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Estrogen-dependent upregulation of IRF5 in human immune cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
Universidade Federal de Pernambuco, UFPE, Brasil.
Andalucian Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucia, 18100, Armilla, Granada, Spain.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: To contribute to the knowledge of the mechanisms behind the strong sex-biased prevalence of SLE, we investigated the role of estrogen on the expression of one of the strongest associated gene with SLE, the interferon regulatory factor 5 (IRF5), in human immune cells.

Material and methods:  IRF5, as well as IRF3, IRF4, IRF7 and IRF9 expression was measured in PBMCs, LCLs, monocytes and macrophages from both male and female origin. Cells were treated with different concentrations of estrogen and gene expression was measured by quantitative RT-PCR.

Results: We found that the initial levels of IRF5 in PBMC were almost 2-fold higher in women than men, although not reaching statistical significance. After 12 h in culture the IRF5 levels became roughly equal in both sexes, and further stimulation with estrogen lead to up-regulation of IRF5 expression in both PBMCs and monocytes in both women and men. No difference was seen for IRF3, IRF4, IRF7 and IRF9 expression, and no gene was up-regulated in LCLs, upon estrogen treatment, regardless of the gender.

Conclusions: We showed that in human PBMCs and monocytes from healthy individuals IRF5 expression can be regulated by exogenous estrogen. This feature might be specific to IRF5 since four other IRF genes tested did not show any up-regulation in these cells.

National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-166901OAI: oai:DiVA.org:uu-166901DiVA: diva2:478713
Available from: 2012-01-16 Created: 2012-01-16 Last updated: 2012-02-10
In thesis
1. Functional Role of Genetic Polymorphisms Associated with Systemic Lupus Erythematosus
Open this publication in new window or tab >>Functional Role of Genetic Polymorphisms Associated with Systemic Lupus Erythematosus
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disorder characterized by a failure in the mechanism of self-tolerance and production of autoantibodies, potentially affecting any organ in the body. The genetic factors behind the disease have been extensively studied in the past years and to date a list of more than 30 loci have been associated with SLE. However, very little is known about the functional significance of the risk variants. In this thesis, we focused on the analysis of SLE-associated variants in three genes: interferon regulatory factor 5 (IRF5), CD226 and the microRNA 146a.

In paper I, we analyzed four polymorphisms in the IRF5 gene in a large set of individuals from different populations. We replicated a strong association of a promoter indel in our meta-analysis, but expression analysis indicated that it is rather another variant, SNP rs10954213 in the poly(A) signal of the gene that is in fact the major contributor to the altered gene expression in leukocytes. In manuscript II, we further characterized the regulation of IRF5 expression, showing that this gene can be up-regulated by estrogen in PBMCs and monocytes, regardless of the genotype, which could to some extent, explain the sex-bias of SLE. In paper III, we investigated the association of CD226 with SLE and the potential functional effect of the associated variants. The genetic analysis showed an association of a three-SNP-haplotype located at the 3’UTR region of the gene. The risk haplotype correlated with lower CD226 protein expression on the surface of cytotoxic and helper T cells, as well as in NK T cells. Reporter assays pointed to rs727088 in the 3’UTR as the main responsible variant for altered gene expression. In paper IV, we described the association of a variant in microRNA miR-146a, involved in the interferon pathway, with SLE in Europeans, which could in addition be correlated with decreased expression of both mature and primary miR-146a in leukocytes.

In summary, we have investigated the genetic association of three genes with SLE in a large cohort of individuals and identified variants responsible for functional alterations of these genes, providing further insight into the pathogenesis of SLE.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 69 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 736
autoimmunity, systemic lupus erythematosus, genetic association, single nucleotide polymorphism, IRF5, CD226, miR-146a
National Category
Medical and Health Sciences Medical Genetics
Research subject
Medical Science; Medical Genetics
urn:nbn:se:uu:diva-166909 (URN)978-91-554-8258-9 (ISBN)
Public defence
2012-03-02, Rudbecksalen, Dag Hammarsjölds väg 20, Rudbecklaboratoriet, Uppsala, 13:15 (English)
Available from: 2012-02-09 Created: 2012-01-16 Last updated: 2012-02-15

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