Histone deacetylase 7 promotes Toll-like Receptor 4-dependent pro-inflammatory gene expression in macrophages

Shakespear, Melanie R., Hohenhaus, Daniel M., Kelly, Greg M., Kamal, Nabilah A., Gupta, Praveer, Labzin, Larisa I., Schroder, Kate, Garceau, Valerie, Barbero, Sheila, Iyer, Abishek, Hume, David A., Reid, Robert C., Irvine, Katharine M., Fairlie, David P. and Sweet, Matthew J. (2013) Histone deacetylase 7 promotes Toll-like Receptor 4-dependent pro-inflammatory gene expression in macrophages. Journal of Biological Chemistry, 288 35: 25362-25374. doi:10.1074/jbc.M113.496281

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Author Shakespear, Melanie R.
Hohenhaus, Daniel M.
Kelly, Greg M.
Kamal, Nabilah A.
Gupta, Praveer
Labzin, Larisa I.
Schroder, Kate
Garceau, Valerie
Barbero, Sheila
Iyer, Abishek
Hume, David A.
Reid, Robert C.
Irvine, Katharine M.
Fairlie, David P.
Sweet, Matthew J.
Title Histone deacetylase 7 promotes Toll-like Receptor 4-dependent pro-inflammatory gene expression in macrophages
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2013-06-12
Year available 2013
Sub-type Article (original research)
DOI 10.1074/jbc.M113.496281
Open Access Status File (Publisher version)
Volume 288
Issue 35
Start page 25362
End page 25374
Total pages 13
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 1303 Biochemistry
1312 Molecular Biology
1307 Cell Biology
Abstract Broad-spectrum inhibitors of histone deacetylases (HDACs) constrain Toll-like receptor (TLR)-inducible production of key pro-inflammatory mediators. Here we investigated HDAC-dependent inflammatory responses in mouse macrophages. Of the classical Hdacs, Hdac7 was expressed at elevated levels in inflammatory macrophages (thioglycollate-elicited peritoneal macrophages, TEPM), as compared to bone marrow-derived macrophages (BMM) and the RAW264 cell line. Over-expression of a specific alternatively spliced isoform of Hdac7 lacking the N-terminal 22 amino acids (Hdac7-u), but not the Refseq Hdac7 (Hdac7-s), promoted lipopolysaccharide (LPS)-inducible expression of Hdac-dependent genes (Edn1, Il-12p40, Il-6) in RAW264 cells. A novel class IIa selective HDAC inhibitor reduced recombinant human HDAC7 enzyme activity, as well as TLR-induced production of inflammatory mediators in TEPM. Both LPS and Hdac7-u upregulated the activity of the Edn1 promoter in an HDAC-dependent fashion in RAW264 cells. A hypoxia-inducible factor (HIF)-1 binding site in this promoter was required for HDAC-dependent TLR-inducible promoter activity and for Hdac7- and HIF-1α-mediated trans-activation. Co-immunoprecipitation assays showed that both Hdac7-u and Hdac7-s interacted with HIF-1α, whereas only Hdac7-s interacted with the transcriptional repressor CtBP1. Thus, Hdac7-u positively regulates HIF-1α-dependent TLR signalling in macrophages, whereas an interaction with CtBP1 likely prevents Hdac7-s from exerting this effect. Hdac7 may represent a potential inflammatory disease target.
Keyword Toll-like receptor
Histone deacetylase
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 569735
Institutional Status UQ
Additional Notes Published online: 12 July 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 27 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 17 Jul 2013, 02:53:30 EST by Dr Kate Schroder on behalf of School of Chemistry & Molecular Biosciences