title: Functional polymorphisms of TLR8 are associated with hepatitis C virus infection.
abstract: Chronic hepatitis C virus (HCV) infection is a worldwide threat to public health. Toll-like receptor 8 (TLR8) is critical for eliminating RNA viruses, and variation within the TLR8 gene may alter the function of TLR8 in response to HCV infection. Our previous study demonstrated that the TLR8-129G>C (rs3764879) and TLR8+1G>A (rs3764880) variants were in complete linkage disequilibrium, and that the frequency of TLR8-129C/+1A was significantly higher in male patients with HCV infection compared with the healthy controls. In the present study, we found that the promoter activity of TLR8-129G was higher than that of TLR8-129C in THP-1 cells. Moreover, TLR8-129G mRNA stability and competitive DNA-binding ability were significantly lower than that of TLR8-129C. To investigate the functional effects of TLR8 polymorphisms, we compared the nuclear factor-κB (NF-κB)-driven luciferase activity in HEK293 cells transfected with the TLR8 variants. TLR8+1A plasmids induced less NF-κB signalling than did those transfected with TLR8+1G after 20 μm CL075 (P = 0.011) stimulation. We also analysed the mRNA expression and cytokine production in whole blood and monocytes from people of various genotypes stimulated ex vivo by the interferon-γ and TLR7/8 agonist CL075, R848. TLR8 expression in CD14⁺ cells derived from volunteers with TLR8-129G/+1G was significantly higher than that derived from TLR8-129C/+1A, and interleukin-12p40 production was higher in volunteers with TLR8-129G/+1G after stimulation. The data indicate that variations in TLR8 genes may modulate immune responses during HCV infection.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Laboratory Medicine, E-DA Hospital/I-SHOU University, Kaohsiung, Taiwan.
authors.forename: Chiou-Huey
authors.initials: CH
authors.lastname: Wang
authors.forename: Hock-Liew
authors.initials: HL
authors.lastname: Eng
authors.forename: Kuei-Hsiang
authors.initials: KH
authors.lastname: Lin
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Liu
authors.forename: Cheng-Hsien
authors.initials: CH
authors.lastname: Chang
authors.forename: Tsun-Mei
authors.initials: TM
authors.lastname: Lin
mesh_terms: D000328:Adult; D001665:Binding Sites; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D004247:DNA / Q000378:metabolism; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006367:HeLa Cells; D019698:Hepatitis C, Chronic / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D004247:DNA; D008156:Luciferases
keywords: Toll-like receptor 8; hepatitis C virus; polymorphisms; promoter; stimulation