title: Regulation of Epigenetic Modifiers, Including KDM6B, by Interferon-γ and Interleukin-4 in Human Macrophages.
abstract: BACKGROUND
  Interferon-γ (IFN-γ) or interleukin-4 (IL-4) drives widely different transcriptional programs in macrophages. However, how IFN-γ and IL-4 alter expression of histone-modifying enzymes involved in epigenetic regulation and how this affects the resulting phenotypic polarization is incompletely understood.
  
  
  RESULTS
  We investigated steady-state messenger RNA levels of 84 histone-modifying enzymes and related regulators in colony-stimulating factor-1 differentiated primary human macrophages using quantitative polymerase chain reaction. IFN-γ or IL-4 treatment for 6-48 h changed 11 mRNAs significantly. IFN-γ increased CIITA, KDM6B, and NCOA1, and IL-4 also increased KDM6B by 6 h. However, either cytokine decreased AURKB, ESCO2, SETD6, SUV39H1, and WHSC1, whereas IFN-γ alone decreased KAT2A, PRMT7, and SMYD3 mRNAs only after 18 h, which coincided with decreased cell proliferation. Rendering macrophages quiescent by growth factor starvation or adenovirus-mediated overexpression of p27kip1inhibited expression of AURKB, ESCO2, SUV39H1, and WHSC1, and mRNA levels were restored by overexpressing the S-phase transcription factor E2F1, implying their expression, at least partly, depended on proliferation. However, CIITA, KDM6B, NCOA1, KAT2A, PRMT7, SETD6, and SMYD3 were regulated independently of effects on proliferation. Silencing KDM6B, the only transcriptional activator upregulated by both IFN-γ and IL-4, pharmacologically or with short hairpin RNA, blunted a subset of responses to each cytokine.
  
  
  CONCLUSIONS
  These findings demonstrate that IFN-γ or IL-4 can regulate the expression of histone acetyl transferases and histone methyl transferases independently of effects on proliferation and that upregulation of the histone demethylase, KDM6B, assists phenotypic polarization by both cytokines.
authors.affiliation: Chair of Vascular Cell Biology, School of Clinical Sciences, University of Bristol , Bristol , UK.
authors.forename: Gökçe
authors.initials: G
authors.lastname: Yıldırım-Buharalıoğlu
authors.affiliation: Chair of Vascular Cell Biology, School of Clinical Sciences, University of Bristol , Bristol , UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Bond
authors.affiliation: Chair of Vascular Cell Biology, School of Clinical Sciences, University of Bristol , Bristol , UK.
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Sala-Newby
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada; Department of Physiology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Charles C T
authors.initials: CC
authors.lastname: Hindmarch
authors.affiliation: Chair of Vascular Cell Biology, School of Clinical Sciences, University of Bristol , Bristol , UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
keywords: epigenetics; interferon-γ; interleukin-4; macrophage phenotype; proliferation