Histone deacetylase inhibitors valproic acid and sodium butyrate enhance prostaglandins release in lipopolysaccharide-activated primary microglia.
Modifications of histone deacetylases (HDACs) may be involved in microglia-driven neuroinflammatory responses. Recent studies suggest that several inflammatory molecules can regulate the extent of neurodegeneration and regeneration in the central nervous system (CNS). In the present study, we investigated the effects of HDAC inhibitors (HDACi) valproic acid (VPA) and sodium butyrate (NaBut) on the release of prostaglandins (PGs) in lipopolysaccharide (LPS)-activated microglia. We found that VPA and NaBut significantly enhanced LPS-induced release of PGE2, PGD2 and 8-iso-PGF2α. In addition, both compounds increased cyclooxygenase-2 and microsomal prostaglandin E synthase immunoreactivity and gene expression in LPS-stimulated microglia. Interestingly, treatment of activated microglia with HDACi also enhanced the gene expression and the release of different pro-inflammatory cytokines. Microglia activation with LPS leads to IκB-α degradation, as well as p38, ERK1/2 and JNK MAPKs phosphorylation and thus activation, which is not affected by treatment with VPA and NaBut. Furthermore, VPA and NaBut treatment induced histone acetylation at H3-K18 in microglia. We suggest that VPA and NaBut-driven increase in PGs release in LPS-activated microglia might be regulated at the transcriptional level and involves histone hyperacetylation. Our data demonstrate that VPA and NaBut are able to modulate microglia responses to inflammatory insults and thus possibly can regulate the CNS degenerative and regenerative processes.
Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany.
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Singh
Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany. Electronic address: harsharan.singh.bhatia@uniklinik-freiburg.de.
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Bhatia
Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany; University of Freiburg, Faculty of Biology, Schaenzlestrasse 1, D-79104 Freiburg, Germany.
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Kumar
Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany; Department of Pharmacology, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais, Brazil.
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de Oliveira
Department of Psychiatry, University of Freiburg Medical School, Hauptstrasse 5, D-79104 Freiburg, Germany; VivaCell Biotechnology GmbH, Ferdinand-Porsche-Strasse 5, D-79211 Denzlingen, Germany.
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Fiebich
D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology*; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D008070:Lipopolysaccharides; D011453:Prostaglandins; D020148:Butyric Acid; D014635:Valproic Acid
cyclooxygenase-2; histone deacetylase inhibitors; microglia; microsomal prostaglandin E synthase-1; prostaglandin