Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages.
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.
Italian Institute of Technology at European School of Molecular Medicine, 20139 Milan,  Italy.
Xuefen
X
Chen
Iros
I
Barozzi
Alberto
A
Termanini
Elena
E
Prosperini
Antonio
A
Recchiuti
Jesmond
J
Dalli
Flore
F
Mietton
Gianluca
G
Matteoli
Scott
S
Hiebert
Gioacchino
G
Natoli
D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016207:Cytokines / Q000032:analysis; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D023281:Genomics; D006655:Histone Deacetylases / Q000172:deficiency / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D000099186:Histone Deacetylase 3
D051545:Cyclooxygenase 1; D016207:Cytokines; D017931:DNA Primers; D006655:Histone Deacetylases; D008565:Membrane Proteins; D000099186:Histone Deacetylase 3; C496512:Ptgs1 protein, mouse