Abstract
Toll-like receptors (TLRs) are essential components of the innate immune system. TLR5 is the receptor for flagellin, the principal protein component of bacterial flagella. The TLR5 gene has 6 exons. In an RT-PCR analysis, we found long TLR5 transcripts, in addition to those of the expected size (short TLR5 transcripts). A sequence analysis revealed that the long TLR5 transcripts contain a new exon of 94 nucleotides located between previously reported exons IV and V in the 5′ untranslated region (5′ UTR). A real-time PCR analysis of the two alternatively spliced variants in various cell lines showed that the long TLR5 transcripts are abundantly expressed in nonimmune cells. The ratios of long/short transcripts in human nonimmune cell lines, such as A549, T98G, HaCaT, H460, HEK-293, and Caco-2 cells, and primary mesenchymal stem cells were in the range of 1.25 to 4.31. In contrast, those of human monocytic THP-1 and U937 cells and E6.1 T cells and Ramos B cells were around 0.9. These ratios in human monocytic THP-1 cells were decreased by treatment with IFN-γ in a concentration-dependent manner. Based on our findings, we suggest that the newly found long TLR5 transcripts may be involved in the negative regulation of TLR5 expression and function.
Highlights
Toll-like receptors (TLRs) are innate immune receptors that consist of an extracellular domain for the recognition of pathogenic components and a cytoplasmic tail with a conserved Toll/IL-1 receptor (TIR) domain for the generation of intracellular signaling [1]
Our results indicate that human TLR5 has seven exons and a newly found exon lies between previously reported exons IV and V in the 5 untranslated region (5 UTR)
Since IFN-γ is an important activator of macrophages and downregulates TLR5 expression [14], we investigated whether IFN-γ influences TLR5 alternative splicing
Summary
Toll-like receptors (TLRs) are innate immune receptors that consist of an extracellular domain for the recognition of pathogenic components and a cytoplasmic tail with a conserved Toll/IL-1 receptor (TIR) domain for the generation of intracellular signaling [1]. Upon TLR stimulation by pathogenic components, the TIR domain recruits signaling molecules to activate the transcription of diverse genes, including inflammatory and antimicrobial mediators [1]. Alternative splicing of key TLR signaling components, such as MyD88 and IRAK, has been reported. A splicing variant of MyD88, termed MyD88s, which lacks the intermediate region between the TIR domain and the death domain, inhibits inflammatory signals that are normally mediated by MyD88 in both mouse [8] and human [9] cells. Two splicing variants of murine IRAK2 are inhibitory [10], and a splicing variant of human IRAK1 is inhibitory [11] These studies suggest that the splicing of TLR signaling molecules is involved in the resolution of TLR-directed immune responses
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