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JQ1, a BET inhibitor, controls TLR4-induced IL-10 production in regulatory B cells by BRD4-NF-κB axis

  • Received : 2017.10.13
  • Accepted : 2017.11.28
  • Published : 2017.12.31

Abstract

Regulatory B cells, also well-known as IL-10-producing B cells, play a role in the suppression of inflammatory responses. However, the epigenetic modulation of regulatory B cells is largely unknown. Recent studies showed that the bromodomain and extra-terminal domain (BET) protein inhibitor JQ1 controls the expression of various genes involving cell proliferation and cell cycle. However, the role of BET proteins on development of regulatory B cells is not reported. In this study, JQ1 potently suppressed IL-10 expression and secretion in murine splenic and peritoneal B cells. While bromodomain-containing protein 4 (BRD4) was associated with $NF-{\kappa}B$ on IL-10 promoter region by LPS stimulation, JQ1 interfered the interaction of BRD4 with $NF-{\kappa}B$ on IL-10 promoter. In summary, BRD4 is essential for toll like receptor 4 (TLR4)-mediated IL-10 expression, suggesting JQ1 could be a potential candidate in regulating IL-10-producing regulatory B cells in cancer.

Keywords

References

  1. DiLillo DJ, Matsushita T and Tedder TF (2010) B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N Y Acad Sci 1183, 38-57 https://doi.org/10.1111/j.1749-6632.2009.05137.x
  2. Watanabe R, Fujimoto M, Ishiura N et al (2007) CD19 expression in B cells is important for suppression of contact hypersensitivity. Am J Pathol 171, 560-570 https://doi.org/10.2353/ajpath.2007.061279
  3. Yang M, Deng J, Liu Y et al (2012) IL-10-producing regulatory B10 cells ameliorate collagen-induced arthritis via suppressing Th17 cell generation. Am J Pathol 180, 2375-2385 https://doi.org/10.1016/j.ajpath.2012.03.010
  4. Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M and Tedder TF (2008) Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 118, 3420-3430
  5. Kim HS, Kim AR, Kim DK et al (2015) Interleukin-10-producing $CD5^{+}$ B cells inhibit mast cells during immunoglobulin E-mediated allergic responses. Sci Signal 8, ra28 https://doi.org/10.1126/scisignal.2005861
  6. Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN and Fallon PG (2004) Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol 173, 6346-6356 https://doi.org/10.4049/jimmunol.173.10.6346
  7. Kim AR, Kim HS, Kim DK et al (2016) Mesenteric IL-10-producing $CD5^{+}$ regulatory B cells suppress cow's milk casein-induced allergic responses in mice. Sci Rep 6, 19685 https://doi.org/10.1038/srep19685
  8. Zhou J, Min Z, Zhang D, Wang W, Marincola F and Wang X (2014) Enhanced frequency and potential mechanism of B regulatory cells in patients with lung cancer. J Transl Med 12, 304 https://doi.org/10.1186/s12967-014-0304-0
  9. Zhang H, Yue R, Zhao P et al (2017) Proinflammatory follicular helper T cells promote immunoglobulin G secretion, suppress regulatory B cell development, and correlate with worse clinical outcomes in gastric cancer. Tumour Biol 39, 1010428317705747
  10. Lu Y, Meng F, Yang Y et al (2017) Significance of B10 cell in patients with thymoma complicated with myasthenia gravis. Oncotarget 8, 73774-73786
  11. Sarvaria A, Madrigal JA and Saudemont A (2017) B cell regulation in cancer and anti-tumor immunity. Cell Mol Immunol 14, 662-674 https://doi.org/10.1038/cmi.2017.35
  12. Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M and Tedder TF (2008) A regulatory B cell subset with a unique $CD1d^{hi}CD5^+$ phenotype controls T cell-dependent inflammatory responses. Immunity 28, 639-650 https://doi.org/10.1016/j.immuni.2008.03.017
  13. Evans JG, Chavez-Rueda KA, Eddaoudi A et al (2007) Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol 178, 7868-7878 https://doi.org/10.4049/jimmunol.178.12.7868
  14. Xiao S, Brooks CR, Sobel RA and Kuchroo VK (2015) Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. J Immunol 194, 1602-1608 https://doi.org/10.4049/jimmunol.1402632
  15. Sun J, Wang J, Pefanis E et al (2015) Transcriptomics Identify CD9 as a Marker of Murine IL-10-Competent Regulatory B Cells. Cell Rep 13, 1110-1117 https://doi.org/10.1016/j.celrep.2015.09.070
  16. Jin G, Hamaguchi Y, Matsushita T et al (2013) B-cell linker protein expression contributes to controlling allergic and autoimmune diseases by mediating IL-10 production in regulatory B cells. J Allergy Clin Immunol 131, 1674-1682 https://doi.org/10.1016/j.jaci.2013.01.044
  17. Matsushita T, Le Huu D, Kobayashi T et al (2016) A novel splenic B1 regulatory cell subset suppresses allergic disease through phosphatidylinositol 3-kinase-Akt pathway activation. J Allergy Clin Immunol 138, 1170-1182 https://doi.org/10.1016/j.jaci.2015.12.1319
  18. Owen DJ, Ornaghi P, Yang JC et al (2000) The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J 19, 6141-6149 https://doi.org/10.1093/emboj/19.22.6141
  19. Zeng L and Zhou MM (2002) Bromodomain: an acetyl-lysine binding domain. FEBS Lett 513, 124-128 https://doi.org/10.1016/S0014-5793(01)03309-9
  20. Mele DA, Salmeron A, Ghosh S, Huang HR, Bryant BM and Lora JM (2013) BET bromodomain inhibition suppresses TH17-mediated pathology. J Exp Med 210, 2181-2190 https://doi.org/10.1084/jem.20130376
  21. Asangani IA, Dommeti VL, Wang X et al (2014) Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510, 278-282 https://doi.org/10.1038/nature13229
  22. Garcia PL, Miller AL, Kreitzburg KM et al (2016) The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene 35, 833-845 https://doi.org/10.1038/onc.2015.126
  23. Filippakopoulos P, Qi J, Picaud S et al (2010) Selective inhibition of BET bromodomains. Nature 468, 1067-1073 https://doi.org/10.1038/nature09504
  24. Gao F, Yang Y, Wang Z, Gao X and Zheng B (2015) BRAD4 plays a critical role in germinal center response by regulating Bcl-6 and NF-${\kappa}B$ activation. Cell Immunol 294, 1-8 https://doi.org/10.1016/j.cellimm.2015.01.010
  25. Stanlie A, Yousif AS, Akiyama H, Honjo T and Begum NA (2014) Chromatin reader Brd4 functions in Ig class switching as a repair complex adaptor of nonhomologous end-joining. Mol Cell 55, 97-110 https://doi.org/10.1016/j.molcel.2014.05.018
  26. Yoshizaki A, Miyagaki T, DiLillo DJ et al (2012) Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264-268 https://doi.org/10.1038/nature11501
  27. Geijtenbeek TB and Gringhuis SI (2009) Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 9, 465-479 https://doi.org/10.1038/nri2569
  28. Liu Z, Wang P, Chen H et al (2017) Drug Discovery Targeting Bromodomain-Containing Protein 4. J Med Chem 60, 4533-4558 https://doi.org/10.1021/acs.jmedchem.6b01761
  29. Brown JD, Lin CY, Duan Q et al (2014) NF-${\kappa}B$ directs dynamic super enhancer formation in inflammation and atherogenesis. Mol Cell 56, 219-231 https://doi.org/10.1016/j.molcel.2014.08.024
  30. Saraiva M, Cheistensen JR, Tsytsykova AV et al (2005) Identification of a macrophage-specific chromatin signature in the IL-10 locus. J Immunol 175, 1041-1046 https://doi.org/10.4049/jimmunol.175.2.1041
  31. Hedrich CM, Rauen T, Apostolidis SA et al (2014) Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc Natl Acad Sci U S A 111, 13457-13462 https://doi.org/10.1073/pnas.1408023111
  32. Choi SY, Lee HH, Lee JH et al (2016) TonEBP suppresses IL-10-mediated immunomodulation. Sci Rep 6, 25726 https://doi.org/10.1038/srep25726
  33. Mauri C and Bosma A (2012) Immune regulatory function of B cells. Annu Rev Immunol 30, 221-241 https://doi.org/10.1146/annurev-immunol-020711-074934
  34. Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS and Bhan AK (2002) Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16, 219-230 https://doi.org/10.1016/S1074-7613(02)00274-1
  35. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D and Anderton SM (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3, 944-950
  36. Mauri C, Gray D, Mushtaq N and Londei M (2003) Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 197, 489-501 https://doi.org/10.1084/jem.20021293
  37. Rosser EC and Mauri C (2015) Regulatory B cells: origin, phenotype, and function. Immunity 42, 607-612 https://doi.org/10.1016/j.immuni.2015.04.005
  38. Balkwill F, Montfort A and Capasso M (2013) B regulatory cells in cancer. Trends Immunol 34, 169-173 https://doi.org/10.1016/j.it.2012.10.007
  39. He Y, Qian H, Liu Y, Duan L, Li Y and Shi G (2014) The roles of regulatory B cells in cancer. J Immunol Res 2014, 215471
  40. Zhang Y, Gallastegui N and Rosenblatt JD (2015) Regulatory B cells in anti-tumor immunity. Int Immunol 27, 521-530 https://doi.org/10.1093/intimm/dxv034
  41. Carter NA, Rosser EC and Mauri C (2012) Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis. Arthritis Res Ther 14, R32 https://doi.org/10.1186/ar3736
  42. Nicodeme E, Jeffrey KL, Schaefer U et al (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119-1123 https://doi.org/10.1038/nature09589
  43. Fu LL, Tian M, Li X et al (2015) Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget 6, 5501-5516
  44. Chaidos A, Caputo V and Karadimitris A (2015) Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence. Ther Adv Hematol 6, 128-141 https://doi.org/10.1177/2040620715576662
  45. Barrett E, Brothers S, Wahlestedt C and Beurel E (2014) I-BET151 selectively regulates IL-6 production. Biochim Biophys Acta 1842, 1549-1555 https://doi.org/10.1016/j.bbadis.2014.05.013
  46. Kim HS, Jang JH, Lee MB et al (2016) A novel IL-10-producing innate lymphoid cells (ILC10) in a contact hypersensitivity mouse model. BMB Rep 49, 293-296 https://doi.org/10.5483/BMBRep.2016.49.5.023
  47. Kim HS, Lee JH, Han HD et al (2015) Autocrine stimulation of IL-10 is critical to the enrichment of IL-10-producing CD40(hi)CD5(+) regulatory B cells in vitro and in vivo. BMB Rep 48, 54-59 https://doi.org/10.5483/BMBRep.2015.48.1.213

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