Transcriptional Regulation of the Novel Toll-like Receptor Tlr13

Abstract

Little has been known about Tlr13 (Toll-like receptor 13), a novel member of the Toll-like receptor family. To elucidate the molecular basis of murine Tlr13 gene expression, the activity of the Tlr13 gene promoter was characterized. Reporter gene analysis and electrophoretic mobility shift assays demonstrated that Tlr13 gene transcription was regulated through three cis-acting elements that interacted with the Ets2, Sp1, and PU.1 transcription factors. Furthermore, our work suggests that these transcription factors may cooperate, culminating in maximal transcription of the Tlr13 gene. In contrast, NF-B appeared to act as an inhibitor of Tlr13 transcription. Overexpression of Ets2 caused a strong increase in the transcriptional activity of the Tlr13 promoter; however, overexpression of NF-B p65 dramatically inhibited it. Additionally, interferon-␤ is capable of acting Tlr13 transcription, but the activated signaling of lipopolysaccharide/TLR4 and peptidoglycan/TLR2 strongly inhibited the Tlr13 gene promoter. Thus, these findings reveal the mechanism of Tlr13 gene regulation, thereby providing insight into the function of Tlr13 in the immune response to pathogen.Upon infection, microorganisms are first recognized by cells of the host innate immune system, such as macrophages and dendritic cells, as well as mucosal epithelial cells (1-6). Recognition of pathogens is primarily mediated by a set of germ lineencoded molecules on innate immune cells that are referred to as pattern recognition receptors (7,8). These pattern recognition receptors are expressed as either membrane-bound or soluble proteins that recognize invariant molecular structures from the pathogen called pathogen-associated molecular patterns (7,8).Recent studies on the recognition of microbial pathogenassociated molecular patterns have highlighted the vital role of one group of pattern recognition receptors, the Toll-like receptors (TLRs) 2 (9, 10). It is already clear that TLRs play a crucial role in the recognition of "molecular signatures" produced by infecting microbes to engage differential signaling pathways (11,12). Signaling through TLRs activates various transcription factors, such as nuclear factor-B (NF-B), activating protein-1 (AP-1), and interferon regulatory factors to induce an immunological response (3, 11).Tlr13 is a novel and poorly characterized member of the Tolllike receptor family (3, 13). Although the elucidation of the function of Tlr13 depends mainly on the identification of its natural ligand, its transcriptional regulation also provide some clues. For example, which type of cells expresses Tlr13? Which transcription factors control Tlr13 expression? How do different pathogen-associated molecular patterns from different pathogens regulate Tlr13 expression? This information will perhaps help us understand not only how this novel TLR responds to different infections but also which pathogens might be recognized by Tlr13 to activate the innate immune response. Recently, Aderem et al. (14) reported that Tlr13 belongs to the Tlr1...

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