Human Gene Set: GSE33162_UNTREATED_VS_4H_LPS_STIM_HDAC3_KO_MACROPHAGE_DN


Standard name GSE33162_UNTREATED_VS_4H_LPS_STIM_HDAC3_KO_MACROPHAGE_DN
Systematic name M9037
Brief description Genes down-regulated in macrophages with knockout of HDAC3 [GeneID=8841]: untreated versus LPS.
Full description or abstract Pan-Hdac inhibitors (HDACi) are endowed with a potent anti-inflammatory activity, but the relative role of each of the eleven Hdac proteins sensitive to HDACi to the inflammatory gene expression program is unknown. Using an integrated genomic approach we found that Hdac3-deficient macrophages are unable to activate almost half of the inflammatory gene expression program when stimulated with lipopolysaccharide (LPS). A large part of the activation defect is due to loss of basal and LPS-inducible expression of IFNb, which in basal cells maintains Stat1 protein levels, and after stimulation acts in an autocrine/paracrine manner to promote a secondary wave of Stat1-dependent gene expression. We show that loss of Hdac3-mediated repression of nuclear receptors leads to hyperacetylation of thousands of genomic sites and associated gene derepression. The upregulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), has a causative role in the phenotype, since its chemical inhibition reverts the Ifnb activation defect. These data may have relevance for the use of selective Hdac inhibitors as anti-inflammatory agents.
Collection C7: Immunologic Signature
      IMMUNESIGDB: ImmuneSigDB
Source publication Pubmed 22802645   Authors: Chen X,Barozzi I,Termanini A,Prosperini E,Recchiuti A,Dalli J,Mietton F,Matteoli G,Hiebert S,Natoli G
Exact source GSE33162_3528_200_DN
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Source species Mus musculus
Contributed by Jernej Godec (Dana-Farber Cancer Institute)
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Version history 7.3: Moved to ImmuneSigDB sub-collection.

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