LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression

Thanda Aung Hnin, Kate Schroder, Stewart R. Himes, Kristian Brion, Wendy Van Zuylen, Angela Trieu, Harukazu Suzuki, Yoshihide Hayashizaki, David A. Hume, Matthew J. Sweet, Timothy Ravasi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

Abstract

Bacterial LPS triggers dramatic changes in gene expression in macrophages. We show here that LPS regulated several members of the histone deacetylase (HDAC) family at the mRNA level in murine bone marrow-derived macrophages (BMM). LPS transiently repressed, then induced a number of HDACs (Hdac-4, 5, 7) in BMM, whereas Hdac-1 mRNA was induced more rapidly. Treatment of BMM with trichostatin A (TSA), an inhibitor of HDACs, enhanced LPS-induced expression of the Cox-2, Cxcl2, and Ifit2 genes. In the case of Cox-2, this effect was also apparent at the promoter level. Overexpression of Hdac-8 in RAW264 murine macrophages blocked the ability of LPS to induce Cox-2 mRNA. Another class of LPS-inducible genes, which included Ccl2, Ccl7, and Edn1, was suppressed by TSA, an effect most likely mediated by PU.1 degradation. Hence, HDACs act as potent and selective negative regulators of proinflammatory gene expression and act to prevent excessive inflammatory responses in macrophages.

Original languageEnglish (US)
Pages (from-to)1315-1327
Number of pages13
JournalFASEB Journal
Volume20
Issue number9
DOIs
StatePublished - Jul 1 2006

Keywords

  • Epigenetic
  • Histone code
  • Inflammation
  • Innate immunity
  • Transcriptional regulatory networks

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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