title: Dimethyl fumarate regulates histone deacetylase expression in astrocytes.
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 4h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24h, 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 24h, 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.
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago IL, 60612, United States.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.forename: Paul E
authors.initials: PE
authors.lastname: Polak
authors.forename: Shao Xia
authors.initials: SX
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Braun
authors.forename: Marina
authors.initials: M
authors.lastname: Guizzetti
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Zhang
authors.forename: Israel
authors.initials: I
authors.lastname: Rubinstein
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology*; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005650:Fumarates; D006655:Histone Deacetylases; D000069462:Dimethyl Fumarate
keywords: Astrocyte; Histone deacetylase; Multiple sclerosis; Nrf2