IL6 gene allele-specific C/EBPα-binding activity affects the development of HBV infection through modulation of Th17/Treg balance

• Published in: Genes and immunity Vol. 16; no. 8; pp. 528 - 535
• Main Authors: Zhang, G, Wang, W, Li, S, Yang, H, Zhang, M, Zhang, P, Wen, Y, Wu, A, Yang, L, Zhou, B, Chen, X
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2015; Nature Publishing Group
• Subjects: 101/58; 13/21; 38; 38/109; 38/22; 38/44; 38/71; 38/77; 631/250/2499; 82/80; Alanine Transaminase - blood; Alleles; Antiviral agents; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; CCAAT-Enhancer-Binding Proteins - metabolism; CD14 antigen; Chronic infection; Complications and side effects; Core protein; Gene Expression; Gene polymorphism; Genetic aspects; Genetic polymorphisms; Genetic Predisposition to Disease; Helper cells; Hepatitis; Hepatitis B; Hepatitis B - genetics; Hepatitis B - immunology; Hepatitis B - pathology; Hepatitis B virus; Hepatitis C; Hepatitis C virus; HIV; HIV Infections - genetics; HIV Infections - immunology; Human Genetics; Human immunodeficiency virus; Humans; Immunology; Infections; Influence; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - immunology; Lentivirus; Liver diseases; Lymphocytes T; Monocytes; original-article; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Retroviridae; T-Lymphocytes, Regulatory - immunology; Th17 Cells - immunology; Viral Load; China
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2015.40

Interleukin-6 (IL-6) has an important role in the pathogenesis of chronic viral hepatitis and related liver diseases. Although host genetics associated with the response to anti-viral treatment have been reported, little is known about the relationship between IL6 genetic polymorphisms and the outcome of hepatitis B virus (HBV) infection. In this study, we determined the genotype distribution of rs1800796 polymorphism in healthy controls and cases including chronic HBV (CHB), hepatitis C virus and HIV infection. The rs1800796 was found to be associated with clinical outcome of CHB in experimental and validation cohort. The rs1800796C allele has twofold higher promoter activity than G allele. Consistently, CD14 + monocytes from subjects carrying the rs1800796C allele produced more IL-6 in response to in vitro HBV core antigen stimulation than those carrying G allele. Moreover, CHB patients carrying rs1800796C allele have significantly higher T-helper 17 (Th17) and regulatory T cell (Treg) ratio. Finally, a transcription factor C/EBPα binds in higher affinity to rs1800796C allele than to G allele. These results suggest that genetic predisposition to higher IL-6 production is associated with increased risk to HBV infection and hepatic inflammation, which might be due to C/EBPα-mediated regulatory effect on Th17 and Treg responses. Appropriate manipulation of IL-6 expression might be used to prevent and treat HBV infection.