PU.1 and ICSBP control constitutive and IFN-gamma-regulated Tlr9 gene expression in mouse macrophages

Schroder, Kate, Lichtinger, Monika, Irvine, Katharine M., Brion, Kristian, Trieu, Angela, Ross, Ian L., Ravasi, Timothy, Stacey, Katryn J., Rehli, Michael, Hume, David A. and Sweet, Matthew J. (2007) PU.1 and ICSBP control constitutive and IFN-gamma-regulated Tlr9 gene expression in mouse macrophages. Journal of Leukocyte Biology, 81 6: 1577-1590. doi:10.1189/jlb.0107036


Author Schroder, Kate
Lichtinger, Monika
Irvine, Katharine M.
Brion, Kristian
Trieu, Angela
Ross, Ian L.
Ravasi, Timothy
Stacey, Katryn J.
Rehli, Michael
Hume, David A.
Sweet, Matthew J.
Title PU.1 and ICSBP control constitutive and IFN-gamma-regulated Tlr9 gene expression in mouse macrophages
Formatted title
PU.1 and ICSBP control constitutive and IFN-γ-regulated Tlr9 gene expression in mouse macrophages
Journal name Journal of Leukocyte Biology   Check publisher's open access policy
ISSN 0741-5400
Publication date 2007-06-01
Sub-type Article (original research)
DOI 10.1189/jlb.0107036
Volume 81
Issue 6
Start page 1577
End page 1590
Total pages 14
Place of publication Bethesda, Maryland, U.S.A.
Publisher Federation of American Societies for Experimental Biology
Language eng
Subject C1
730102 Immune system and allergy
320202 Cellular Immunology
270201 Gene Expression
270202 Genome Structure
Formatted abstract
 Macrophages are activated by unmethylated CpG-containing DNA (CpG DNA) via TLR9. IFN- and LPS can synergize with CpG DNA to enhance proinflammatory responses in murine macrophages. Here, we show that LPS and IFN- up-regulated Tlr9 mRNA in murine bone marrow-derived macrophages (BMM). The ability of LPS and IFN- to induce Tlr9 mRNA expression in BMM was dependent on the presence of the growth factor, CSF-1, which is constitutively present in vivo. However, there were clear differences in mechanisms of Tlr9 mRNA induction. LPS stimulation rapidly removed the CSF-1 receptor (CSF-1R) from the cell surface, thereby blocking CSF-1-mediated transcriptional repression and indirectly inducingTlr9 mRNA expression. By contrast, IFN- activated the Tlr9 promoter directly and only marginally affected cell surface CSF-1R expression. An 100-bp proximal promoter of the murine Tlr9 gene was sufficient to confer basal and IFN--inducible expression in RAW264.7 cells. A composite IFN regulatory factor (IRF)/PU.1 site upon the major transcription start site was identified. Mutation of the binding sites for PU.1 or IRF impaired basal promoter activity, but only the IRF-binding site was required for IFN- induction. The mRNA expression of the IRF family member IFN consensus-binding protein [(ICSBP)/IRF8] was coregulated with Tlr9 in macrophages, and constitutive and IFN--inducible Tlr9 mRNA expression was reduced in ICSBP-deficient BMM. This study therefore characterizes the regulation of mouse Tlr9 expression and defines a molecularmechanism by which IFN- amplifies mouse macrophage responses to CpG DNA.
Keyword Cell Biology
Hematology
Immunology
colony-stimulating factor-1
inflamination
lipopolysaccharide
interferon
IRF8
Toll-like receptor
Sequence-binding-protein
Toll-like Receptor-9
Plasmacytoid Dendritic Cells
Murine Peritoneal-macrophages
Stimulated Response Element
Bacterial Cpg-dna
Nf-kappa-b
Interferon-gamma
Transcriptional-regulation
Cutting Edge
Q-Index Code C1
Q-Index Status Confirmed Code
Additional Notes Originally published online as doi:10.1189/jlb.0107036 on March 14, 2007

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 31 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 19 Feb 2008, 03:24:26 EST