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1.  Diverging Antioxidative Responses to IGF-1 in Cultured Human Skin Fibroblasts Versus Vascular Endothelial Cells 
Insulin-like growth factor 1 (IGF-1) stimulates cell proliferation and is crucial for maintenance of somatic tissues. However, this effect is associated with the inhibition of FOXO transcription factors and downregulation of antioxidative enzymes. In this study, we compared the responses of primary dermal fibroblasts and human umbilical vein endothelial cells with IGF-1 treatment. We found that IGF-1 primarily downregulated enzymatic antioxidants in skin fibroblasts. However, human umbilical vein endothelial cells were protected from an IGF-1–mediated decrease in antioxidative capacity. Moreover, IGF-1 also activated endothelial nitric oxide synthase in human umbilical vein endothelial cells. These observations suggest a dichotomous role for IGF-1, which provides for growth and repair needs of the soma, while attenuating the effect of oxidative stress on the vasculature by activating endothelial nitric oxide synthase. This increases the production of nitric oxide, an antiproliferative and, under certain circumstances, an antioxidant agent. Findings could help clarify the role of IGF-1 in aging and longevity of lower organisms, short-lived mammals, and humans.
doi:10.1093/gerona/gls081
PMCID: PMC3536545  PMID: 22466317
Insulin/IGF-1 signaling; Oxidative stress; Molecular biology of aging
2.  Monocytes from Irf5−/− mice have an intrinsic defect in their response to pristane-induced lupus‡ 
The transcription factor interferon regulatory factor 5 (IRF5) has been identified as a human systemic lupus erythematosus (SLE) susceptibility gene by numerous joint linkage and genome-wide association studies. Although IRF5 expression is significantly elevated in primary blood cells of SLE patients, it is not yet known how IRF5 contributes to SLE pathogenesis. Recent data from mouse models of lupus indicate a critical role for IRF5 in the production of pathogenic autoantibodies and the expression of Th2 cytokines and type I IFN. In the current study, we examined the mechanism(s) by which loss of Irf5 protects mice from pristane-induced lupus at early time points of disease development. We demonstrate that Irf5 is required for Ly6C(hi) monocyte trafficking to the peritoneal cavity (PC), which is believed to be one of the initial key events leading to lupus pathogenesis in this model. Chemotaxis assays using peritoneal lavage from pristane-injected Irf5+/+ and Irf5−/− littermates support an intrinsic defect in Irf5−/− monocytes. We found the expression of chemokine receptors CXCR4 and CCR2 to be dysregulated on Irf5−/− monocytes and less responsive to their respective ligands, CXCL12 and CCL2. Bone marrow reconstitution experiments further supported an intrinsic defect in Irf5−/− monocytes since Irf5+/+ monocytes were preferentially recruited to the PC in response to pristane. Together, these findings demonstrate an intrinsic role for IRF5 in the response of monocytes to pristane, and their recruitment to the primary site of inflammation that is thought to trigger lupus onset in this experimental model of SLE.
doi:10.4049/jimmunol.1201162
PMCID: PMC3454479  PMID: 22933628
3.  Protection of Irf5-deficient mice from pristane-induced lupus involves altered cytokine production and class switching 
European journal of immunology  2012;42(6):1477-1487.
Summary
Polymorphisms in the transcription factor interferon (IFN) regulatory factor 5 (IRF5) have been identified that show strong association with increased risk of developing the autoimmune disease systemic lupus erythematosus (SLE). A potential pathologic role for IRF5 in SLE development is supported by the fact that increased IRF5 mRNA and protein abundance are observed in primary blood cells of SLE patients that correlate with increased risk of developing the disease. Here, we demonstrate that IRF5 is required for pristane-induced SLE via its ability to control multiple facets of autoimmunity. We show that IRF5 has a distinct influence on pathological hypergammaglobulinemia and provide evidence for its role in regulating IgG1 class switching and antigen specificity. Examination of in vivo cytokine expression (and autoantibody production) identified an imbalance in Irf5−/− mice favoring Th2 polarization. In addition, we provide clear evidence that loss of Irf5 significantly weakens the in vivo type I IFN signature critical for disease pathogenesis in this model of murine lupus. Together, these findings demonstrate the global effect that IRF5 has on autoimmunity and provides significant new insight into how overexpression of IRF5 in blood cells of SLE patients may contribute to disease pathogenesis.
doi:10.1002/eji.201141642
PMCID: PMC3684952  PMID: 22678902
interferon regulatory factor 5 (IRF5, IRF-5); systemic lupus erythematosus (SLE); autoantibody; type I interferon; Th2
4.  IRF5 activation in monocytes of SLE patients is triggered by circulating autoantigens independent of type I IFN 
Arthritis and Rheumatism  2012;64(3):788-798.
Objective
Genetic variants of interferon regulatory factor 5 (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). IRF5 regulates the expression of proinflammatory cytokines and type I interferons (IFN) believed to be involved in SLE pathogenesis. The aim of this study was to determine the activation status of IRF5 by assessing its nuclear localization in immune cells of SLE patients and healthy donors, and to identify SLE triggers of IRF5 activation.
Methods
IRF5 nuclear localization in subpopulations of peripheral blood mononuclear cells (PBMC) from 14 genotyped SLE patients and 11 healthy controls was assessed using imaging flow cytometry. IRF5 activation and function were examined after ex vivo stimulation of healthy donor monocytes with SLE serum or components of SLE serum. Cellular localization was determined by ImageStream and cytokine expression by Q-PCR and ELISA.
Results
IRF5 was activated in a cell type-specific manner; monocytes of SLE patients had constitutively elevated levels of nuclear IRF5 compared to NK and T cells. SLE serum was identified as a trigger for IRF5 nuclear accumulation; however, neither IFNα nor SLE immune complexes could induce nuclear localization. Instead, autoantigens comprised of apoptotic/necrotic material triggered IRF5 nuclear accumulation in monocytes. Production of cytokines IFNα, TNFα and IL6 in monocytes stimulated with SLE serum or autoantigens was distinct yet correlated with the kinetics of IRF5 nuclear localization.
Conclusion
This study provides the first formal proof that IRF5 activation is altered in monocytes of SLE patients that is in part contributed by the SLE blood environment.
doi:10.1002/art.33395
PMCID: PMC3288585  PMID: 21968701
5.  RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE 
PLoS ONE  2013;8(1):e54487.
Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have been consistently replicated and shown to confer risk for or protection from the development of systemic lupus erythematosus (SLE). IRF5 expression is significantly upregulated in SLE patients and upregulation associates with IRF5-SLE risk haplotypes. IRF5 alternative splicing has also been shown to be elevated in SLE patients. Given that human IRF5 exists as multiple alternatively spliced transcripts with distinct function(s), it is important to determine whether the IRF5 transcript profile expressed in healthy donor immune cells is different from that expressed in SLE patients. Moreover, it is not currently known whether an IRF5-SLE risk haplotype defines the profile of IRF5 transcripts expressed. Using standard molecular cloning techniques, we identified and isolated 14 new differentially spliced IRF5 transcript variants from purified monocytes of healthy donors and SLE patients to generate an IRF5 variant transcriptome. Next-generation sequencing was then used to perform in-depth and quantitative analysis of full-length IRF5 transcript expression in primary immune cells of SLE patients and healthy donors by next-generation sequencing. Evidence for additional alternatively spliced transcripts was obtained from de novo junction discovery. Data from these studies support the overall complexity of IRF5 alternative splicing in SLE. Results from next-generation sequencing correlated with cloning and gave similar abundance rankings in SLE patients thus supporting the use of this new technology for in-depth single gene transcript profiling. Results from this study provide the first proof that 1) SLE patients express an IRF5 transcript signature that is distinct from healthy donors, 2) an IRF5-SLE risk haplotype defines the top four most abundant IRF5 transcripts expressed in SLE patients, and 3) an IRF5 transcript signature enables clustering of SLE patients with the H2 risk haplotype.
doi:10.1371/journal.pone.0054487
PMCID: PMC3548774  PMID: 23349905
6.  Genetic variants and disease-associated factors contribute to enhanced IRF-5 expression in blood cells of systemic lupus erythematosus patients 
Arthritis and rheumatism  2010;62(2):562-573.
Objective
Genetic variants of the interferon (IFN) regulatory factor 5 (IRF5) gene are associated with systemic lupus erythematosus (SLE) susceptibility. The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFN. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients.
Methods
IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time PCR, minigene assay, and flow cytometry. The rs2004640, rs10954213, rs10488631 and the CGGGG indel were genotyped in these patients. Genotypes of these polymorphisms defined a common risk and protective haplotype.
Results
IRF-5 expression and alternative splicing were significantly upregulated in SLE patients versus healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 gave the only significant independent association that correlated with increased transcription from non-coding exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG indel, along with type I IFNs in regulating IRF-5 expression.
Conclusions
This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly upregulated in primary blood cells of SLE patients. The risk haplotype is associated with enhanced IRF-5 transcript and protein expression in SLE patients.
doi:10.1002/art.27223
PMCID: PMC3213692  PMID: 20112383

Results 1-6 (6)