BET Bromodomain Inhibition Suppresses HIF-1α-Mediated IL-17 Expression in Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis
International Journal of Immunology
Volume 6, Issue 4, December 2018, Pages: 48-57
Received: Nov. 11, 2018;
Accepted: Dec. 7, 2018;
Published: Jan. 2, 2019
Views 282 Downloads 56
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
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.
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.
Choy E (2012): Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 51 Suppl 5:v3-11.
McGeachy MJ, Cua DJ (2008): Th17 cell differentiation: the long and winding road. Immunity 28 (4):445-453.
Miossec P, Korn T, Kuchroo VK (2009): Interleukin-17 and type 17 helper T cells. N Engl J Med 361 (9):888-898.
Lubberts E (2008): IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 41 (2):84-91.
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.
Ouyang W, Kolls JK, Zheng Y (2008): The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28 (4):454-467.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Barbi J, Pardoll D, Pan F (2013): Metabolic control of the Treg/Th17 axis. Immunol Rev 252 (1):52-77.
Hargreaves DC, Horng T, Medzhitov R (2009): Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138 (1):129-145.
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.
Nicodeme E, Jeffrey KL, Schaefer U et al. (2010): Suppression of inflammation by a synthetic histone mimic. Nature 468 (7327):1119-1123.
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.
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.
Mele DA, Salmeron A, Ghosh S et al. (2013): BET bromodomain inhibition suppresses TH17-mediated pathology. J Exp Med 210 (11):2181-2190.
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.
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.
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.
Dong C (2008): TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8 (5):337-348.
Leipe J, Grunke M, Dechant C et al. (2010): Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 62 (10):2876-2885.
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.
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.
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.
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.
Clapier CR, Cairns BR (2009): The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273-304.
Natoli G (2009): Control of NF-kappaB-dependent transcriptional responses by chromatin organization. Cold Spring Harb Perspect Biol 1 (4):a000224.
Chiang CM (2009): Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4. F1000 Biol Rep 1:98.
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.
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.
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.
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.