C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity.
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/EBPδ and C/EBPβ activity. In addition, we observed that R848 stimulation increases TLR8 transcriptional activity via an enhanced binding of C/EBPδ, and not C/EBPβ, to its responsive sites within the TLR8 promoter. Moreover, we showed that IFN-γ also increased TLR8 transcription activity via the binding of STAT1 transcription factor to IFN-γ 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.
Zannetti
Claudia
C
Infection and Cancer Biology Group, International Agency for Research on Cancer, Lyon 69008, France. claudia.zannetti@inserm.fr
Bonnay
François
F
Takeshita
Fumihiko
F
Parroche
Peggy
P
Ménétrier-Caux
Christine
C
Tommasino
Massimo
M
Hasan
Uzma A
UA
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012367:RNA, Viral / Q000276:immunology / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000502:physiology*
D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C497252:CEBPD protein, human; D012367:RNA, Viral; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D051743:CCAAT-Enhancer-Binding Protein-delta; D007371:Interferon-gamma