Polarization of primary human monocytes by IFN-gamma induces chromatin changes and recruits RNA Pol II to the TNF-alpha promoter.
Monocyte polarization by IFN-gamma or IL-4 drives a complex series of cellular responses leading to increased intracellular killing (IFN-gamma) or enhanced healing (IL-4) among other functional responses. We studied the effect of IL-4 and IFN-gamma polarization on histone modifications at the TNF-alpha locus in human primary monocytes. IFN-gamma polarization markedly increased the expression of TNF-alpha, whereas IL-4 treatment decreased the expression. We found that IFN-gamma alone increased histone H4 acetylation at the TNF-alpha promoter. The effect of IFN-gamma on TNF-alpha expression was durable upon cytokine washout and even repolarization with IL-4. Concordantly, IFN-gamma-mediated H4 acetylation was also durable. IFN-gamma recruited activating transcription factor-2 via p38 to the TNF-alpha promoter, but inhibition of p38 had minimal effect on H4 acetylation. In a novel finding, we found that IFN-gamma recruited RNA Pol II to the human TNF-alpha promoter via ERK signaling, but did so without initiating transcription, leading to a poised condition. These studies provide an important perspective on monocyte polarization. Polarization by IFN-gamma has a durable effect on TNF-alpha expression, and histone acetylation may provide a mechanism for persistence of the effect.
Garrett
Stacey
S
Division of Allergy Immunology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Dietzmann-Maurer
Kelly
K
Song
Li
L
Sullivan
Kathleen E
KE
D000107:Acetylation; D051696:Activating Transcription Factors / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D051696:Activating Transcription Factors; D002843:Chromatin; D006655:Histone Deacetylases; D006657:Histones; D007371:Interferon-gamma; D015847:Interleukin-4; D008070:Lipopolysaccharides; D012319:RNA Polymerase II; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000099186:Histone Deacetylase 3; C502592:SUPT20H protein, human