C/EBPδ and STAT-1 Are Required for TLR8 Transcriptional Activity

Abstract

Toll-like receptor 8 (TLR8), which is expressed primarily in myeloid cells, plays a central role in initiating immune responses to viral single-stranded RNA. Despite the great interest in the field of TLR8 research, very little is known in terms of TLR8 biology and its transcriptional regulation. Here, we describe the isolation of the hTLR8 promoter and the characterization of the molecular mechanisms involved in its regulation. Reporter gene analysis and ChIP assays demonstrated that the hTLR8 regulation of the basal transcription is regulated via three C/EBP cis-acting elements that required C/EBP␦ and C/EBP␤ activity. In addition, we observed that R848 stimulation increases TLR8 transcriptional activity via an enhanced binding of C/EBP␦, and not C/EBP␤, to its responsive sites within the TLR8 promoter. Moreover, we showed that IFN-␥ also increased TLR8 transcription activity via the binding of STAT1 transcription factor to IFN-␥ activated sequence elements on the TLR8 promoter and enhanced TLR8 functionality. These results shed new light on the mechanisms involved during TLR8-mediated innate immune response.

The T Antigen Locus of Merkel Cell Polyomavirus Downregulates Human Toll-Like Receptor 9 Expression

“…These transcription factors positively regulate the expression of TLR8 and TLR9 (31,36). In addition, C/EBP␤ plays a key role in the interferon signaling network by interacting with other transcription factors such as NF-B, SP1, and STAT3 to regulate IL-6, IL-8, and tumor necrosis factor alpha (TNF-␣) cytokine transcription (40).…”

“…Members of the C/EBP family positively activate transcription of several TLR genes, for example, TLR8 and TLR9 (31,36). Therefore, we next evaluated whether MCPyV inhibits TLR9 expression by targeting C/EBP transcription factors.…”

Transcriptional Regulation of the Human Tumor Suppressor DOK1 by E2F1

“…pcDNA3-p65 was obtained from Tom Gilmore (Boston University), and the pN3-SP1 plasmid was obtained from Guntram Suske (Philipps University Marburg, Germany). The CREB1 plasmid has been described previously (36), and p53 was obtained from Pierre Hainaut (IARC, France). The Renilla construct was obtained from BD Clontech.…”

TLR9 Transcriptional Regulation in Response to Double-Stranded DNA Viruses

“…Measles virus infection of dendritic or epithelial cells leads to IFN-b induction, which positively induces the transcription of TLR3 (40). TLR7 and TLR8 transcriptional activity are induced in response to specific and nonspecific ligands (41). Cross-regulation of TLR mRNA levels in avian macrophages was recently reported by exposure to all of the tested agonists (42).…”