BET Bromodomain Inhibition Suppresses HIF-1α-Mediated IL-17 Expression in Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis
Youjun Xiao,
Maohua Shi,
Jingnan Wang,
Ruiru Li,
Qian Qiu,
Minxi Lao,
Shan Zeng,
Cuicui Wang,
Siqi Xu,
Yaoyao Zou,
Liuqin Liang,
Hanshi Xu
Issue:
Volume 6, Issue 4, December 2018
Pages:
48-57
Received:
11 November 2018
Accepted:
7 December 2018
Published:
2 January 2019
DOI:
10.11648/j.iji.20180604.11
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Abstract: Objectives: The purpose of this study was to explore the potential of the bromodomain and extra-terminal domain (BET) bromodomain to regulate IL-17 expression in peripheral blood from patients with rheumatoid arthritis (RA) and its underlying mechanisms. Methods: The level of IL-17A, TNFα and IFNγ in PBMCs from patients with RA was evaluated by a cytometric bead array. The IL-17A and IFNγ production in the supernatants of splenocytes and the serum level of IL-17A in mice were detected by ELISA. The intracellular cytokines were measured by flow cytometric analysis. The protein expression was measured using western blot. Results: This study show that the presence of JQ1 decreased the product and mRNA expression of IL-17A, but not IFNγ and TNFα, in anti-CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs) from treatment-naive patients with early RA. The percentages of IL-17A-expressing CD4+ T cells were also reduced by JQ1 in stimulated PBMCs. JQ1 also inhibited the expression of the transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and T-bet. Furthermore, JQ1 inhibited hypoxia-inducible factor-1α (HIF-1α) expression, but did not affect activity of mammalian target of rapamycin complex 1 (mTORC1). HIF-1α inhibitor reduced percentage of IL-17A- expressing CD4+ T cells. Conclusions: This study indicated that the epigenetic readers BET bromodomain might contribute to regulating HIF-1α-mediated IL-17 expression in RA. BET bromodomain inhibition might be a novel therapeutic approach for RA.
Abstract: Objectives: The purpose of this study was to explore the potential of the bromodomain and extra-terminal domain (BET) bromodomain to regulate IL-17 expression in peripheral blood from patients with rheumatoid arthritis (RA) and its underlying mechanisms. Methods: The level of IL-17A, TNFα and IFNγ in PBMCs from patients with RA was evaluated by a c...
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