Published online before print March 14, 2007
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-regulated Tlr9 gene expression in mouse macrophages
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* Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, and
|| School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, Australia;
Cooperative Research Centre for Chronic Inflammatory Diseases, Australia;
Abt. für Hämatologie und Internistische Onkologie, Klinikum der Universität Regensburg, Germany; and
Scripps NeuroAIDS Preclinical Studies Centre and Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, California, USA
1 Correspondence: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane 4072, Australia. E-mail: m.sweet{at}imb.uq.edu.au
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 inducing Tlr9 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 molecular mechanism by which IFN- amplifies mouse macrophage responses to CpG DNA.
Key Words: colony-stimulating factor-1 • inflammation • lipopolysaccharide • interferon • IRF8 • Toll-like receptor
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