Disease relevance of Irf3

• The data suggest that pre-activated IRF-3 is a major factor in the differences in IL-12 production between B10.S and SJL/J macrophages responding to TMEV [1].
• In vivo interferon regulatory factor 3 tumor suppressor activity in B16 melanoma tumors [2].
• In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection [3].
• Local delivery of murine recombinant IFN-beta protected C57BL/6 and IRF-3(-/-) mice against IVAG HSV-2 challenge [4].
• The host response to West Nile Virus infection limits viral spread through the activation of the interferon regulatory factor 3 pathway [5].

High impact information on Irf3

• We show that IRF-3 is a potent transcriptional activator and demonstrate that HPV16 E6 can inhibit its transactivation function [6].
• Activation of type I interferons by cytosolic DNA is TLR independent and requires IRF3 but occurs without detectable activation of NF-kappaB and MAP kinases [7].
• In contrast, IkappaBNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation [8].
• By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFkappaB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs) [9].
• In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7 [10].

Biological context of Irf3

• IRF-3 is expressed ubiquitously and is activated by serine phosphorylation in response to viral infection or TLR signaling [11].
• Analysis of phosphorylation, nuclear translocation, dimerization, binding to CREB-binding protein, recognition of DNA, and induction of gene expression were used comparatively with IRF-3 as a measure of IRF-5 activation [11].
• However, similar to the biological effects of IRF-3 activation, a constitutively active mutation of IRF-5 promoted apoptosis [11].
• Finally, IRF3-stimulated response elements were necessary and sufficient for TLR3-dependent induction and glucocorticoid inhibition [12].
• To address whether IRF-3 is required for viral induction of IFN-beta, cell cultures were transfected with a plasmid constitutively expressing a dominant negative IRF-3 protein [13].

Anatomical context of Irf3

• Western blot analysis demonstrated that activation of IRF-3 was also increased in RA synovium [14].
• In animals receiving IRF-3 B16 melanoma cells, tumors grew at a 4- to 5-fold reduced rate, and tumors that developed from these mice had a moderate-to-dense infiltration of inflammatory cells, whereas only low levels of lymphocyte infiltration were observed in mock-transduced B16 tumors [2].
• In addition, no degradation of IRF-3 was observed in TBK1(-/-) mouse embryonic fibroblasts [3].
• Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3 [3].
• Interferon regulatory factor 3 is required for viral induction of beta interferon in primary cardiac myocyte cultures [13].

Associations of Irf3 with chemical compounds

• Curcumin also inhibited LPS-induced IRF3 activation [15].
• Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes [16].
• Unlike dendritic cells, B cell-mediated type I IFN induction depended on the transcription factor IRF3, but similar to dendritic cells this pathway was independent of the IRF3 kinase TBK1 [17].

Enzymatic interactions of Irf3

• Evidence indicates that the kinases TANK-binding kinase 1 and inhibitor of NF-kappaB kinase-epsilon specifically phosphorylate and thereby activate IRF-3 [11].

Regulatory relationships of Irf3

• Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene [18].
• On the other hand, ISG15, ISG54 and IP-10 are induced by either IRF-3 or IFN stimulated gene factor 3 (ISGF3) [19].
• Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication [20].
• Induction of RANTES/CCL5 by herpes simplex virus is regulated by nuclear factor kappa B and interferon regulatory factor 3 [21].

Other interactions of Irf3

• These studies support the distinct activation profiles of IRF-3 in comparison to IRF-5, but reveal a potential shared biological effect [11].
• We defined the GRIP1:IRF3 interface and showed that endogenous GRIP1 and IRF3 interact in mammalian cells [12].
• In cells lacking p48, an essential component of IFN stimulated gene factor 3 (ISGF3), ectopic expression of IRF-7 but not IRF-3 can rescue the deficiency to induce IFN-alpha genes [22].
• GR interference persisted in MyD88- and IFNA receptor-deficient mice, suggesting a specific disruption of TLR3-IRF3 pathway, not of autocrine IFN signaling [12].
• We have identified two members of the IRF family (IRF-2 and IRF-3) that specifically bind to these sites [23].

Analytical, diagnostic and therapeutic context of Irf3

• Competition with GR for GRIP1 antagonizes IRF3-mediated transcription, identifying the GRIP1:IRF3 interaction as a novel target for glucocorticoid immunosuppression [12].
• These findings suggest a novel role for IRF-3 as a potential molecular target for gene therapy of cancer [2].
• The biases of the T-cell responses towards type 1 or type 2 were stronger for immunizations with IRF-3 as an adjuvant than for immunizations with IRF-7 as an adjuvant [24].

References