Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF- B p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells

Choo, Qiuyi; Ho, Paul C.; Tanaka, Yoshiya; Lin, Hai‐Shu

doi:10.1093/rheumatology/keq108

Cited by 107 publications

(104 citation statements)

References 48 publications

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“…This finding is consistent with reports that HDAC inhibitors MS-275 and SAHA could induce growth arrest and suppress LPS-stimulated nuclear accumulation of NF-κB p65 in human rheumatoid arthritis synovial fibroblastic E11 cells. 31 Furthermore, in the present study, we found that the effect of HDAC inhibition on blocking LPS-induced reduction of Thy-1 protein levels was more apparent at the protein level than at the level of mRNA. Moreover, LPS and HDAC inhibition seemed to disproportionately affect Thy-1 protein expression (Figure 4), implying some indefinite factors, such as posttranscriptional processes, may be involved in the regulation of Thy-1 expression.…”

Section: Discussionsupporting

confidence: 56%

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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Lipopolysaccharide (LPS)-induced proliferation of lung fibroblasts is closely correlated with loss of gene expression of thymocyte differentiation antigen-1 (Thy-1), accompanied with deacetylation of histones H3 and H4 at the Thy-1 gene promoter region; however, the mechanism remains enigmatic. We report here that LPS downregulates Thy-1 gene expression by activating histone deacetylases (HDACs) via Toll-like receptor 4 (TLR4) signaling. Treatment of primary cultured mouse lung fibroblasts with LPS resulted in significant upregulation of TLR4 and enhanced cell proliferation that was abolished by silencing TLR4 with lentivirus-delivered TLR4 shRNA. Interestingly, LPS increased the mRNA and protein levels of HDAC-4, -5, and -7, an effect that was abrogated by HDAC inhibitor trichostatin A (TSA) or TLR4-shRNA-lentivirus. Consistent with these findings, Ace-H3 and Ace-H4 were decreased by LPS that was prevented by TSA. Most importantly, chromosome immunoprecipitation (ChIP) analysis demonstrated that LPS decreased the association of Ace-H4 at the Thy-1 promoter region that was efficiently restored by pretreatment with TSA. Accordingly, LPS decreased the mRNA and protein levels of Thy-1 that was inhibited by TSA. Furthermore, silencing the Thy-1 gene by lentivirus-delivered Thy-1 shRNA could promote lung fibroblast proliferation, even in the absence of LPS. Conversely, overexpressing Thy-1 gene could inhibit lung fibroblast proliferation and reduce LPS-induced lung fibroblast proliferation. Our data suggest that LPS upregulates and activates HDACs through TLR4, resulting in deacetylation of histones H3 and H4 at the Thy-1 gene promoter that may contribute to Thy-1 gene silencing and lung fibroblast proliferation. Pulmonary fibrosis is characterized by aberrant proliferation and activation of lung fibroblasts. 1,2 The phenotypic transition of lung fibroblasts during the process of pulmonary fibrosis can be stimulated by various pathological conditions, including lipopolysaccharide (LPS), a component of bacteria membranes and an important player during the development of pulmonary fibrosis. 3,4 LPS-induced proliferation of lung fibroblast is associated with the silencing of thymocyte differentiation antigen-1 (Thy-1) and deacetylation of histones H3 and H4 at the Thy-1 gene promoter; 5,6 however, the mechanism by which LPS promotes the deacetylation of histones H3 and H4 leading to downregulation of Thy-1 gene expression is largely unknown.Thy-1 is a cell surface glycoprotein that is present in normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis (IPF). 7 Heterogeneous surface expression of Thy-1 in fibroblasts results in the specialization of fibroblast, including Thy-1 (+) and Thy-1 (− ) subsets. Hagood et al 5,8,9 reported that lack of Thy-1 expression on lung fibroblasts contributed to IPF. Recently, it was found that epigenetic mechanisms, such as promoter hypermethylation and histone modification, play an important role in Thy-1 gene silencing in lung fibroblasts. 6,7 Our...

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Section: Discussionsupporting

confidence: 56%

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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“…13,26,27) We found that IL-1b and LPS stimulation increased HDAC1 expression, while emodin remarkably reduced IL-1b and LPS-mediated expression of HDAC1, but not HDAC2, in the …”

Section: Emodin Suppressed Inflammatory Responses Via Inhibition Of Hmentioning

confidence: 77%

Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

Song

Jeong

et al. 2011

Biological & Pharmaceutical Bulletin

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“…SAHA, MS-275, as well as other HDAC inhibitors, can induce cyclin-dependent kinases (CDKs) inhibitors p21 and/or p16 which play important roles in cell cycle control and increased cell proliferation (52). Choo et al (47) recently have published that MS-275 and SAHA inhibited human RA synovial fibroblastic E11 cell proliferation in a noncytotoxic manner. The antiproliferative activities were associated with G0/G1 phase arrest and induction of CDK inhibitor p21 (52) 0.…”

Section: Influence On T-cell Differentiationmentioning

confidence: 99%

“…In vivo use of HDACi also inhibited T-cell cytokine production and proliferation and promoted T-cell anergy in conjunction with altered chromatin remodeling of the IL-2 promoter and acetylation of key transcription factors, including NFκB (46,47). Brogdon et al (48) Influence on RA Synovial Fibroblasts Different HDACi have been shown to suppress in vitro proliferation and to inhibit growth and DNA synthesis in RA synovial fibroblasts (41,42).…”

Section: Influence On T-cell Differentiationmentioning

confidence: 99%

HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

Vojinović

Damjanov²

2011

Mol Med

104

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Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF- B p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells

Cited by 107 publications

References 48 publications

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis

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