI and inducible nitric oxide synthase (iNOS) expression leading to cytokine synergism.

SS is a systemic autoimmune disease involving multiple organs. It is characterized by extensive dryness, extreme fatigue, chronic pain, neuropathies and lymphomas. It is called primary SS (pSS) when it occurs alone or secondary SS when it is in association with other autoimmune diseases like SLE and RA. SS is further characterized by infiltration of TH cells and a TH1/TH2 imbalance has been shown to play a role in SS pathogenesis. Like SLE, an IFN gene signature has been shown to be associated with SS and the strength of the IFN signature positively correlated with disease severity. IRF1 plays an important role in TH differentiation and is known to regulate gene expression of factors involved in TH1 differentiation.

These types of studies will be essential to understanding of dysregulated IRF signaling in human autoimmune diseases since in the majority of diseases studied.


  1. Janfeshan S , Yaghobi R , Eidi A , et al. Expression Profile of Interferon Regulatory Factor 1 in Chronic Hepatitis B Virus-Infected Liver Transplant Patients[J]. Experimental & Clinical Transplantation Official Journal of the Middle East Society for Organ Transplantation, 2016, 15(6).
  2. Alessandro A , Tim C , Mancini E J . IRF4 in multiple myeloma—Biology, disease and therapeutic target[J]. Leukemia Research, 2018, 72:52-58.
  3. Ashwinder K , Learn-Han L , Sek-Chuen C , et al. IRF5-mediated immune responses and its implications in immunological disorders[J]. International Reviews of Immunology, 2018:1-20.
  4. Matta B , Song S , Li D , et al. Interferon regulatory factor signaling in autoimmune disease[J]. Cytokine, 2017:S1043466617300406.

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