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Transcriptional regulation of lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) expression in murine macrophages: role of interferon regulatory factors 1 (IRF-1) and 2 (IRF-2)

Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA

Natalia Cuesta

Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA

Stefanie N. Vogel

Department of Microbiology and Immunology, University of Maryland, Baltimore (UMB), School of Medicine, Baltimore, Maryland, USA, svogel{at}som.umaryland.edu

Activation of TLRs is most closely associated with induction of pro-inflammatory gene expression; however, expression of many other genes, including the TLR genes themselves, has also been shown to be modulated following TLR engagement. A large family of nuclear transcription factors, the interferon regulatory factors (IRFs), have been implicated in TLR signaling leading to pro-inflammatory gene expression. Given that IRF-1 and IRF-2 counter-regulate the transcriptional activity of many genes, we hypothesized that IRF-1 and IRF-2 might also regulate TLR gene expression following LPS stimulation of murine macrophages. mRNA derived from medium- or LPS-treated primary peritoneal macrophages was analyzed for TLR gene expression using quantitative real-time PCR. In wild-type macrophages, LPS up-regulated expression of TLRs 1—3 and 6—9 steady-state mRNA, while TLR4 mRNA was modestly downregulated. IRF-2^{—/ —} macrophages responded to LPS with dysregulated expression of TLR3, TLR4, and TLR5 mRNA, whereas IRF-1 deficiency dampened LPS-induced mRNA expression for TLR3, TLR6, and TLR9. Functional studies revealed aberrant TLR3 signaling in IRF-2^{—/ —} macrophages. Collectively, these findings reveal an additional level of complexity associated with TLR transcriptional regulation and suggest that the trans-acting factors, IRF-1 and IRF-2, contribute to the innate immune response to infections by regulating TLR gene expression.

Key Words: Gene expression • interferon regulatory factors • macrophage • Toll-like receptor • transcriptional regulation

Journal of Endotoxin Research, Vol. 12, No. 5, 285-295 (2006)
DOI: 10.1177/09680519060120050401


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