scholarly journals OP0194 HISTONE DEACETYLASE 1 (HDAC1): A KEY MEDIATOR OF T CELLS FOR THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

2019 ◽  
Author(s):  
Lisa Göschl ◽  
Victoria Saferding ◽  
Nicole Boucheron ◽  
Johan Backlund ◽  
Alexander Platzer ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase 1

scholarly journals Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis

2020 ◽  
Author(s):  
Jin Kyun Park ◽  
Yu Jin Jang ◽  
Bo Ram Oh ◽  
Jieun Shin ◽  
Daekwon Bae ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Histone Deacetylase ◽  
Treatment Option ◽  
Murine Model ◽  
Mononuclear Cells ◽  
Raw 264.7 Cells ◽  
Dependent Manner ◽  
Tnf Α ◽  
Hdac6 Inhibitor

Abstract Objectives Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). Methods HDAC6 was overexpressed in mouse peritoneal macrophages and RAW 264.7 cells and the effects of a HDAC6 inhibitor CKD-506 on cytokine production and activity of NF-κB and AP-1 signaling were examined. Peripheral blood mononuclear cells (PBMCs) from RA patients and fibroblast-like synoviocytes (FLS) were activated in the presence of CKD-506. Next, regulatory T cells (Treg) were induced from RA patients and co-cultured with healthy effector T cells (Teff) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis was assessed in a murine model of adjuvant-induced arthritis (AIA). Results Overexpression of HDAC6 induced in macrophages to produce TNF-α and IL-6. The inhibitory effect of CKD-506 was mediated via blockade of NF-κB and AP-1 activation. HDAC6 inhibition reduced TNF-α and IL-6 production by activated RA-PBMCs. Also, CKD-506 inhibited production of MMP-1, MMP-3, IL-6 and IL-8 by activated FLS. In addition, CKD-506 inhibited proliferation of Teffs directly and indirectly by improving iTreg function. In AIA rats, oral CKD-506 improved clinical arthritis in a dose-dependent manner. A combination of sub-therapeutic CKD-506 and methotrexate exerted a synergistic effect. Conclusion The novel HDAC6 inhibitor CKD-506 induces regulatory immune responses in monocytes/macrophages, improves Treg function, and ameliorates arthritis severity in a murine model of RA. Thus, CKD-506 might be a novel and effective treatment option for RA.

scholarly journals Displacement of SATB1-Bound Histone Deacetylase 1 Corepressor by the Human Immunodeficiency Virus Type 1 Transactivator Induces Expression of Interleukin-2 and Its Receptor in T Cells

2005 ◽  
Vol 25 (5) ◽  
pp. 1620-1633 ◽  
Author(s):  
P. Pavan Kumar ◽  
Prabhat Kumar Purbey ◽  
Dyavar S. Ravi ◽  
Debashis Mitra ◽  
Sanjeev Galande
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Histone Deacetylase ◽  
Interleukin 2 ◽  
Histone Deacetylase 1 ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT One hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the dysregulation of cytokine gene expression in T cells. Transfection of T cells with human T-cell leukemia type 1 or 2 transactivator results in the induction of the T-cell-restricted cytokine interleukin-2 (IL-2) and its receptor (IL-2Rα). However, no T-cell-specific factor(s) has been directly linked with the regulation of IL-2 and IL-2Rα transcription by influencing the promoter activity. Thymocytes from SATB1 (special AT-rich sequence binding protein 1) knockout mice have been shown to ectopically express IL-2Rα, suggesting involvement of SATB1 in its negative regulation. Here we show that SATB1, a T-cell-specific global gene regulator, binds to the promoters of human IL-2 and IL-2Rα and recruits histone deacetylase 1 (HDAC1) in vivo. SATB1 also interacts with Tat in HIV-1-infected T cells. The functional interaction between HIV-1 Tat and SATB1 requires its PDZ-like domain, and the binding of the HDAC1 corepressor occurs through the same. Furthermore, Tat competitively displaces HDAC1 that is bound to SATB1, leading to increased acetylation of the promoters in vivo. Transduction with SATB1 interaction-deficient soluble Tat (Tat 40-72) and reporter assays using a transactivation-negative mutant (C22G) of Tat unequivocally demonstrated that the displacement of HDAC1 itself is sufficient for derepression of these promoters in vivo. These results suggest a novel mechanism by which HIV-1 Tat might overcome SATB1-mediated repression in T cells.

scholarly journals Histone deacetylase 1 interacts with HIV-1 Integrase and modulates viral replication

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Fadila Larguet ◽  
Clément Caté ◽  
Benoit Barbeau ◽  
Eric Rassart ◽  
Elsy Edouard
Keyword(s):  
Mass Spectrometry ◽  
T Cells ◽  
Host Cell ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Reverse Transcription ◽  
Cd4 T Cells ◽  
Histone Deacetylase 1 ◽  
Binding Partners ◽  
Hiv 1

Abstract Background HIV-1 hijacks the cellular machinery for its own replication through protein-protein interactions between viral and host cell factors. One strategy against HIV-1 infection is thus to target these key protein complexes. As the integration of reverse transcribed viral cDNA into a host cell chromosome is an essential step in the HIV-1 life cycle, catalyzed by the viral integrase and other important host factors, we aimed at identifying new integrase binding partners through a novel approach. Methods A LTR-derived biotinylated DNA fragment complexed with the integrase on magnetic beads was incubated with extracts from integrase-expressing 293 T cells. Liquid chromatography-mass spectrometry/mass spectrometry and co-immunoprecipitation/pull-down experiments were used for the identification of binding partners. Transfections of histone deacetylase 1 (HDAC1) expression vectors and/or specific siRNA were conducted in HeLa-CD4 and 293 T cells followed by infection with fully infectious NL4–3 and luciferase-expressing pseudotyped viruses or by proviral DNA transfection. Fully infectious and pseudotyped viruses produced from HDAC1-silenced 293 T cells were tested for their infectivity toward HeLa-CD4 cells, T cell lines and primary CD4+ T cells. Late RT species and integrated viral DNA were quantified by qPCR and infectivity was measured by luciferase activity and p24 ELISA assay. Results were analyzed by the Student’s t-test. Results Using our integrase-LTR bait approach, we successfully identified new potential integrase-binding partners, including HDAC1. We further confirmed that HDAC1 interacted with the HIV-1 integrase in co-immunoprecipitation and pull-down experiments. HDAC1 knockdown in infected HeLa cells was shown to interfere with an early preintegration step of the HIV-1 replication cycle, which possibly involves reverse transcription. We also observed that, while HDAC1 overexpression inhibited HIV-1 expression after integration, HDAC1 knockdown had no effect on this step. In virus producer cells, HDAC1 knockdown had a limited impact on virus infectivity in either cell lines or primary CD4+ T cells. Conclusions Our results show that HDAC1 interacts with the HIV-1 integrase and affects virus replication before and after integration. Overall, HDAC1 appears to facilitate HIV-1 replication with a major effect on a preintegration step, which likely occurs at the reverse transcription step.

scholarly journals Histone deacetylase 1 regulates tissue destruction in rheumatoid arthritis

2015 ◽  
Vol 24 (19) ◽  
pp. 5367-5377 ◽  
Author(s):  
Sarah Hawtree ◽  
Munitta Muthana ◽  
J. Mark Wilkinson ◽  
Mohammed Akil ◽  
Anthony G. Wilson
Keyword(s):  
Rheumatoid Arthritis ◽  
Histone Deacetylase ◽  
Tissue Destruction ◽  
Histone Deacetylase 1
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