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1.  Vibrating Perception Threshold and Body Mass Index Are Associated with Abnormal Foot Plantar Pressure in Type 2 Diabetes Outpatients 
Diabetes Technology & Therapeutics  2012;14(11):1053-1059.
Abstract
Aims
This study investigated the influencing factors of foot plantar pressure and attempted to find practical indicators to predict abnormal foot pressure in patients with type 2 diabetes mellitus (T2DM).
Subjects and Methods
Vibration perception threshold (VPT) and foot plantar pressure in 1,126 T2DM outpatients were examined. Patients were assigned to Group A (n=599), Group B (n=312), and Group C (n=215) according to VPT values and to Group I (n=555), Group II (n=436), and Group III (n=135) based on body mass index (BMI). The clinical characteristics and pressure–time integral (PTI) were compared among the three groups, and the associated factors of the total PTI in the entire foot (T-PTI) were analyzed.
Results
PTI of Group C in heel medial and heel lateral was significantly higher than that of Group A (all P<0.01). PTI of Group B in the right fifth metatarsal and heel medial was significantly higher than that of Group A (all P<0.05). T-PTI of Group C was significantly higher than those of Groups A and B, and that of Group B was higher than that of Group A (all P<0.01). PTI of Groups II and III in the second, third, and fourth metatarsal, midfoot, heel medial, and heel lateral was significantly higher than that of Group I (all P<0.05). T-PTI of Groups II and III was significantly higher than that of Group I (all P<0.01). Pearson correlation analysis showed that T-PTI was positively associated with age, VPT, waist circumference, waist-to-hip ratio, and BMI (P<0.05). In multiple stepwise regression analysis, VPT (P=0.004) and BMI (P=0.000) were independent risk factors of T-PTI, and each 1 unit increase in BMI increased the T-PTI by 5.962 kPa•s. Receiver operator characteristic curve analysis further revealed that the optimal cutpoint of VPT and BMI to predict the abnormal PTI was 21 V (odds ratio=2.33, 95% confidence interval 1.67–3.25) and 24.9 kg/m2 (odds ratio=2.12, 95% confidence interval 1.55–2.90), respectively.
Conclusions
Having a VPT higher than 21 V and a BMI above 24.9 kg/m2 increases the risk of excessive foot plantar pressure in Chinese T2DM.
doi:10.1089/dia.2012.0146
PMCID: PMC3482851  PMID: 22934798
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.  Increased expression of NAD(P)H oxidase subunit p67phox in the renal medulla contributes to excess oxidative stress and salt-sensitive hypertension 
Cell Metabolism  2012;15(2):201-208.
SUMMARY
NAD(P)H oxidase has been shown to be important in the development of salt-sensitive hypertension. Here we show that the expression of a subunit of NAD(P)H oxidase, p67phox, was increased in response to a high salt diet in the outer renal medulla of the Dahl salt-sensitive (SS) rat, an animal model for human salt-sensitive hypertension. The higher expression of p67phox, not the other subunits observed, was associated with higher NAD(P)H oxidase activity and salt-sensitivity in SS rats compared with a salt-resistant strain. Genetic mutations of the SS allele of p67phox were found in the promoter region and contributed to higher promoter activity than that of the salt-resistant strain. To verify the importance of p67phox, we disrupted p67phox in SS rats using zinc finger nucleases technology. These rats exhibited a significant reduction of salt-sensitive hypertension and renal medullary oxidative stress and injury. p67phox could represent a target for salt-sensitive hypertension therapy.
doi:10.1016/j.cmet.2012.01.003
PMCID: PMC3280886  PMID: 22326221
6.  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
7.  Bioinformatics Analysis of the Factors Controlling Type I IFN Gene Expression in Autoimmune Disease and Virus-Induced Immunity 
Patients with systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) display increased levels of type I interferon (IFN)-induced genes. Plasmacytoid dendritic cells (PDCs) are natural interferon producing cells and considered to be a primary source of IFN-α in these two diseases. Differential expression patterns of type I IFN-inducible transcripts can be found in different immune cell subsets and in patients with both active and inactive autoimmune disease. A type I IFN gene signature generally consists of three groups of IFN-induced genes – those regulated in response to virus-induced type I IFN, those regulated by the IFN-induced mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway, and those by the IFN-induced phosphoinositide-3 kinase (PI-3K) pathway. These three groups of type I IFN-regulated genes control important cellular processes such as apoptosis, survival, adhesion, and chemotaxis, that when dysregulated, contribute to autoimmunity. With the recent generation of large datasets in the public domain from next-generation sequencing and DNA microarray experiments, one can perform detailed analyses of cell-type specific gene signatures as well as identify distinct transcription factors (TFs) that differentially regulate these gene signatures. We have performed bioinformatics analysis of data in the public domain and experimental data from our lab to gain insight into the regulation of type I IFN gene expression. We have found that the genetic landscape of the IFNA and IFNB genes are occupied by TFs, such as insulators CTCF and cohesin, that negatively regulate transcription, as well as interferon regulatory factor (IRF)5 and IRF7, that positively and distinctly regulate IFNA subtypes. A detailed understanding of the factors controlling type I IFN gene transcription will significantly aid in the identification and development of new therapeutic strategies targeting the IFN pathway in autoimmune disease.
doi:10.3389/fimmu.2013.00291
PMCID: PMC3776951  PMID: 24065968
type I interferons; bioinformatics; autoimmunity; transcriptional regulation; transcription; genetic
8.  Differential Requirement of Histone Acetylase and Deacetylase Activities for IRF5-Mediated Proinflammatory Cytokine Expression 
Recent evidence indicates a new role for histone deacetylases (HDACs) in the activation of genes governing the host immune response. Virus, along with other pathogenic stimuli, triggers an antiviral defense mechanism through the induction of IFN, IFN-stimulated genes, and other proinflammatory cytokines. Many of these genes have been shown to be regulated by transcription factors of the IFN regulatory factor (IRF) family. Recent studies from IRF5 knockout mice have confirmed a critical role for IRF5 in virus-induced type I IFN expression and proinflammatory cytokines IL-6, IL-12, and TNF-α; yet, little is known of the molecular mechanism of IRF5-mediated proinflammatory cytokine expression. In this study, we show that both HDACs and histone acetyltransferases (HATs) associate with IRF5, leading to alterations in its transactivation ability. Using the HDAC inhibitor trichostatin A, we demonstrate that ISRE, IFNA, and IL6 promoters require HDAC activity for transactivation and transcription, whereas TNFα does not. Mapping the interaction of corepressor proteins (HDAC1, silencing mediator of retinoid and thyroid receptor/nuclear corepressor of retinoid receptor, and Sin3a) and HATs to IRF5 revealed distinct differences, including the dependence of IRF5 phosphorylation on HAT association resulting in IRF5 acetylation. Data presented in this study support a mechanism whereby virus triggers the dynamic conversion of an IRF5-mediated silencing complex to that of an activating complex on promoters of target genes. These data provide the first evidence, to our knowledge, of a tightly controlled transcriptional mechanism whereby IRF5 regulates proinflammatory cytokine expression in conjunction with HATs and HDACs.
doi:10.4049/jimmunol.1000482
PMCID: PMC3233222  PMID: 20935208
9.  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
10.  Overexpression of the steroidogenic acute regulatory protein increases the expression of ATP-binding cassette transporters in microvascular endothelial cells (bEnd.3)*  
Objective: To determine the effect of steroidogenic acute regulatory protein (StAR) overexpression on the levels of adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) in an endothelial cell line (bEnd.3). Methods: The StAR gene was induced in bEnd.3 cells with adenovirus infection. The infection efficiency was detected by fluorescence activated cell sorter (FACS) and fluorescence microscopy. The expressions of StAR gene and protein levels were detected by real-time polymerase chain reaction (PCR) and Western blot. The gene and protein levels of ABCA1 and ABCG1 were detected by real-time PCR and Western blot after StAR overexpression. Results: The result shows that StAR was successfully overexpressed in bEnd.3 cells by adenovirus infection. The mRNA and protein expressions of ABCA1 and ABCG1 were greatly increased by StAR overexpression in bEnd.3 cells. Conclusion: Overexpression of StAR increases ABCA1 and ABCG1 expressions in endothelial cells.
doi:10.1631/jzus.B0900369
PMCID: PMC2865837  PMID: 20443213
Steroidogenic acute regulatory protein (StAR); Endothelial cells; Cholesterol; Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1); ATP-binding cassette transporter G1 (ABCG1); bEnd.3
11.  Effects of RNA interference-induced tryptase down-regulation in P815 cells on IL-6 and TNF-α release of endothelial cells*  
Objective: To explore the effects of down-regulated tryptase expression in mast cells on the synthesis and release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) of vascular endothelial cells. Methods: Tryptase-siRNA (small-interfering RNA) vector was constructed to inhibit tryptase expression in P815 cells. The medium of P815 cells treated by the tryptase-siRNA (RNAi-P815 group) or pure vector (P815 group) was collected and used to culture bEnd.3 cells. The messenger RNAs (mRNAs) of IL-6 and TNF-α in bEnd.3 cells and their protein levels in the medium were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results: IL-6 and TNF-α mRNAs in bEnd.3 cells cultured in RNAi-P815-conditioned medium decreased significantly compared to those in P815-conditioned medium. Consistently, IL-6 and TNF-α protein levels in the medium of bEnd.3 of RNAi-P815 group were lower than those of P815 group. Conclusion: Reduced tryptase expression significantly inhibited the synthesis and release of IL-6 and TNF-α in vascular endothelial cells. RNA interference targeting tryptase expression may be a new anti-inflammatory strategy for vascular diseases.
doi:10.1631/jzus.B0810188
PMCID: PMC2491696  PMID: 18763316
Tryptase; RNA interference; Interleukin-6 (IL-6); Tumor necrosis factor-alpha (TNF-α); Endothelial cells

Results 1-11 (11)