Histone deacetylase 3, a class I histone deacetylase, suppresses MAPK11-mediated activating transcription factor-2 activation and represses TNF gene expression.
During inflammatory events, the induction of immediate-early genes, such as TNF-alpha, is regulated by signaling cascades including the JAK/STAT, NF-kappaB, and the p38 MAPK pathways, which result in phosphorylation-dependent activation of transcription factors. We observed the direct interaction of histone deacetylase (HDAC) 3, a class I histone deacetylase, with MAPK11 (p38 beta isoform) by West-Western-based screening analysis, pull-down assay, and two-hybrid system analysis. Results further indicated that HDAC3 decreases the MAPK11 phosphorylation state and inhibits the activity of the MAPK11-dependent transcription factor, activating transcription factor-2 (ATF-2). LPS-mediated activation of ATF-2 was inhibited by HDAC3 in a time- and dose-dependent manner. Inhibition of HDAC3 expression by RNA interference resulted in increased ATF-2 activation in response to LPS stimulation. In agreement with decreased ATF-2 transcriptional activity by HDAC3, HDAC3-repressed TNF gene expression, and TNF protein production observed in response to LPS stimulation. Therefore, our results indicate that HDAC3 interacts directly and selectively with MAPK11, represses ATF-2 transcriptional activity, and acts as a regulator of TNF gene expression in LPS-stimulated cells, especially in mononuclear phagocytes.
Mahlknecht
Ulrich
U
Department of Hematology/Oncology, University of Frankfurt Medical Center, Frankfurt am Main, Germany. Ulrich_Mahlknecht@med.uni-heidelberg.de
Will
Jutta
J
Varin
Audrey
A
Hoelzer
Dieter
D
Herbein
Georges
G
D051698:Activating Transcription Factor 2; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D020868:Gene Silencing / Q000276:immunology*; D006655:Histone Deacetylases / Q000145:classification / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048290:Mitogen-Activated Protein Kinase 11; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000145:classification / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D020298:U937 Cells; D000099186:Histone Deacetylase 3
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D006655:Histone Deacetylases; D007527:Isoenzymes; D008070:Lipopolysaccharides; D048290:Mitogen-Activated Protein Kinase 11; D020928:Mitogen-Activated Protein Kinases; D010446:Peptide Fragments; D012097:Repressor Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000099186:Histone Deacetylase 3; C497105:ATF2 protein, human