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Paeonol protects against TNF-α-induced proliferation and cytokine release of rheumatoid arthritis fibroblast-like synoviocytes by upregulating FOXO3 through inhibition of miR-155 expression

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Abstract

Background

Fibroblast-like synoviocytes (FLS) play an essential role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis. Paeonol (Pae) is a phenolic compound found in many traditional Chinese medicine remedies. However, the effects of Pae on TNF-α-stimulated FLS and the underlying molecular mechanism are unknown. In this study, we aimed to investigate the anti-proliferative and anti-inflammatory effect of Pae against activated FLS.

Materials and methods

Rheumatoid arthritis FLS (RA-FLS) were pre-treated with different doses (25, 50, and 100 µM) of Pae or miR-155 inhibitor for 30 min or transfected with miR-155 mimic, and then treated with 50 ng/mL of tumor necrosis factor alpha (TNF-α) for 1 h. Cells that were untreated served as control. At 24 h after drug pretreatment, the proliferation of FLS was detected using the MTT assay. The concentrations of interleukin IL-6 and IL-1β in cell culture supernatant were examined by enzyme-linked immunosorbent assay (ELISA), and mRNA levels of Foxo3 and miR-155 expression in FLS were quantified by reverse transcription-polymerase chain reaction (RT-PCR). Protein expressions of forkhead box O3 (FOXO3), cyclin D1, and c-Myc were detected by Western Blot.

Results

TNF-α induced the proliferation of FLS, whereas Pae inhibited this proliferation in a dose-dependent manner. Pae attenuated TNF-α-induced production of IL-6 and IL-1β, and inhibited the expression of miR-155 in a dose-dependent manner. In addition, miR-155 inhibitor decreased TNF-α-induced proliferation of FLS, and attenuated TNF-α-induced production of IL-6 and IL-1β. In addition, pretreatment with different doses of Pae or miR-155 inhibitor markedly attenuated TNF-α-induced decrease in protein expression of FOXO3 in FLS. Mechanistic studies revealed FOXO3 as miR-155-5p direct target and inhibition of FOXO3 led to the abolishment of Pae protective effects.

Conclusions

Paeonol protected against TNF-α-induced proliferation and cytokine release of FLS by decreasing the expression of miR-155 and upregulating its target FOXO3.

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    Authors and Affiliations

    1. Department of Bone, First Affiliated Hospital of Harbin Medical University, Harbin, China

      Ning Liu, Wenbo Wang, Xingkai Zhao & Xia Li

    2. Department of Gynecology and Obstetrics, First Affiliated Hospital of Harbin Medical University, Harbin, China

      Xue Feng

    3. College of Bioinformatics Science and Technology, Harbin Medical University, No. 157 Baojian Road, Nangang District, Harbin, 150081, China

      Xia Li

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    1. Ning Liu
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    2. Xue Feng
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    3. Wenbo Wang
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    4. Xingkai Zhao
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    5. Xia Li
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    Correspondence to Xia Li.

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    Responsible Editor: Yoshiya Tanaka.

    Ning Liu and Xue Feng contributed equally to this work.

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    Liu, N., Feng, X., Wang, W. et al. Paeonol protects against TNF-α-induced proliferation and cytokine release of rheumatoid arthritis fibroblast-like synoviocytes by upregulating FOXO3 through inhibition of miR-155 expression. Inflamm. Res. 66, 603–610 (2017). https://doi.org/10.1007/s00011-017-1041-7

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    • DOI: https://doi.org/10.1007/s00011-017-1041-7

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