Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Moulton, Vaishali R.; Holcomb, Dana R.; Zajdel, Melissa C.; Tsokos, George C.

doi:10.2119/molmed.2011.00506

Cited by 53 publications

(36 citation statements)

References 37 publications

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“…E2 has also been shown to enhance the level of BAFF production by myeloid cells [47,50,57], which promotes B cell maturation to a MZ phenotype [58]. E2 also reduces T cell production of IL-2, potentially leading to a reduced population of T regulatory cells [59]. Finally, E2 enhances BCR-mediated apoptosis and augments p202b expression, which protects the B cell from TLR-mediated activation [60].…”

Section: Discussionmentioning

confidence: 99%

Hormonal milieu at time of B cell activation controls duration of autoantibody response

Jeganathan

Peeva

Diamond

2014

Journal of Autoimmunity

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A strong gender bias is seen in many autoimmune diseases including systemic lupus erythematosus (SLE). To investigate the basis for the female preponderance in SLE, we have been studying BALB/c mice in which B cells express the R4A heavy chain of an anti-DNA antibody in association with an endogenous light chain repertoire (R4Atg mice). In unmanipulated mice, approximately 5% of B cells express the R4A transgene. R4Atg mice do not spontaneously develop elevated serum titers of anti-DNA antibodies. Administration of either estradiol (E2) or prolactin (Pr) results in escape from tolerance of autoreactive B cells, expressed as an increase in transgene-expressing B cells and elevated serum titers of anti-DNA antibodies. We previously demonstrated that autoreactive B cells maturing in an estrogenic milieu develop as marginal zone (MZ) B cells; when these same B cells mature in the presence of increased prolactin, they develop as follicular (Fo) B cells. To determine the long term consequence of this differential maturation of DNA-reactive B cells, we treated R4Atg BALB/c mice with E2 or Pr for 6 weeks until serum titers of anti-DNA antibody were high, at which time hormonal exposure was discontinued. In E2-treated mice, the anti-DNA titers remained high even 3 months after discontinuation of hormone exposure. Nascent B cells underwent normal tolerance induction, but existing autoreactive MZ B cells persisted and continued to secrete autoantibody. In contrast, Pr caused only a short-term increase in anti-DNA antibody titers. By 3 months after cessation of hormone treatment, serum anti-DNA antibody titers and B cell subsets were indistinguishable from those in placebo (P) treated mice. These findings suggest that autoantibody responses are sustained for variable lengths of time depending on the B cell subset producing the autoantibodies. This observation may be relevant to understanding the heterogeneous presentation of patients with SLE and to the design of therapies targeting speci?c B-cell populations in autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Hormonal milieu at time of B cell activation controls duration of autoantibody response

Jeganathan

Peeva

Diamond

2014

Journal of Autoimmunity

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“…46, 47 Estrogen upregulates SP-1 in human T cells and increases SP-1 binding to the cyclic AMP response element modulator α. 48 …”

Section: Discussionmentioning

confidence: 99%

Estradiol differentially regulates calreticulin: a potential link with abnormal T cell function in systemic lupus erythematosus?

Ward

Rider

Abdou

et al. 2013

Lupus

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Objective Systemic lupus erythematosus (SLE) is an autoimmune disease that affects women nine times more often than men. The present study investigates estradiol-dependent control of the calcium buffering protein, calreticulin, to gain further insight into the molecular basis of abnormal T cell signaling in SLE T cells. Methods T cells were purified from blood samples obtained from healthy females and SLE patients. Calreticulin expression was quantified by real time polymerase chain amplification. Calreticulin and estrogen receptor-α were co-precipitated and analyzed by Western blotting to determine if the proteins associate in T cells. Results Calreticulin expression increased (p= 0.034)in activated control T cells, while estradiol decreased (p = 0.044) calreticulin in resting T cells. Calreticulin expression decreased in activated SLE T cell samples and increased in approximately 50% of resting T cell samples. Plasma estradiol was similar (p > 0.05) among SLE patients and control volunteers. Estrogen receptor-αand calreticulin co-precipitated from nuclear and cytoplasmic T cell compartments. Conclusions The results indicate that estradiol tightly regulates calreticulin expression in normal human T cells and the dynamics are different between activated and resting T cells. The absence of this tight regulation in SLE T cells could contribute to abnormal T cell function.

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“…Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which multiple pathogenic mechanisms are involved in [1, 2]. Recently, accumulating studies have documented that epigenetic alterations in certain genes of T cells play critical roles in the pathogenesis of SLE [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus

et al. 2016

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BackgroundUp-regulated cyclic adenosine 5'-monophosphate response element modulator α (CREMα) which can inhibit IL-2 and induce IL-17A in T cells plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). This research aimed to investigate the mechanisms regulating CREMα expression in SLE.ResultsFrom the chromatin immunoprecipitation (ChIP) microarray data, we found a sharply increased H3 lysine 4 trimethylation (H3K4me3) amount at the CREMα promoter in SLE CD4+ T cells compared to controls. Then, by ChIP and real-time PCR, we confirmed this result. Moreover, H3K4me3 amount at the promoter was positively correlated with CREMα mRNA level in SLE CD4+ T cells. In addition, a striking increase was observed in SET domain containing 1 (Set1) enrichment, but no marked change in mixed-lineage leukemia 1 (MLL1) enrichment at the CREMα promoter in SLE CD4+ T cells. We also proved Set1 enrichment was positively correlated with both H3K4me3 amount at the CREMα promoter and CREMα mRNA level in SLE CD4+ T cells. Knocking down Set1 with siRNA in SLE CD4+ T cells decreased Set1 and H3K4me3 enrichments, and elevated the levels of DNMT3a and DNA methylation, while the amounts of H3 acetylation (H3ac) and H4 acetylation (H4ac) didn’t alter greatly at the CREMα promoter. All these changes inhibited the expression of CREMα, then augmented IL-2 and down-modulated IL-17A productions. Subsequently, we observed that DNA methyltransferase (DNMT) 3a enrichment at the CREMα promoter was down-regulated significantly in SLE CD4+ T cells, and H3K4me3 amount was negatively correlated with both DNA methylation level and DNMT3a enrichment at the CREMα promoter in SLE CD4+ T cells.ConclusionsIn SLE CD4+ T cells, increased Set1 enrichment up-regulates H3K4me3 amount at the CREMα promoter, which antagonizes DNMT3a and suppresses DNA methylation within this region. All these factors induce CREMα overexpression, consequently result in IL-2 under-expression and IL-17A overproduction, and contribute to SLE at last. Our findings provide a novel approach in SLE treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0294-2) contains supplementary material, which is available to authorized users.

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Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Cited by 53 publications

References 37 publications

Hormonal milieu at time of B cell activation controls duration of autoantibody response

Hormonal milieu at time of B cell activation controls duration of autoantibody response

Estradiol differentially regulates calreticulin: a potential link with abnormal T cell function in systemic lupus erythematosus?

Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus

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