Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Barnes, Betsy J.; Richards, John O.; Mancl, Margo E.; Hanash, Samir M.; Beretta, Laura; Pitha, Paula M.

doi:10.1074/jbc.m400726200

Cited by 206 publications

(204 citation statements)

References 73 publications

(93 reference statements)

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“…In order to gain insights into the functional significance of the SNPs, we investigated whether the IRF5 polymorphisms were associated with the expression of mRNA for IRF5 itself as well as with the expression of mRNA for 14 type I IFN genes and 16 ISG genes that were previously shown by DNA microarray analysis to be induced by IRF5 (15). The mRNA expression data for the B cell lines from 44 JPT and 45 CHB HapMap subjects (The Wellcome Trust Sanger Institute, http:// www.sanger.ac.uk/humgen/genevar/) were analyzed for associations with IRF5 polymorphisms using multiple regression analysis.…”

Section: Resultsmentioning

confidence: 99%

“…We examined associations between IRF5 genotypes and levels of expression of mRNA for IRF5 itself, 14 type I IFN genes, and 16 interferon-stimulated genes (ISGs) that were previously shown by DNA microarray analysis to be regulated by IRF5 (15). In addition, correlation between levels of mRNA for IRF5 and levels of mRNA for other genes was examined.…”

Section: Methodsmentioning

confidence: 99%

“…IRF-5, a member of the IRF family, is a transcription factor that regulates the expression of a wide variety of genes (15). IRF-5 is coded on chromosome 7q32 and is expressed in B cells and dendritic cells.…”

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Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: Support for a crucial role of intron 1 polymorphisms

Kawasaki¹,

Kyogoku²,

Ohashi³

et al. 2008

Arthritis & Rheumatism

100

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Objective. To determine whether the IRF5 gene, which encodes interferon regulatory factor 5, is associated with systemic lupus erythematosus (SLE) in a Japanese population.Methods. A case-control study was performed in 277 SLE patients and 201 healthy controls. Associations between the IRF5 genotype and levels of messenger RNA (mRNA) for interferon (IFN) pathway genes were examined using an mRNA expression database of HapMap samples.Results. Carriers of the rs2004640T single-nucleotide polymorphism (SNP) were slightly increased among SLE patients (58.8%) as compared with controls (50.2%). When data from our Japanese population were combined with previously published data from a Korean population, the T allele frequency was found to be significantly increased in SLE patients (P ‫؍‬ 8.3 ؋ 10 ؊5 ). While no association was observed for the rs10954213 SNP or the exon 6 insertion/deletion, significant associations with 3 intron 1 SNPs (-4001, rs6953165, and rs41298401) were found. The allele frequency of rs41298401G was significantly decreased in SLE patients (13.0% versus 18.7% in controls; P ‫؍‬ 0.017), and the allele frequency of rs6953165G, which was in absolute linkage disequilibrium with -4001A, was increased in SLE patients (8.8% versus 5.2% in controls; P ‫؍‬ 0.034). The Caucasian risk haplotype was not present; instead, a protective haplotype carrying rs2004640G, rs41298401G, the deletion in exon 6, and rs10954213A was identified. SNP rs10954213, but not intron 1 SNPs, was associated with IRF5 at the mRNA level; nevertheless, intron 1 SNPs were also associated with levels of mRNA for several IFN pathway genes, suggesting a functional role.Conclusion. IRF5 was found to be associated with SLE in Asian populations. Intron 1 SNPs, rather than exon 6 and 3 -untranslated region polymorphisms, appeared to play a crucial role.Over the last 2 decades, evidence has emerged of the involvement of type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE) (1). Elevated serum levels of IFN in SLE patients have been reported (2), and gene expression analyses using microarrays have revealed IFN-inducible genes to be upregulated in peripheral blood cells from SLE patients (3-6).Recently, analyses of single-nucleotide polymorphisms (SNPs) in genes of the type I IFN pathway

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: Support for a crucial role of intron 1 polymorphisms

Kawasaki¹,

Kyogoku²,

Ohashi³

et al. 2008

Arthritis & Rheumatism

100

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“…Because IRF-5 is an important mediator of signals from TLR-7-TLR-9 (29,43), we speculate that certain expression patterns of the IRF-5 gene can modify IRF-5-dependent induction of type I IFN, proinflammatory cytokines (e.g., IL-6, TNF␣, IL-12, and IL-1␤), and several chemokines (44,45). Furthermore, the level of TLR-7 expression is increased in RA synovium and can contribute to synergistic cytokine production by dendritic cells (46).…”

Section: Discussionmentioning

confidence: 99%

Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

Sigurðsson¹,

Padyukov²,

Kurreeman³

et al. 2007

Arthritis & Rheumatism

171

127

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Objective. To determine whether genetic variants of the interferon regulatory factor 5 (IRF-5) and Tyk-2 genes are associated with rheumatoid arthritis (RA).Methods. Five single-nucleotide polymorphisms (SNPs) in IRF5 and 3 SNPs in Tyk2 were analyzed in a Swedish cohort of 1,530 patients with RA and 881 controls. A replication study was performed in a Dutch cohort of 387 patients with RA and 181 controls. All patient sera were tested for the presence of autoantibodies against cyclic citrullinated peptides (anti-CCP).Results. Four of the 5 SNPs located in the 5 region of IRF5 were associated with RA, while no association was observed with the Tyk2 SNPs. The minor alleles of 3 of the IRF5 SNPs, which were in linkage disequilibrium and formed a relatively common haplotype with a frequency of ϳ0.33, appeared to confer protection against RA. Although these disease associations were seen in the entire patient group, they were mainly found in RA patients who were negative for anti-CCP. A suggestive association of IRF5 SNPs with anti-CCP-negative RA was also observed in the Dutch cohort.Conclusion. Given the fact that anti-CCPnegative RA differs from anti-CCP-positive RA with respect to genetic and environmental risk factor profiles, our results indicate that genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in anti-CCP-negative RA.The type I interferons (IFNs) comprise a large family of cytokines that are typically produced during viral infections, mainly by plasmacytoid dendritic cells (1). In addition to direct antiviral effects, type I IFNs have many important immunomodulatory functions (1). For instance, they cause maturation of dendritic cells, promote T cell activation, and stimulate B cell development and production of antibodies. Data from previous studies indicate that the type I IFN system plays a pivotal role when self tolerance is broken and autoimmune reactions develop (2). Accordingly, the type I IFN system is activated in many autoimmune diseases, including systemic lupus erythematosus (SLE) (2), priDr. Sigurdsson

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“…IRF-5, in contrast, is important for induction of IFN␣ production by viral infections and TLR-7/8 agonists and is constitutively expressed in NIPCs/PDCs (58,59). In addition, IRF-5 increases the expression of several other genes involved in cell signaling, apoptosis, cell cycle regulation, and immune activation (60). Therefore, polymorphisms altering the function of IRF-5 may, in many ways, facilitate the development of an autoimmune disease such as SLE.…”

Section: Introductionmentioning

confidence: 99%

The type I interferon system in systemic lupus erythematosus

Rönnblom

Eloranta

Alm

2006

Arthritis & Rheumatism

303

246

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Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection

Cited by 206 publications

References 73 publications

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: Support for a crucial role of intron 1 polymorphisms

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: Support for a crucial role of intron 1 polymorphisms

Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

The type I interferon system in systemic lupus erythematosus

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