, Volume 21, Issue 4, pp 301–307 | Cite as

Epigenetic regulation of inflammation: progressing from broad acting histone deacetylase (HDAC) inhibitors to targeting specific HDACs

  • Melissa D. CantleyEmail author
  • David R. Haynes


Inhibition of histone deacetylases (HDAC) is emerging as a novel approach to treat a variety of diseases. Recently, broad acting inhibitors of HDAC have been shown to have anti-inflammatory effects both in vitro and in vivo. It is significant that these anti-inflammatory effects are observed at 10–100 fold lower concentrations than their anti-cancer effects. The broad action of these compounds makes it difficult to determine which HDAC enzymes are important in inflammation. Although showing promise it is unlikely that these drugs will progress to the clinic for treating inflammatory diseases due to number of HDACs they affect and the widespread activity of the enzymes throughout the body. Accordingly, research is now progressing to targeting specific HDAC enzymes to improve efficacy of treatment as well as reduce the risk of any unwanted side effects. Understanding the role specific HDACs play in inflammatory disease will help us to identify novel anti-inflammatory treatments. This manuscript is designed to review our limited knowledge in this field.


Inflammation Histone deacetylase inhibitors Anti-inflammatory treatments 


  1. Ahmad T, Barnes PJ, Adcock IM (2008) Overcoming steroid insensitivity in smoking asthmatics. Curr Opin Investig Drugs 9(5):470–477PubMedGoogle Scholar
  2. Aung HT, Schroder K, Himes SR, Brion K, van Zuylen W, Trieu A, Suzuki H, Hayashizaki Y, Hume DA, Sweet MJ, Ravasi T (2006) LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression. Faseb J 20(9):1315–1327PubMedCrossRefGoogle Scholar
  3. Baek YS, Haas S, Hackstein H, Bein G, Hernandez-Santana M, Lehrach H, Sauer S, Seitz H (2009) Identification of novel transcriptional regulators involved in macrophage differentiation and activation in U937 cells. BMC Immunol 10:18PubMedCrossRefGoogle Scholar
  4. Balasubramanian S, Verner E, Buggy JJ (2009) Isoform-specific histone deacetylase inhibitors: the next step? Cancer Lett 280(2):211–221 Epub 2009 Mar 2016PubMedCrossRefGoogle Scholar
  5. Banerjee A, Trivedi CM, Damera G, Jiang M, Jester W, Hoshi T, Epstein JA, Panettieri RA Jr (2012) Trichostatin A abrogates airway constriction, but not inflammation, in murine and human asthma models. Am J Respir Cell Mol Biol 46(2):132–138PubMedCrossRefGoogle Scholar
  6. Barnes PJ (2006) Reduced histone deacetylase in COPD: clinical implications. Chest 129(1):151–155PubMedCrossRefGoogle Scholar
  7. Barnes PJ (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 71:451–464PubMedCrossRefGoogle Scholar
  8. Beurel E (2011) HDAC6 regulates LPS-tolerance in astrocytes. PLoS One 6(10):e25804 Epub 22011 Oct 25812PubMedCrossRefGoogle Scholar
  9. Cantley MD, Bartold PM, Marino V, Fairlie DP, Le GT, Lucke AJ, Haynes DR (2011a) Histone deacetylase inhibitors and periodontal bone loss. J Periodontal Res 46(6):697–703. doi: 610.1111/j.1600-0765.2011.01392.x Epub.02011.Jul.01311PubMedCrossRefGoogle Scholar
  10. Cantley MD, Fairlie DP, Bartold PM, Rainsford KD, Le GT, Lucke AJ, Holding CA, Haynes DR (2011b) Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro. J Cell Physiol 226(12):3233–3241PubMedCrossRefGoogle Scholar
  11. Chen X, Barozzi I, Termanini A, Prosperini E, Recchiuti A, Dalli J, Mietton F, Matteoli G, Hiebert S, Natoli G (2012) Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc Natl Acad Sci USA 109:E2865–E2874PubMedCrossRefGoogle Scholar
  12. Chou DH, Holson EB, Wagner FF, Tang AJ, Maglathlin RL, Lewis TA, Schreiber SL, Wagner BK (2012) Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol 19(6):669–673PubMedCrossRefGoogle Scholar
  13. Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M, Tak PP, Haynes DR (2002) Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 61(12):1047–1054PubMedCrossRefGoogle Scholar
  14. Crotti T, Smith MD, Hirsch R, Soukoulis S, Weedon H, Capone M, Ahern MJ, Haynes D (2003) Receptor activator NF kappaB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis. J Periodontal Res 38(4):380–387PubMedCrossRefGoogle Scholar
  15. Dallavalle S, Pisano C, Zunino F (2012) Development and therapeutic impact of HDAC6-selective inhibitors. Biochem Pharmacol 84(6):756–765 Epub 2012 Jun 2021PubMedCrossRefGoogle Scholar
  16. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370(Pt 3):737–749PubMedCrossRefGoogle Scholar
  17. de Zoeten EF, Wang L, Butler K, Beier UH, Akimova T, Sai H, Bradner JE, Mazitschek R, Kozikowski AP, Matthias P, Hancock WW (2011) Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells. Mol Cell Biol 31(10):2066–2078 Epub 2011 Mar 2028PubMedCrossRefGoogle Scholar
  18. Dinarello CA, Fossati G, Mascagni P (2011) Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol Med 17(5–6):333–352. doi: 310.2119/molmed.2011.00116 Epub.02011.May.00115PubMedGoogle Scholar
  19. Fischle W, Dequiedt F, Fillion M, Hendzel MJ, Voelter W, Verdin E (2001) Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo. J Biol Chem 276(38):35826–35835 Epub 32001 Jul 35820PubMedCrossRefGoogle Scholar
  20. Gillespie J, Savic S, Wong C, Hempshall A, Inman M, Emery P, Grigg R, McDermott MF (2012) Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum 64(2):418–422. doi: 410.1002/art.33382 PubMedCrossRefGoogle Scholar
  21. Glauben R, Batra A, Fedke I, Zeitz M, Lehr HA, Leoni F, Mascagni P, Fantuzzi G, Dinarello CA, Siegmund B (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 176(8):5015–5022PubMedGoogle Scholar
  22. Gopal YN, Van Dyke MW (2006) Depletion of histone deacetylase protein: a common consequence of inflammatory cytokine signaling? Cell Cycle 5(23):2738–2743 Epub 2006 Dec 2731PubMedCrossRefGoogle Scholar
  23. Grabiec AM, Krausz S, de Jager W, Burakowski T, Groot D, Sanders ME, Prakken BJ, Maslinski W, Eldering E, Tak PP, Reedquist KA (2010) Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J Immunol 184(5):2718–2728 Epub 2010 Jan 2725PubMedCrossRefGoogle Scholar
  24. Grabiec AM, Korchynskyi O, Tak PP, Reedquist KA (2012) Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann Rheum Dis 71(3):424–431 Epub 2011 Sep 2027PubMedCrossRefGoogle Scholar
  25. Grausenburger R, Bilic I, Boucheron N, Zupkovitz G, El-Housseiny L, Tschismarov R, Zhang Y, Rembold M, Gaisberger M, Hartl A, Epstein MM, Matthias P, Seiser C, Ellmeier W (2010) Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J Immunol 185(6):3489–3497 Epub 2010 Aug 3411PubMedCrossRefGoogle Scholar
  26. Gryder BE, Sodji QH, Oyelere AK (2012) Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future Med Chem 4(4):505–524PubMedCrossRefGoogle Scholar
  27. Gupta PK, Reid RC, Liu L, Lucke AJ, Broomfield SA, Andrews MR, Sweet MJ, Fairlie DP (2010) Inhibitors selective for HDAC6 in enzymes and cells. Bioorg Med Chem Lett 20(23):7067–7070 Epub 2010 Oct 7012PubMedCrossRefGoogle Scholar
  28. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10(1):32–42PubMedCrossRefGoogle Scholar
  29. Halili MA, Andrews MR, Labzin LI, Schroder K, Matthias G, Cao C, Lovelace E, Reid RC, Le GT, Hume DA, Irvine KM, Matthias P, Fairlie DP, Sweet MJ (2010) Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS. J Leukoc Biol 87(6):1103–1114 Epub 2010 Mar 1103PubMedCrossRefGoogle Scholar
  30. Han SB, Lee JK (2009) Anti-inflammatory effect of Trichostatin-A on murine bone marrow-derived macrophages. Arch Pharm Res 32(4):613–624 Epub 2009 Apr 2029PubMedCrossRefGoogle Scholar
  31. Han S, Lu J, Zhang Y, Cheng C, Han L, Wang X, Li L, Liu C, Huang B (2006) Recruitment of histone deacetylase 4 by transcription factors represses interleukin-5 transcription. Biochem J 400(3):439–448PubMedCrossRefGoogle Scholar
  32. Haus P, Korbus M, Schroder M, Meyer-Almes FJ (2011) Identification of selective class II histone deacetylase inhibitors using a novel dual-parameter binding assay based on fluorescence anisotropy and lifetime. J Biomol Screen 16(10):1206–1216 Epub 2011 Oct 1225PubMedCrossRefGoogle Scholar
  33. Hu E, Dul E, Sung CM, Chen Z, Kirkpatrick R, Zhang GF, Johanson K, Liu R, Lago A, Hofmann G, Macarron R, de los Frailes M, Perez P, Krawiec J, Winkler J, Jaye M (2003) Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther 307(2):720–728 Epub 2003 Sep 2015PubMedCrossRefGoogle Scholar
  34. Huang WJ, Wang YC, Chao SW, Yang CY, Chen LC, Lin MH, Hou WC, Chen MY, Lee TL, Yang P, Chang CI (2012) Synthesis and biological evaluation of ortho-aryl N-hydroxycinnamides as potent histone deacetylase (HDAC) 8 isoform-selective inhibitors. ChemMedChem 7(10):1815–1824. doi: 1810.1002/cmdc.201200300 Epub.201202012.Aug.201200320PubMedCrossRefGoogle Scholar
  35. Huber LC, Stanczyk J, Jungel A, Gay S (2007) Epigenetics in inflammatory rheumatic diseases. Arthritis Rheum 56(11):3523–3531PubMedCrossRefGoogle Scholar
  36. Inks ES, Josey BJ, Jesinkey SR, Chou CJ (2012) A novel class of small molecule inhibitors of HDAC6. ACS Chem Biol 7(2):331–339 Epub 2011 Nov 2011PubMedCrossRefGoogle Scholar
  37. Inoue K, Kobayashi M, Yano K, Miura M, Izumi A, Mataki C, Doi T, Hamakubo T, Reid PC, Hume DA, Yoshida M, Aird WC, Kodama T, Minami T (2006) Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression. Arterioscler Thromb Vasc Biol 26(12):2652–2659 Epub 2006 Sep 2628PubMedCrossRefGoogle Scholar
  38. Ito K, Caramori G, Lim S, Oates T, Chung KF, Barnes PJ, Adcock IM (2002) Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 166(3):392–396PubMedCrossRefGoogle Scholar
  39. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, Barczyk A, Hayashi S, Adcock IM, Hogg JC, Barnes PJ (2005) Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352(19):1967–1976PubMedCrossRefGoogle Scholar
  40. Joosten LA, Leoni F, Meghji S, Mascagni P (2011) Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis. Mol Med 17(5–6):391–396. doi: 310.2119/molmed.2011.00058 Epub.02011.Feb.00011PubMedGoogle Scholar
  41. Kasler HG, Young BD, Mottet D, Lim HW, Collins AM, Olson EN, Verdin E (2011) Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes. J Immunol 186(8):4782–4793 Epub 2011 Mar 4711PubMedCrossRefGoogle Scholar
  42. Kato H, Tamamizu-Kato S, Shibasaki F (2004) Histone deacetylase 7 associates with hypoxia-inducible factor 1alpha and increases transcriptional activity. J Biol Chem 279(40):41966–41974 Epub 42004 Jul 41926PubMedCrossRefGoogle Scholar
  43. Khan N, Jeffers M, Kumar S, Hackett C, Boldog F, Khramtsov N, Qian X, Mills E, Berghs SC, Carey N, Finn PW, Collins LS, Tumber A, Ritchie JW, Jensen PB, Lichenstein HS, Sehested M (2008) Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 409(2):581–589PubMedCrossRefGoogle Scholar
  44. Kim JH, Kim K, Youn BU, Jin HM, Kim JY, Moon JB, Ko A, Seo SB, Lee KY, Kim N (2011) RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation. Biochem J 436:253–262PubMedCrossRefGoogle Scholar
  45. Kim Y, Kim K, Park D, Lee E, Lee H, Lee YS, Choe J, Jeoung D (2012) Histone deacetylase 3 mediates allergic skin inflammation by regulating expression of MCP1 protein. J Biol Chem 287(31):25844–25859 Epub 22012 Jun 25847PubMedCrossRefGoogle Scholar
  46. Lee AY, Paweletz CP, Pollock RM, Settlage RE, Cruz JC, Secrist JP, Miller TA, Stanton MG, Kral AM, Ozerova ND, Meng F, Yates NA, Richon V, Hendrickson RC (2008) Quantitative analysis of histone deacetylase-1 selective histone modifications by differential mass spectrometry. J Proteome Res 7(12):5177–5186PubMedCrossRefGoogle Scholar
  47. Leoni F, Zaliani A, Bertolini G, Porro G, Pagani P, Pozzi P, Dona G, Fossati G, Sozzani S, Azam T, Bufler P, Fantuzzi G, Goncharov I, Kim SH, Pomerantz BJ, Reznikov LL, Siegmund B, Dinarello CA, Mascagni P (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc Natl Acad Sci USA 99(5):2995–3000 Epub 2002 Feb 2926PubMedCrossRefGoogle Scholar
  48. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, Modena D, Moras ML, Pozzi P, Reznikov LL, Siegmund B, Fantuzzi G, Dinarello CA, Mascagni P (2005) The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 11(1–12):1–15PubMedCrossRefGoogle Scholar
  49. Lin HS, Hu CY, Chan HY, Liew YY, Huang HP, Lepescheux L, Bastianelli E, Baron R, Rawadi G, Clement-Lacroix P (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 150(7):862–872 Epub 2007 Feb 2026PubMedCrossRefGoogle Scholar
  50. Mullican SE, Gaddis CA, Alenghat T, Nair MG, Giacomin PR, Everett LJ, Feng D, Steger DJ, Schug J, Artis D, Lazar MA (2011) Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev 25(23):2480–2488PubMedCrossRefGoogle Scholar
  51. Nasu Y, Nishida K, Miyazawa S, Komiyama T, Kadota Y, Abe N, Yoshida A, Hirohata S, Ohtsuka A, Ozaki T (2008) Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis Cartilage 16(6):723–732 Epub 2008 Jan 2015PubMedCrossRefGoogle Scholar
  52. Pan H, Cao J, Xu W (2012) Selective histone deacetylase inhibitors. Anticancer Agents Med Chem. 12(3):247–270PubMedCrossRefGoogle Scholar
  53. Pham L, Kaiser B, Romsa A, Schwarz T, Gopalakrishnan R, Jensen ED, Mansky KC (2011) HDAC3 and HDAC7 have opposite effects on osteoclast differentiation. J Biol Chem 286(14):12056–12065 Epub 12011 Feb 12015PubMedCrossRefGoogle Scholar
  54. Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P, Pili R (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66(17):8814–8821PubMedCrossRefGoogle Scholar
  55. Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41(11):1199–1206 Epub 2009 Oct 1194PubMedCrossRefGoogle Scholar
  56. Smil DV, Manku S, Chantigny YA, Leit S, Wahhab A, Yan TP, Fournel M, Maroun C, Li Z, Lemieux AM, Nicolescu A, Rahil J, Lefebvre S, Panetta A, Besterman JM, Deziel R (2009) Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors. Bioorg Med Chem Lett 19(3):688–692 Epub 2008 Dec 2014PubMedCrossRefGoogle Scholar
  57. Soltanoff CS, Yang S, Chen W, Li YP (2009) Signaling networks that control the lineage commitment and differentiation of bone cells. Crit Rev Eukaryot Gene Expr 19(1):1–46PubMedCrossRefGoogle Scholar
  58. Tang W, Luo T, Greenberg EF, Bradner JE, Schreiber SL (2011) Discovery of histone deacetylase 8 selective inhibitors. Bioorg Med Chem Lett 21(9):2601–2605 Epub 2011 Feb 2602PubMedCrossRefGoogle Scholar
  59. Taylor PC, Sivakumar B (2005) Hypoxia and angiogenesis in rheumatoid arthritis. Curr Opin Rheumatol 17(3):293–298PubMedCrossRefGoogle Scholar
  60. Usui T, Okada M, Mizuno W, Oda M, Ide N, Morita T, Hara Y, Yamawaki H (2012) HDAC4 mediates development of hypertension via vascular inflammation in spontaneous hypertensive rats. Am J Physiol Heart Circ Physiol 302(9):H1894–H1904. doi: 1810.1152/ajpheart.01039.02011 Epub.02012.Mar.01032PubMedCrossRefGoogle Scholar
  61. Vojinovic J, Damjanov N, D’Urzo C, Furlan A, Susic G, Pasic S, Iagaru N, Stefan M, Dinarello CA (2011) Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 63(5):1452–1458. doi: 1410.1002/art.30238 PubMedCrossRefGoogle Scholar
  62. Wang W, Ha CH, Jhun BS, Wong C, Jain MK, Jin ZG (2010) Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS. Blood 115(14):2971–2979 Epub 2009 Dec 2930PubMedCrossRefGoogle Scholar
  63. Winkler AR, Nocka KN, Williams CM (2012) Smoke exposure of human macrophages reduces HDAC3 activity, resulting in enhanced inflammatory cytokine production. Pulm Pharmacol Ther 25(4):286–292 Epub 2012 May 2018PubMedCrossRefGoogle Scholar
  64. Yan K, Cao Q, Reilly CM, Young NL, Garcia BA, Mishra N (2011) Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. J Biol Chem 286(33):28833–28843 Epub 22011 Jun 28827PubMedCrossRefGoogle Scholar
  65. Yang XJ, Seto E (2008) The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9(3):206–218PubMedCrossRefGoogle Scholar
  66. Zhang ZY, Schluesener HJ (2012) HDAC inhibitor MS-275 attenuates the inflammatory reaction in rat experimental autoimmune prostatitis. Prostate 72(1):90–99. doi: 10.1002/pros.21410 Epub.22011.May.21412PubMedCrossRefGoogle Scholar
  67. Zhang ZY, Zhang Z, Schluesener HJ (2010) MS-275, an histone deacetylase inhibitor, reduces the inflammatory reaction in rat experimental autoimmune neuritis. Neuroscience 169(1):370–377 Epub 2010 May 2016PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Discipline of Anatomy and Pathology, School of Medical SciencesUniversity of AdelaideAdelaideAustralia

Personalised recommendations