TLR7 and TLR8 gene variations and susceptibility to hepatitis C virus infection.
Toll-like receptors (TLRs) play pivotal roles in the innate immune system and control inflammatory responses and adaptive immunity. We previously evaluated associations between TLR7 and TLR8 gene SNPs and susceptibility to hepatitis C virus (HCV) infection. Our results suggested that TLR7IVS2-151G and TLR8-129G alleles were present at higher frequency in males of an HCV-infected group as compared to a control group (24.1% vs. 14.4%, p = 0.028; 17.6% vs. 6.8%, p = 0.004, respectively). Based upon their recognition of single stranded viral RNA, this suggested that TLR7 and TLR8 played a significant role in anti-HCV immune responses. Here, we studied the functional effects of these polymorphisms by analyzing the mRNA expressions of TLR7 and TLR8 and cytokine production induced ex vivo by TLR7- and TLR8-specific agonists using whole blood of subjects with different genotypes. The percentage of CD14+ cells from those with an AG haplotype that expressed TLR7 and TLR8 was significantly lower, but higher in intensity compared to cells from those with GG and AC haplotypes. Cells from those with an AG haplotype produced more IFN-α and less amounts of pro-inflammatory cytokines upon stimulation. This suggests that variations in TLR7 and TLR8 genes might impair immune responses during HCV infection.
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chiou-Huey
CH
Wang
Hock-Liew
HL
Eng
Kuei-Hsiang
KH
Lin
Cheng-Hsien
CH
Chang
Chi-An
CA
Hsieh
Yen-Li
YL
Lin
Tsun-Mei
TM
Lin
D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000235:genetics*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
D016207:Cytokines; D012333:RNA, Messenger; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8