Estrogen Receptor α Regulates Tripartite Motif–Containing Protein 21 Expression, Contributing to Dysregulated Cytokine Production in Systemic Lupus Erythematosus

Smith, Siobhan; Gabhann, Joan Ní; McCarthy, Eoghan; Coffey, Barbara M.; Mahony, Rebecca; Byrne, J.; Stacey, Kevin; Ball, Elizabeth; Bell, A. L.; Cunnane, Gaye; Doran, Michele F.; Molloy, Eamonn; Lee, Ruth Z.; Harvey, Bill; Kearns, Grainne; Jefferies, Caroline A.

doi:10.1002/art.38187

Cited by 22 publications

(19 citation statements)

References 49 publications

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“…These studies support the hypothesis that ERα and interferons interact in a mutually positive feedback loop to regulate innate immunity [ 39 ]. TRIM-21 also is induced by estradiol/ERα in human monocytes, and this leads to increased IRF3 stability and production of IFNβ and IL-23 [ 44 ]. Estradiol also increases expression of the TLR8 gene in human PBMCs [ 45 ].…”

Section: Ers Regulate Innate Immune Signaling Pathwaysmentioning

confidence: 99%

Estrogen receptors regulate innate immune cells and signaling pathways

Kovats

2015

Cellular Immunology

730

590

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Humans show strong sex differences in immunity to infection and autoimmunity, suggesting sex hormones modulate immune responses. Indeed, receptors for estrogens (ER) regulate cells and pathways in the innate and adaptive immune system, as well as immune cell development. ERs are ligand-dependent transcription factors that mediate long-range chromatin interactions and form complexes at gene regulatory elements, thus promoting epigenetic changes and transcription. ERs also participate in membrane-initiated steroid signaling to generate rapid responses. Estradiol and ER activity show profound dose- and context-dependent effects on innate immune signaling pathways and myeloid cell development. While estradiol most often promotes the production of type I interferon, innate pathways leading to pro-inflammatory cytokine production may be enhanced or dampened by ER activity. Regulation of innate immune cells and signaling by ERs may contribute to the reported sex differences in innate immune pathways. Here we review the recent literature and highlight several molecular mechanisms by which ERs regulate the development or functional responses of innate immune cells.

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Section: Ers Regulate Innate Immune Signaling Pathwaysmentioning

confidence: 99%

Estrogen receptors regulate innate immune cells and signaling pathways

Kovats

2015

Cellular Immunology

730

590

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“…3B), suggesting that there are other mechanisms by which E2 maintains a steady-state level of SSA protein in MCF7 cells. Based on the previous report showing SSA as an ER␣ target gene in SLE patients (26), we examined the E2-dependent induction of SSA transcripts which is evident in MCF7 cells (see Fig. S3 in the supplemental material).…”

Section: Identification Of Ssa As a Coaa-interacting Proteinmentioning

confidence: 99%

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

Kang

Jung

Qin

et al. 2014

Molecular and Cellular Biology

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Coactivator activator (CoAA) is a dual-functional coregulator that regulates steroid receptor-mediated transcription and alternative splicing. Previously, we have shown that CoAA has tumor-suppressive potential in tumorigenic human kidney cells. Here, we uncover a molecular mechanism by which Sjogren syndrome-associated autoantigen (SSA), an estrogen receptor (ER) coactivator, induces MYC oncogene by removing repressive CoAA through E2-dependent degradation of CoAA and promotes G 1 /S transition of the cell cycle as well as anchorage-independent growth capability of breast cancer cells. We also show that E2 and ER enhance the E3 ligase activity of SSA to modulate CoAA through splicing isoform-selective ubiquitylation. We propose this as one potential molecular basis for the reduced tumor incidence in autoimmune disease patients and suggest SSA as a potential therapeutic target to treat breast cancer.

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“…28–30 Furthermore, ESR1 could regulate protein 21 expression, which inhibited cytokine production in SLE. 31 Thus, Anti-estrogen drugs had been demonstrated effective in treating SLE. Tamoxifen on SLE of (NZBxNZW)F1 female mice was associated with specific reduction of IgG3 autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

The multi-targets mechanism of hydroxychloroquine in the treatment of systemic lupus erythematosus based on network pharmacology

Xie

Geng

et al. 2020

Lupus

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Background Network pharmacology is used with bioinformatic tools to broaden the understanding of drugs’ potential targets and the intersections with key genes of particular disease. Here we applied network pharmacology to collect testable hypotheses about the multi-targets mechanism of hydroxychloroquine (HCQ) against systemic lupus erythematosus (SLE). Methods Firstly, we predicted the potential targets of HCQ. Secondly, we got the related genes of SLE returned from databases. Thirdly, the intersections of the potential targets (HCQ) and related genes (SLE) were analyzed with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, we validated our predictions of the potential targets by performing docking studies with HCQ. Results The results suggest that the efficacy of HCQ against SLE is mainly associated with the targets of cyclin-dependent kinase 2 (CDK2), estrogen receptor alpha (ESR1) and CDK1, which regulate PI3K/Akt/GSK3β as well as interferon (IFN) signaling pathway. Biological process of the network associated with the three targets is concentrated in the inhibition of immune response, negative regulation of gene expression and regulation of immune system process. Molecular docking analysis proves that hydrogen bonding and π-π stacking are the main forms of interaction. Conclusions Our research provides protein targets affected by HCQ in the treatment of SLE. Three key targets (CDK2, ESR1 and CDK1) involving 1766 proteins become the multi-targets mechanism of HCQ in the treatment of SLE. As well, the research also provides a new idea for introducing network pharmacology into the evaluation of the drugs with multi-targets in dermatology.

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Estrogen Receptor α Regulates Tripartite Motif–Containing Protein 21 Expression, Contributing to Dysregulated Cytokine Production in Systemic Lupus Erythematosus

Cited by 22 publications

References 49 publications

Estrogen receptors regulate innate immune cells and signaling pathways

Estrogen receptors regulate innate immune cells and signaling pathways

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

The multi-targets mechanism of hydroxychloroquine in the treatment of systemic lupus erythematosus based on network pharmacology

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Estrogen Receptor α Regulates Tripartite Motif–Containing Protein 21 Expression, Contributing to Dysregulated Cytokine Production in Systemic Lupus Erythematosus

Cited by 22 publications

References 49 publications

Estrogen receptors regulate innate immune cells and signaling pathways

Estrogen receptors regulate innate immune cells and signaling pathways

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G1/S Arrest To Promote Breast Tumorigenicity

The multi-targets mechanism of hydroxychloroquine in the treatment of systemic lupus erythematosus based on network pharmacology

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Product

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E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity