Transcriptional Regulation of<i>CD1D1</i>by Ets Family Transcription Factors

Geng, Yanbiao; Laslo, Peter; Barton, Kevin; Wang, Chyung Ru

doi:10.4049/jimmunol.175.2.1022

Cited by 32 publications

(31 citation statements)

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“…Despite the Ets-binding domain on the regulatory regions of CD1d [28] and BIC (pri-microRNA-155) gene [40], it is still unknown whether Ets-1 regulates their expression in B cells. We confirmed the correlations in DCs and further observed that Ets-1 directly regulates CD1d.…”

Section: Discussionmentioning

confidence: 99%

“…Ets family transcription factors transcriptionally regulate CD1d1 and BIC (Pri-miR-155) [28,40]. We surveyed the expression of Ets-1 in SLE mice by real-time PCR, and the result showed decreased levels of Ets-1 in SLE mice compared with those of the controls (Fig.…”

Section: Ets-1 Also Regulates the Expression Of Cd1dmentioning

confidence: 99%

“…However, it is unclear whether CD1d expression on B cells is regulated to alter iNKT-cell function in SLE. In addition, Ets family proteins transcriptionally regulate CD1d1 expression in B cells [28]. Ets-1 is one of the most important transcription factors within the Ets family [29].…”

Section: Introductionmentioning

confidence: 99%

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TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

et al. 2015

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B cells present lipid antigens to CD1d-restricted invariant natural killer T (iNKT) cells to maintain autoimmune tolerance, and this process is disrupted in systemic lupus erythematosus (SLE). Inflammation may inhibit CD1d expression to exacerbate the pathology of lupus. However, how inflammation regulates CD1d expression on B cells is unclear in SLE.In the present study, we showed that the surface expression of CD1d on B cells from SLE mice was decreased and that stimulation of inflammatory responses through TLR9 decreased the membrane and total CD1d levels of CD1d on B cells. Moreover, inflammation-related microRNA-155 (miR-155) negatively correlated with the expression of CD1d in B cells. miR-155 directly targeted the 3 -untranslated region (3 -UTR) of CD1d upon TLR9 activation in both humans and mice. The inhibitory effects of miR-155 on CD1d expression in B cells impaired their antigen-presenting capacity to iNKT cells. In addition, Ets-1, a susceptibility gene of SLE, also directly regulated the expression of the CD1d gene at the transcriptional level. These findings provide new insight into the mechanism underlying decreased CD1d expression on B cells in SLE, suggesting that inhibition of inflammation may increase CD1d expression in B cells to ameliorate SLE via modulating iNKT cells.Keywords: B cells r CD1d r Ets-1 r miR-155 r SLE Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSystemic lupus erythematosus (SLE) is a complex and chronic autoimmune disease with an unclear etiology [1]. B cells play a central role in the pathogenesis of SLE [2], and patients with SLE exhibit abnormal B-cell activation and increased sensitivity and proliferation of B cells [3]. Moreover, the Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn clinical success of B-cell depletion therapy further proves the important role of B cells in SLE pathogenesis [4,5]. B cells not only produce antibodies and release cytokines and chemokines but also present both peptide and lipid antigens [6].CD1 family molecules are nonclassical MHC proteins related to the class I MHC proteins and are involved in the presentation of lipid antigens to T cells. Several studies have suggested that CD1d may play an immunoregulatory role in the development of lupus, and CD1d deficiency exacerbates lupus nephritis in the pristineinduced model [7] and inflammatory dermatitis in MRL-lpr/lpr C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1934-1945 Cellular immune response 1935 mice [8]. Importantly, endogenous DNA stimulates inflammatory responses through TLR9 and exacerbates lupus disease pathology [9,10]. Viral infection could downregulate the expression of CD1d in APCs, such as B cells [11,12], DCs, and macrophages [13]. A number of exogenous viruses, especially Epstein-Barr virus (EBV) [14,15], also have been linked to the pathogenesis of SLE [16]. Our previous studies have indicated that ligands for both TLR9 and TLR7 lead to B...

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Section: Discussionmentioning

confidence: 99%

Section: Ets-1 Also Regulates the Expression Of Cd1dmentioning

confidence: 99%

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TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

et al. 2015

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“…This type of control ensures simultaneous expression of the key players required for endogenous lipid antigen presentation. Previously, several other transcription factors have been implicated in the regulation of CD1d expression in different cell types, including Ets family members (in hematopoietic cells) (55), retinoic acid receptor (in dendritic cells and mature adipocytes) (56), and PPAR␥ (in mature adipocytes) (29). However, we consider it unlikely that CD1d is under direct control of PPAR␥ during adipocyte differentiation as (i) we could not detect prominent PPAR␥ binding sites in a 200-kb chromosomal region surrounding the CD1d gene in mature adipocytes (41,42) or after short term stimulation (1 h) of mature 3T3-L1 adipocytes with the PPAR␥ ligand rosiglitazone (43) (Fig.…”

Section: Discussionmentioning

confidence: 99%

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

Rakhshandehroo

Gijzel

Siersbæk

et al. 2014

Journal of Biological Chemistry

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Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Lipid antigen presentation genes, including microsomal triglyceride transfer protein (MTP), are switched on during adipocyte differentiation, and affect iNKT cell activity. Conclusion: Adipocytes can communicate with iNKT cells by presenting endogenous and exogenous lipid antigens. Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.

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“…Consequently, the effects of LEF-1 on the expression of the CD1D gene are limited to the regulation of the distal promoter of the CD1D gene. Together with the known CD1D transcriptional regulators SP1, Ets families, and all-trans-retinoic acid (17,32,33), our results suggest a complicated regulatory mechanism involved in the regulation of the cell-type-specific expression of the human CD1D gene.…”

Section: Discussionmentioning

confidence: 97%

Human CD1D Gene Expression Is Regulated by LEF-1 through Distal Promoter Regulatory Elements

Chen¹,

Zhang

Pincus

et al. 2010

The Journal of Immunology

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CD1d-expressing cells present lipid Ag to CD1d-restricted NKT cells, which play an important role in immune regulation and tumor rejection. Lymphoid enhancer-binding factor-1 (LEF-1) is one of the regulators of the Wnt signaling pathway, which is a powerful regulator in cellular growth, differentiation, and transformation. There is little evidence connecting Wnt signaling to CD1d expression. In this study, we have identified LEF-1 as a regulator of the expression of the gene encoding the human CD1d molecule (CD1D). We found that LEF-1 binds specifically to the CD1D promoter. Overexpression of LEF-1 in K562 or Jurkat cells suppresses CD1D promoter activity and downregulates endogenous CD1D transcripts, whereas knockdown of LEF-1 using LEF-1-specific small interfering RNA increases CD1D transcripts in K562 and Jurkat cells but there are different levels of surface CD1d on these two cell types. Chromatin immunoprecipitation showed that the endogenous LEF-1 is situated at the CD1D promoter and interacts with histone deacetylase-1 to facilitate the transcriptional repressor activity. Knockdown of LEF-1 using small interfering RNA potentiates an acetylation state of histone H3/H4, supporting the notion that LEF-1 acts as a transcriptional repressor for the CD1D gene. Our finding links LEF-1 to CD1D and suggests a role of Wnt signaling in the regulation of the human CD1D gene.

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Transcriptional Regulation ofCD1D1by Ets Family Transcription Factors

Cited by 32 publications

References 69 publications

TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

Human CD1D Gene Expression Is Regulated by LEF-1 through Distal Promoter Regulatory Elements

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