Functional polymorphisms of TLR8 are associated with hepatitis C virus infection

Immunology. 2014 Apr;141(4):540-8. doi: 10.1111/imm.12211.

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.

Keywords: Toll-like receptor 8; hepatitis C virus; polymorphisms; promoter; stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Binding Sites
  • Case-Control Studies
  • Cytokines / blood
  • DNA / metabolism
  • Genes, Reporter
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • HeLa Cells
  • Hepatitis C, Chronic / blood
  • Hepatitis C, Chronic / diagnosis
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / immunology
  • Humans
  • Immunity, Innate / genetics*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / virology
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • Male
  • NF-kappa B / genetics
  • Odds Ratio
  • Phenotype
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic
  • RNA Stability
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Time Factors
  • Toll-Like Receptor 8 / agonists
  • Toll-Like Receptor 8 / genetics*
  • Toll-Like Receptor 8 / immunology
  • Toll-Like Receptor 8 / metabolism
  • Transfection

Substances

  • Cytokines
  • NF-kappa B
  • RNA, Messenger
  • TLR8 protein, human
  • Toll-Like Receptor 8
  • DNA
  • Luciferases