Dimethyl fumarate regulates histone deacetylase expression in astrocytes

Sergey Kalinin, Paul E. Polak, Shao Xia Lin, David Braun, Marina Guizzetti, Xiaolu Zhang, Israel Rubinstein, Douglas L. Feinstein

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4. h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24. h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24. h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.

Original languageEnglish (US)
Pages (from-to)13-19
Number of pages7
JournalJournal of Neuroimmunology
Volume263
Issue number1-2
DOIs
StatePublished - Oct 15 2013

Keywords

  • Astrocyte
  • Histone deacetylase
  • Multiple sclerosis
  • Nrf2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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  • Cite this

    Kalinin, S., Polak, P. E., Lin, S. X., Braun, D., Guizzetti, M., Zhang, X., Rubinstein, I., & Feinstein, D. L. (2013). Dimethyl fumarate regulates histone deacetylase expression in astrocytes. Journal of Neuroimmunology, 263(1-2), 13-19. https://doi.org/10.1016/j.jneuroim.2013.07.007