Abstract
As sensors of invading microorganisms, Toll-like receptors (TLRs) are expressed not only on macrophages and dendritic cells (DCs) but also on epithelial cells. In the TLR family, Tlr11 appears to have the unique feature in that it is expressed primarily on epithelial cells, although it is also expressed on DCs and macrophages. Here, we demonstrate that transcription of the Tlr11 gene is regulated through two cis-acting elements, one Ets-binding site and one interferon regulatory factor (IRF)-binding site. The Ets element interacts with the epithelium-specific transcription factors, ESE-1 and ESE-3, and the IRF motif interacts with IRF-8. Thus, Tlr11 expression on epithelial cells is regulated by the transcription factors that are presumably distinct from transcription factors that regulate the expression of TLRs in innate immune cells such as macrophages and DCs. Our results imply that the distinctive transcription regulatory machinery for TLRs on epithelium may represent a promising new avenue for the development of epithelia-specific therapeutic interventions.
Highlights
The expression and function of Toll-like receptor (TLR)2 genes in innate immune cells have been studied extensively [1,2,3], and the mechanisms that regulate Toll-like receptors (TLRs) expression in these cells have been well defined [4, 5]
Determination of Transcription Start Sites of Tlr11 Gene— We previously demonstrated that Tlr11 is primarily expressed by the urinary tract epithelial cells, and Tlr11 expression in epithelial cells appears to be stronger than in typical myeloid innate immune cells such as macrophages and dendritic cells (DCs) [21]
We previously demonstrated that Tlr11 is expressed in epi- ment, the promoter with this binding site mutation failed to thelial cells and recognizes the urinary pathogen E. coli [21]. become activated by IRF8 (Fig. 4C)
Summary
Cell Lines and Reagents—Renca (a kidney epithelial cell), Raw 264.7, and HEK293 cells were purchased from ATCC. An approximate 2.0-kb fragment that contains the immediate 5Ј-flanking Tlr sequence of the putative murine Tlr promoter (GenBankTM accession number 209865968) was amplified using the Expand High Fidelity PCR system (Roche Applied Science) and the primers T11PS/T11PAS-1929 (Table 1). This 2.0-kb fragment was subcloned into the pGL3-basic vector (Promega). A p value of less than 0.05 was considered to be statistically significant
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