<i>IRF-1</i>Gene Variations Influence IgE Regulation and Atopy

Schedel, Michaela; Pinto, Leonardo Araújo; Schaub, Bianca; Rosenstiel, Philip; Cherkasov, Dmitry; Cameron, Lisa; Klopp, Norman; Illig, Thomas; Vogelberg, Christian; Weiland, Stephan K.; Mutius, Erika von; Lohoff, Michael; Kabesch, Michael

doi:10.1164/rccm.200703-373oc

Cited by 39 publications

(41 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More importantly, we show that GRa is not required for CpdA-beneficial effects as previously thought. The observation that IRF-1 is increased in the airways of patients with asthma (50), combined with studies showing that polymorphisms in IRF-1 gene are associated with increased risk of childhood asthma (51) and with IgE regulation and atopy (52), strongly indicates that IRF-1 is a potential player in the pathogenesis of asthma. Our study shows that, in addition to directly impairing GC sensitivity (25), IRF-1 also regulates the expression of a number of GC-insensitive proasthmatic genes.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

Gavrila

Chachi

Tliba

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Preclinical models of human conditions including asthma showed the therapeutic potential of Compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRa) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokineinduced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNF-a/IFN-g for 24 hours in the presence or absence of CpdA. ELISA and quantitative PCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRa by CpdA was assessed by quantitative PCR, immunostaining, and receptor antagonism using RU486. An effect of CpdA on the transcription factor interferon regulatory factor 1 (IRF-1) was investigated using immunoblot, immunostaining, and small interfering RNA (siRNA) knockdown. CpdA inhibited production of fluticasone-resistant chemokines CCL5, CX3CL1, and CXCL10 at protein and mRNA levels in both asthmatic and healthy cells. CpdA failed to induce expression of GC-induced Leucine Zipper while transiently inducing mitogen-activated protein kinase phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRa nuclear translocation, nor was it prevented by RU486 antagonism. Activation of IRF-1 by TNF-a/IFN-g was inhibited by CpdA. IRF-1 siRNA knockdown reduced cytokine-induced CCL5 and CX3CL1 production. siRNA MKP-1 prevented the inhibitory effect of CpdA on cytokine-induced CXCL10 production. For the first time, we show that CpdA inhibits the production of GC-resistant chemokines via GRa-independent mechanisms involving the inhibition of IRF-1 and up-regulation of MKP-1. Thus, targeting CpdA-sensitive pathways in ASM cells represents an alternative therapeutic approach to treat GC resistance in asthma.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

Gavrila

Chachi

Tliba

et al. 2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…We speculate that the strong exposure of our asthmatic patients to mite allergens could modify the expected effects of the TGFB1 gene and its polymorphisms on IgE levels. This particular factor in the tropics, together with the genetic background of our population, allowed us to detect an association of the C-509 allele with higher levels of specific IgE to one of the most prevalent mites in house dust, adding TGFB1 to the increasing list of non-human leukocyte antigen genes influencing the specific immune response [28,43,64,65]. …”

Section: Discussionmentioning

confidence: 99%

The C-509T Promoter Polymorphism of the Transforming Growth Factor Beta-1 Gene Is Associated with Levels of Total and Specific IgE in a Colombian Population

Acevedo

Vergara

Gusmão

et al. 2009

Int Arch Allergy Immunol

View full text Add to dashboard Cite

Background: The C-509T polymorphism of the transforming growth factor beta-1 (TGFB1) gene has been associated with asthma and asthma-related phenotypes, but its influence on total and specific IgE levels is controversial. Objective: To investigate the association between C-509T and asthma, as well as total IgE and specific IgE against Blomia tropicalis and Dermatophagoides pteronyssinus, in a Colombian population. Methods: The study population consisted of 417 asthmatics, 390 controls and 116 nuclear families. The C-509T polymorphism was genotyped using single-base extension minisequencing or Taq Man probes. IgE and TGFβ1 levels were measured by ELISA. Regression analysis and family-based association tests were performed in cases/controls and families. Associations were corrected by population structure using a panel of 52 ancestry informative markers in the case-control dataset. Results: There was no association between C-509T and asthma. In asthmatics, the CC genotype was associated with higher total IgE levels compared with the other genotypes [mean IgE: 2.81 ± 0.42 vs. 2.71 ± 0.45 log IU/ml; p = 0.016, corrected p value (p_c) = 0.019]. When only atopic asthmatics were included, the significance remained (p = 0.02, p_c = 0.03). In the family-based analyses, the C allele was associated with higher total IgE levels (p = 0.02) and the CC genotype with specific IgE to D. pteronyssinus (p = 0.01). Conclusions: C-509T is associated with total IgE levels and specific IgE to D. pteronyssinus in asthmatic patients. In contrast to other studies, we found the CC genotype to be associated with higher levels of total and specific IgE. Differences in the frequency of this allele among populations could alter its effects as a risk factor for asthma-associated phenotypes.

show abstract

“…A previous report has provided evidence of NF-KB activity in nasal polyps specimen from AERD patients (Picado et al, 2003), while a conceptually similar finding has shown that accumulation of eosinophils in nasal polyp epithelium is mediated by NF-KB (Takeno et al, 2002). On the other hand, knockout mouse study reveals that IRF-1 deficiency results in elevated production of Th2-related cytokines in asthma (McElligott et al, 1997), and that IRF-1 polymorphisms affect regulation of IgE and the risk of atopy (Schedel et al, 2008), factors that have been identified as key mediators of asthma. The lack of previous functional reports demonstrating the exact molecular mechanisms of association does not exclude a possibility that FGD6 may induce AERD development either directly or via other functional elements mediated by the gene.…”

Section: Discussionmentioning

confidence: 95%

Genetic analysis between FGD6 and aspirin exacerbated respiratory disease in a Korean population

et al. 2011

View full text Add to dashboard Cite

The human FYVE, RhoGEF and PH domain containing 6 (FGD6) gene regulates mechanisms that are implicated in airway bronchospasm, and therefore, may be a risk factor for aspirin exacerbated respiratory disease (AERD). This study aims to investigate the association between FGD6 variations and AERD in a Korean asthma cohort. A total of 34 single nucleotide polymorphisms (SNPs) were selected for genotyping based on previously reported polymorphisms in the HapMap database. Genotyping was carried out using TaqMan assay and nine major haplotypes from two haplotype blocks were obtained in 163 AERD cases and 429 aspirin-tolerant asthma (ATA) controls. Genotype frequency distributions of C. F. A. Pasaje and J. S. Bae contributed equally to this work.FGD6 polymorphisms and haplotypes were analyzed using logistic and regression models. Findings from logistic and regression analyses revealed a lack of association of FGD6 genetic variations with AERD and fall rate of FEV1 (P > 0.05 in co-dominant, dominant and recessive models). This preliminary report provides evidences that variations in the FGD6 gene do not influence the risk of AERD and its relevant phenotype in a Korean population. This report may contribute to the etiology of aspirin hypersensitivity in Korean asthma patients.

show abstract

IRF-1Gene Variations Influence IgE Regulation and Atopy

Abstract: Our results suggest that functionally relevant IRF-1 polymorphisms influence atopy risk, potentially by altering transcription factor binding, IRF-1 gene expression, and IFN-gamma regulation.

Cited by 39 publications

References 24 publications

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

The C-509T Promoter Polymorphism of the Transforming Growth Factor Beta-1 Gene Is Associated with Levels of Total and Specific IgE in a Colombian Population

Genetic analysis between FGD6 and aspirin exacerbated respiratory disease in a Korean population

Contact Info

Product

Resources

About