Volume 6, Issue 4, December 2018, Page: 48-57
BET Bromodomain Inhibition Suppresses HIF-1α-Mediated IL-17 Expression in Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis
Youjun Xiao, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Maohua Shi, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Jingnan Wang, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Ruiru Li, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Qian Qiu, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Minxi Lao, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Shan Zeng, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Cuicui Wang, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Siqi Xu, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Yaoyao Zou, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Liuqin Liang, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Hanshi Xu, Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Received: Nov. 11, 2018;       Accepted: Dec. 7, 2018;       Published: Jan. 2, 2019
DOI: 10.11648/j.iji.20180604.11      View  28      Downloads  9
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.
Keywords
Bromodomain and Extra-Terminal Domain, Th17, Rheumatoid Arthritis, HIF-1α
To cite this article
Youjun Xiao, Maohua Shi, Jingnan Wang, Ruiru Li, Qian Qiu, Minxi Lao, Shan Zeng, Cuicui Wang, Siqi Xu, Yaoyao Zou, Liuqin Liang, Hanshi Xu, BET Bromodomain Inhibition Suppresses HIF-1α-Mediated IL-17 Expression in Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis, International Journal of Immunology. Vol. 6, No. 4, 2018, pp. 48-57. doi: 10.11648/j.iji.20180604.11
Copyright
Copyright © 2018 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reference
[1]
Choy E (2012): Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 51 Suppl 5:v3-11.
[2]
McGeachy MJ, Cua DJ (2008): Th17 cell differentiation: the long and winding road. Immunity 28 (4):445-453.
[3]
Miossec P, Korn T, Kuchroo VK (2009): Interleukin-17 and type 17 helper T cells. N Engl J Med 361 (9):888-898.
[4]
Lubberts E (2008): IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 41 (2):84-91.
[5]
Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S (2009): Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 5 (6):325-331.
[6]
Ouyang W, Kolls JK, Zheng Y (2008): The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28 (4):454-467.
[7]
Shen H, Goodall JC, Hill Gaston JS (2009): Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum 60 (6):1647-1656.
[8]
van Hamburg JP, Asmawidjaja PS, Davelaar N et al. (2011): Th17 cells, but not Th1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum 63 (1):73-83.
[9]
Nistala K, Moncrieffe H, Newton KR et al. (2008): Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum 58 (3):875-887.
[10]
Nakae S, Nambu A, Sudo K, Iwakura Y (2003): Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171 (11):6173-6177.
[11]
Lubberts E, Joosten LA, Oppers B et al. (2001): IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 167 (2):1004-1013.
[12]
Murphy CA, Langrish CL, Chen Y et al. (2003): Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198 (12):1951-1957.
[13]
Kotake S, Udagawa N, Takahashi N et al. (1999): IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103 (9):1345-1352.
[14]
Sato K, Suematsu A, Okamoto K et al. (2006): Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203 (12):2673-2682.
[15]
Kurebayashi Y, Nagai S, Ikejiri A, Koyasu S (2013): Recent advances in understanding the molecular mechanisms of the development and function of Th17 cells. Genes Cells 18 (4):247-265.
[16]
Delgoffe GM, Kole TP, Zheng Y et al. (2009): The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30 (6):832-844.
[17]
Delgoffe GM, Pollizzi KN, Waickman AT et al. (2011): The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12 (4):295-303.
[18]
Dang EV, Barbi J, Yang HY et al. (2011): Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146 (5):772-784.
[19]
Barbi J, Pardoll D, Pan F (2013): Metabolic control of the Treg/Th17 axis. Immunol Rev 252 (1):52-77.
[20]
Hargreaves DC, Horng T, Medzhitov R (2009): Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138 (1):129-145.
[21]
Filippakopoulos P, Picaud S, Mangos M et al. (2012): Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149 (1):214-231.
[22]
Nicodeme E, Jeffrey KL, Schaefer U et al. (2010): Suppression of inflammation by a synthetic histone mimic. Nature 468 (7327):1119-1123.
[23]
Belkina AC, Nikolajczyk BS, Denis GV (2013): BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J Immunol 190 (7):3670-3678.
[24]
Bandukwala HS, Gagnon J, Togher S et al. (2012): Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc Natl Acad Sci U S A 109 (36):14532-14537.
[25]
Mele DA, Salmeron A, Ghosh S et al. (2013): BET bromodomain inhibition suppresses TH17-mediated pathology. J Exp Med 210 (11):2181-2190.
[26]
Arnett FC, Edworthy SM, Bloch DA et al. (1988): The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31 (3):315-324.
[27]
Shi LZ, Wang R, Huang G et al. (2011): HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208 (7):1367-1376.
[28]
Stahl EA, Raychaudhuri S, Remmers EF et al. (2010): Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42 (6):508-514.
[29]
Dong C (2008): TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8 (5):337-348.
[30]
Leipe J, Grunke M, Dechant C et al. (2010): Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 62 (10):2876-2885.
[31]
Kirkham BW, Lassere MN, Edmonds JP et al. (2006): Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 54 (4):1122-1131.
[32]
Genovese MC, Van den Bosch F, Roberson SA et al. (2010): LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 62 (4):929-939.
[33]
Ivanov, II, McKenzie BS, Zhou L et al. (2006): The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126 (6):1121-1133.
[34]
Chang MR, Lyda B, Kamenecka TM, Griffin PR (2014): Pharmacologic repression of retinoic acid receptor-related orphan nuclear receptor gamma is therapeutic in the collagen-induced arthritis experimental model. Arthritis Rheumatol 66 (3):579-588.
[35]
Clapier CR, Cairns BR (2009): The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273-304.
[36]
Natoli G (2009): Control of NF-kappaB-dependent transcriptional responses by chromatin organization. Cold Spring Harb Perspect Biol 1 (4):a000224.
[37]
Chiang CM (2009): Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4. F1000 Biol Rep 1:98.
[38]
Jang MK, Mochizuki K, Zhou M et al. (2005): The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 19 (4):523-534.
[39]
Yang Z, Yik JH, Chen R et al. (2005): Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell 19 (4):535-545.
[40]
Jiang YW, Veschambre P, Erdjument-Bromage H et al. (1998): Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc Natl Acad Sci U S A 95 (15):8538-8543.
[41]
Gartlehner G, Hansen RA, Jonas BL, Thieda P, Lohr KN (2006): The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol 33 (12):2398-2408.
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