Journal of Neuroimmune Pharmacology

, Volume 5, Issue 4, pp 521–532

Histone Deacetylase Inhibitors Suppress the Expression of Inflammatory and Innate Immune Response Genes in Human Microglia and Astrocytes

  • Hyeon-Sook Suh
  • Shinyeop Choi
  • Pallavi Khattar
  • Namjong Choi
  • Sunhee C. Lee


Histone deacetylase inhibitors (HDACi) have been proposed as therapies for certain cancers and as an anti-reservoir therapy for HIV+ individuals with highly active anti-retroviral therapy, yet their roles in glial inflammatory and innate antiviral gene expression have not been defined. In this study, we examined the effects of two non-selective HDACi, trichostatin A and valproic acid, on antiviral and cytokine gene expression in primary human microglia and astrocytes stimulated with TLR3 or TLR4 ligand. HDACi potently suppressed the expression of innate antiviral molecules such as IFNβ, interferon-simulated genes, and proteins involved in TLR3/TLR4 signaling. HDACi also suppressed microglial and astrocytic cytokine and chemokine gene expression, but with different effects on different groups of cytokines. These results have important implications for the clinical use of HDACi.


histone deacetylase microglia cytokines innate immunity HIV astrocytes valproic acid TLR 



Histone deacetylase


HDAC inhibitor


Type I interferon receptor


IFN-stimulated response element

PIC (poly I:C)

Polyinosinic–polycytidylic acid


Porphobilinogen deaminase


Real-time RT–PCR


Valproic acid


Indoleamine 2, 3-dioxygenase


Interferon regulatory factor


IFN-stimulated genes




Toll-like receptor


Toll/interleukin-1 receptor domain-containing adaptor protein inducing IFNβ


Trichostatin A

Supplementary material

11481_2010_9192_MOESM1_ESM.xls (441 kb)


  1. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801CrossRefPubMedGoogle Scholar
  2. Archin NM, Keedy KS, Espeseth A, Dang H, Hazuda DJ, Margolis DM (2009) Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. AIDS 23:1799–1806CrossRefPubMedGoogle Scholar
  3. Camelo S, Iglesias AH, Hwang D, Due B, Ryu H, Smith K, Gray SG, Imitola J, Duran G, Assaf B, Langley B, Khoury SJ, Stephanopoulos G, De GU, Ratan RR, Ferrante RJ, Dangond F (2005) Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 164:10–21CrossRefPubMedGoogle Scholar
  4. Carpentier PA, Duncan DS, Miller SD (2008) Glial toll-like receptor signaling in central nervous system infection and autoimmunity. Brain Behav Immun 22:140–147CrossRefPubMedGoogle Scholar
  5. Chang HM, Paulson M, Holko M, Rice CM, Williams BR, Marie I, Levy DE (2004) Induction of interferon-stimulated gene expression and antiviral responses require protein deacetylase activity. Proc Natl Acad Sci U S A 101:9578–9583CrossRefPubMedGoogle Scholar
  6. Chen L, Fischle W, Verdin E, Greene WC (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293:1653–1657CrossRefGoogle Scholar
  7. Dewhurst S, Maggirwar SB, Schifitto G, Gendelman HE, Gelbard HA (2007) Glycogen synthase kinase 3 Beta (GSK-3beta) as a therapeutic target in neuroAIDS. J Neuroimmune Pharmacol 2:93–96CrossRefPubMedGoogle Scholar
  8. Dokmanovic M, Marks PA (2005) Prospects: histone deacetylase inhibitors. J Cell Biochem 96:293–304CrossRefPubMedGoogle Scholar
  9. Dou H, Birusingh K, Faraci J, Gorantla S, Poluektova LY, Maggirwar SB, Dewhurst S, Gelbard HA, Gendelman HE (2003) Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis. J Neurosci 23:9162–9170PubMedGoogle Scholar
  10. Genin P, Morin P, Civas A (2003) Impairment of interferon-induced IRF-7 gene expression due to inhibition of ISGF3 formation by trichostatin A. J Virol 77:7113–7119CrossRefPubMedGoogle Scholar
  11. Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Roach JC, Kennedy K, Hai T, Bolouri H, Aderem A (2006) Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441:173–178CrossRefPubMedGoogle Scholar
  12. Hiscott J, Lin R, Nakhaei P, Paz S (2006) MasterCARD: a priceless link to innate immunity. Trends Mol Med 12:53–56CrossRefPubMedGoogle Scholar
  13. John GR, Lee SC, Song X, Rivieccio M, Brosnan CF (2005) IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia 49:161–176CrossRefPubMedGoogle Scholar
  14. Kiernan R, Bres V, Ng RW, Coudart MP, El MS, Sardet C, Jin DY, Emiliani S, Benkirane M (2003) Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J Biol Chem 278:2758–2766CrossRefPubMedGoogle Scholar
  15. Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther 321:892–901CrossRefPubMedGoogle Scholar
  16. Klampfer L, Huang J, Swaby LA, Augenlicht L (2004) Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem 279:30358–30368CrossRefPubMedGoogle Scholar
  17. Lee SC, Liu W, Brosnan CF, Dickson DW (1992) Characterization of primary human fetal dissociated central nervous system cultures with an emphasis on microglia. Lab Invest 67:465–476PubMedGoogle Scholar
  18. Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM (2005) Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366:549–555CrossRefPubMedGoogle Scholar
  19. 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 11:1–15CrossRefPubMedGoogle Scholar
  20. Liu J, Zhao M-L, Brosnan CF, Lee SC (1996) Expression of type II nitric oxide synthase in primary human astrocytes and microglia: role of IL-1b and IL-1 receptor antagonist. J Immunol 157:3569–3576PubMedGoogle Scholar
  21. Liu JS, Amaral TD, Brosnan CF, Lee SC (1998) IFNs are critical regulators of IL-1 receptor antagonist and IL-1 expression in human microglia. J Immunol 161:1989–1996PubMedGoogle Scholar
  22. Maggirwar SB, Tong N, Ramirez S, Gelbard HA, Dewhurst S (1999) HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity. J Neurochem 73:578–586CrossRefPubMedGoogle Scholar
  23. Mahlknecht U, Will J, Varin A, Hoelzer D, Herbein G (2004) Histone deacetylase 3, a class I histone deacetylase, suppresses MAPK11-mediated activating transcription factor-2 activation and represses TNF gene expression. J Immunol 173:3979–3990PubMedGoogle Scholar
  24. Marks PA (2007) Discovery and development of SAHA as an anticancer agent. Oncogene 26:1351–1356CrossRefPubMedGoogle Scholar
  25. Marks PA, Xu WS (2009) Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem 107:600–608CrossRefPubMedGoogle Scholar
  26. Martin M, Rehani K, Jope RS, Michalek SM (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 6:777–784CrossRefPubMedGoogle Scholar
  27. McManus CM, Liu JS, Hahn MT, Hua LL, Brosnan CF, Berman JW, Lee SC (2000) Differential induction of chemokines in human microglia by type I and II interferons. Glia 29:273–280CrossRefPubMedGoogle Scholar
  28. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51CrossRefPubMedGoogle Scholar
  29. Monneret C (2005) Histone deacetylase inhibitors. Eur J Med Chem 40:1–13CrossRefPubMedGoogle Scholar
  30. Nguyen TL, Abdelbary H, Arguello M, Breitbach C, Leveille S, Diallo JS, Yasmeen A, Bismar TA, Kirn D, Falls T, Snoulten VE, Vanderhyden BC, Werier J, Atkins H, Vaha-Koskela MJ, Stojdl DF, Bell JC, Hiscott J (2008) Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis. Proc Natl Acad Sci U S A 105:14981–14986CrossRefPubMedGoogle Scholar
  31. Nusinzon I, Horvath CM (2003) Interferon-stimulated transcription and innate antiviral immunity require deacetylase activity and histone deacetylase 1. Proc Natl Acad Sci U S A 100:14742–14747CrossRefPubMedGoogle Scholar
  32. Nusinzon I, Horvath CM (2006) Positive and negative regulation of the innate antiviral response and beta interferon gene expression by deacetylation. Mol Cell Biol 26:3106–3113CrossRefPubMedGoogle Scholar
  33. Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, Yang S, Hong JS (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res 134:162–169CrossRefPubMedGoogle Scholar
  34. Rascle A, Johnston JA, Amati B (2003) Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5. Mol Cell Biol 23:4162–4173CrossRefPubMedGoogle Scholar
  35. Rivieccio MA, John GR, Song X, Suh HS, Zhao Y, Lee SC, Brosnan CF (2005) The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture. J Immunol 174:3719–3726PubMedGoogle Scholar
  36. Rivieccio MA, Suh HS, Zhao Y, Zhao ML, Chin KC, Lee SC, Brosnan CF (2006) TLR3 ligation activates an antiviral response in human fetal astrocytes: a role for viperin/cig5. J Immunol 177:4735–4741PubMedGoogle Scholar
  37. Sakamoto S, Potla R, Larner AC (2004) Histone deacetylase activity is required to recruit RNA polymerase II to the promoters of selected interferon-stimulated early response genes. J Biol Chem 279:40362–40367CrossRefPubMedGoogle Scholar
  38. Schifitto G, Peterson DR, Zhong J, Ni H, Cruttenden K, Gaugh M, Gendelman HE, Boska M, Gelbard H (2006) Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report. Neurology 66:919–921CrossRefPubMedGoogle Scholar
  39. Schifitto G, Zhong J, Gill D, Peterson DR, Gaugh MD, Zhu T, Tivarus M, Cruttenden K, Maggirwar SB, Gendelman HE, Dewhurst S, Gelbard HA (2009) Lithium therapy for human immunodeficiency virus type 1-associated neurocognitive impairment. J Neurovirol 15:176–186CrossRefPubMedGoogle Scholar
  40. Suh HS, Kim MO, Lee SC (2005) Inhibition of granulocyte-macrophage colony-stimulating factor signaling and microglial proliferation by anti-CD45RO: role of Hck tyrosine kinase and phosphatidylinositol 3-kinase/Akt. J Immunol 174:2712–2719PubMedGoogle Scholar
  41. Suh HS, Zhao ML, Rivieccio M, Choi S, Connolly E, Zhao Y, Takikawa O, Brosnan CF, Lee SC (2007) Astrocyte indoleamine 2, 3 dioxygenase (IDO) is induced by the TLR3 ligand poly IC: mechanism of induction and role in anti-viral response. J Virol 81:9838–9850CrossRefPubMedGoogle Scholar
  42. Suh HS, Brosnan CF, Lee SC (2009a) Chapter 4: TLRs in CNS viral infections. Toll-like Receptors: Roles in Infection and Neuropathology. Kielian, T (ed). Curr Top Microbiol Immunol 336:63–81Google Scholar
  43. Suh HS, Zhao ML, Choi N, Belbin TJ, Brosnan CF, Lee SC (2009b) TLR3 and TLR4 are innate antiviral immune receptors in human microglia: role of IRF3 in modulating antiviral and inflammatory response in the CNS. Virology 392:246–259CrossRefPubMedGoogle Scholar
  44. Sui Z, Sniderhan LF, Fan S, Kazmierczak K, Reisinger E, Kovacs AD, Potash MJ, Dewhurst S, Gelbard HA, Maggirwar SB (2006) Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons. Eur J NeuroSci 23:2623–2634CrossRefPubMedGoogle Scholar
  45. Suuronen T, Huuskonen J, Pihlaja R, Kyrylenko S, Salminen A (2003) Regulation of microglial inflammatory response by histone deacetylase inhibitors. J Neurochem 87:407–416CrossRefPubMedGoogle Scholar
  46. Vlasakova J, Novakova Z, Rossmeislova L, Kahle M, Hozak P, Hodny Z (2007) Histone deacetylase inhibitors suppress IFNalpha-induced up-regulation of promyelocytic leukemia protein. Blood 109:1373–1380CrossRefPubMedGoogle Scholar
  47. Whitmore MM, Iparraguirre A, Kubelka L, Weninger W, Hai T, Williams BR (2007) Negative regulation of TLR-signaling pathways by activating transcription factor-3. J Immunol 179:3622–3630PubMedGoogle Scholar
  48. Zhang B, West EJ, Van KC, Gurkoff GG, Zhou J, Zhang XM, Kozikowski AP, Lyeth BG (2008) HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res 1226:181–191CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Hyeon-Sook Suh
    • 1
  • Shinyeop Choi
    • 1
  • Pallavi Khattar
    • 1
  • Namjong Choi
    • 1
  • Sunhee C. Lee
    • 1
  1. 1.Department of PathologyAlbert Einstein College of MedicineBronxUSA

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