Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 42; pp. 16768 - 16769
• Main Authors: Chen, Xuefen, Barozzi, Iros, Termanini, Alberto, Prosperini, Elena, Recchiuti, Antonio, Dalli, Jesmond, Mietton, Flore, Matteoli, Gianluca, Hiebert, Scott, Natoli, Gioacchino
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.10.2012; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; anti-inflammatory activity; Anti-inflammatory agents; autocrine signaling; Base Sequence; Binding sites; Biological Sciences; Chromatin Immunoprecipitation; Cyclooxygenase 1 - metabolism; Cytokines - analysis; DNA Primers - genetics; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene expression; gene expression regulation; Gene Expression Regulation - genetics; genes; Genomics; histone deacetylase; Histone Deacetylases - deficiency; Histone Deacetylases - metabolism; inflammation; interferon-beta; macrophages; Macrophages - metabolism; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Molecular Sequence Data; phenotype; PNAS Plus; PNAS PLUS (AUTHOR SUMMARIES); prostaglandins; Proteins; Real-Time Polymerase Chain Reaction; receptors; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; T cell receptors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1121131109

Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic approach, we found that Hdac3-deficient macrophages were unable to activate almost half of the inflammatory gene expression program when stimulated with LPS. A large part of the activation defect was attributable to loss of basal and LPS-inducible expression of IFN-β, which maintains Stat1 protein levels in unstimulated cells and acts in an autocrine/paracrine manner after stimulation to promote a secondary wave of Stat1-dependent gene expression. Loss of Hdac3-mediated repression of nuclear receptors led to hyperacetylation of thousands of genomic sites and associated gene derepression. The up-regulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), a nuclear receptor target, had a causative role in the phenotype because its chemical inhibition reverted, albeit partially, the Ifn-β activation defect. These data indicate a central role for Hdac3 in inflammation and may have relevance for the use of selective Hdac inhibitors as antiinflammatory agents.