Early Growth Response-1 Plays a Non-redundant Role in the Differentiation of B Cells into Plasma Cells

Oh, Yeon-Kyung; Jang, Eunkyeong; Paik, Doo Jin; Youn, Jeehee

doi:10.4110/in.2015.15.3.161

Cited by 18 publications

(20 citation statements)

References 16 publications

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“…The EGR1 binding box was previously demonstrated necessary for BLIMP1 expression [46]. Recently in an in vivo study, egr1 −/− mice have impaired ASC differentiation yet with normal B cell development and intact cell proliferation and apoptosis [57]. This feature is highly matching what we have observed in iguratimod-treated human B cells.…”

Section: Discussionsupporting

confidence: 86%

Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis

Yan

Liu

Tang³

et al. 2019

Arthritis Res Ther

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Background This study aimed to explore the molecular mechanism and clinical relevance of iguratimod in the regulation of human B cell terminal differentiation. Methods An in vitro human antibody-secreting cell (ASC) differentiation system was established to test the effect of iguratimod. B cell phenotype and key transcription factors (TFs) relevant to ASC differentiation were analyzed through flow cytometry and qPCR. The COX-2 activity was measured by enzyme immunoassay (EIA). RNA sequencing was used to identify potential targets of iguratimod. We enrolled six treatment-naive rheumatoid arthritis (RA) patients whose blood samples were collected for phenotypic and molecular studies along with 12-week iguratimod monotherapy. Results Iguratimod inhibited human ASC generation without affecting B cell activation and proliferation. Iguratimod showed only weak COX-2 activity. Gene set enrichment analysis (GSEA) identified that protein kinase C (PKC) pathway was targeted by iguratimod which was confirmed by PKC activity detection. Furthermore, early growth response 1 ( EGR1 ), a target of PKC and a non-redundant TF for ASC differentiation, was found to be the most downregulated gene in iguratimod-treated B cells. Lastly, iguratimod monotherapy decreased peripheral ASCs and was associated with improved disease activity. The expression of major ASC-related TFs, including EGR1 , was similarly downregulated in patient blood samples. Conclusions Iguratimod inhibits ASC differentiation both in vitro and in RA patients. Our study suggests that PKC/EGR1 axis, rather than COX-2, is critically involved in the inhibitory effect by iguratimod on human ASC differentiation. Iguratimod could have a broader application to treat B cell-related autoimmune diseases in clinics. Electronic supplementary material The online version of this article (10.1186/s13075-019-1874-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 86%

Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis

Yan

Liu

Tang³

et al. 2019

Arthritis Res Ther

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“…Recently, B cells lacking Egr1 were shown to undergo reduced differentiation to CD138 + plasmablasts when cultured with LPS (117). Furthermore, Egr1 knockout mice secrete less antigen-specific antibody in response to immunization with a T-dependent antigen (117). Since Egr1 is overexpressed in Ets1 −/− B cells, reducing the levels of this gene might be expected to reverse the phenotype of Ets1 −/− B cells and reduce ASC numbers.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

et al. 2017

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BackgroundThe transcription factor Ets1 is highly expressed in B lymphocytes. Loss of Ets1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies, and development of autoimmune disease. Despite the importance of Ets1 in B cell biology, few Ets1 target genes are known in these cells.ResultsTo obtain a more complete picture of the function of Ets1 in regulating B cell differentiation, we performed Ets1 ChIP-seq in primary mouse B cells to identify >10,000-binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although Ets1 bound to many sites in the genome, it was required for regulation of less than 5% of them as evidenced by gene expression changes in B cells lacking Ets1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such Ets1 target genes Ptpn22, Stat4, Egr1, and Prdm1 to assess how they might contribute to Ets1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of Ets1.ConclusionWe have identified genome-wide binding targets for Ets1 in B cells and determined that a relatively small number of these putative target genes require Ets1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune disease susceptibility is among those that are regulated by Ets1. Identification of the target genes of Ets1 in B cells will help provide a clearer picture of how Ets1 regulates B cell responses and how its loss promotes autoantibody secretion.

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“…Spleen cells from mice were prepared as described previously ( 23 ). Mouse CD4 + T cells were purified by negative selection using MACS columns (eBioscience or Stemcell).…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative RT-PCR was conducted as described previously ( 23 ). The primer sequences used were described in Supplementary Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4⁺ T cells

Jang

Lee

et al. 2017

BMB Rep.

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The transcription repressor Bach2 has been proposed as a regulator of T cell quiescence, but the underlying mechanism is not fully understood. Given the importance of interleukin-2 in T cell activation, we investigated whether Bach2 is a component of the network of factors that regulates interleukin-2 expression. In primary and transformed CD4+ T cells, Bach2 overexpression counteracted T cell receptor/CD28- or PMA/ionomycin-driven induction of interleukin-2 expression, and silencing of Bach2 had the opposite effect. Luciferase and chromatin immunoprecipitation assays revealed that Bach2 binds to multiple Maf-recognition element-like sites on the interleukin-2 proximal promoter in a manner competitive with AP-1, and thereby represses AP-1-driven induction of interleukin-2 transcription. Thus, this study demonstrates that Bach2 is a direct repressor of the interleukin-2 gene in CD4+ T cells during the immediate early phase of AP-driven activation, thereby playing an important role in the maintenance of immune quiescence in the steady state.

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Early Growth Response-1 Plays a Non-redundant Role in the Differentiation of B Cells into Plasma Cells

Cited by 18 publications

References 16 publications

Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis

Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4⁺ T cells

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Early Growth Response-1 Plays a Non-redundant Role in the Differentiation of B Cells into Plasma Cells

Cited by 18 publications

References 16 publications

Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis

Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR1 axis

Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor Ets1

Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4+ T cells

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Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4⁺ T cells