TY - JOUR
T1 - Dimethyl fumarate regulates histone deacetylase expression in astrocytes
AU - Kalinin, Sergey
AU - Polak, Paul E.
AU - Lin, Shao Xia
AU - Braun, David
AU - Guizzetti, Marina
AU - Zhang, Xiaolu
AU - Rubinstein, Israel
AU - Feinstein, Douglas L.
N1 - Funding Information:
This work was supported in part by grants from the National Multiple Sclerosis Society and a VA Research Career Scientist award (DLF), NIH grant AA-17180 (M. Guizzetti). We want to thank Drs. Oscar Bizzozero and Jianzheng Zheng for help working out initial western blot conditions.
PY - 2013/10/15
Y1 - 2013/10/15
N2 - 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.
AB - 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.
KW - Astrocyte
KW - Histone deacetylase
KW - Multiple sclerosis
KW - Nrf2
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U2 - 10.1016/j.jneuroim.2013.07.007
DO - 10.1016/j.jneuroim.2013.07.007
M3 - Article
C2 - 23916696
AN - SCOPUS:84884819095
SN - 0165-5728
VL - 263
SP - 13
EP - 19
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
IS - 1-2
ER -