Abstract 3751: Expression analysis of the IL28A, IL28B, IL29 and IL28L genes in primary human peripheral blood mononuclear cells and hepatocytes: Effects of activation mode, time-course and genotypes

Abstract

Abstract Expression analysis of the IL28A, IL28B, IL29 and IL28L genes in primary human peripheral blood mononuclear cells and hepatocytes: Effects of activation mode, time-course and genotypes. Chronic hepatitis C virus (HCV) infection is the leading cause of liver cancer and liver transplantation in the United States. Recently, several genome-wide association studies (GWAS) identified genetic variants within the IL28A/B locus on chromosome 19q13.2 as the strongest predictors of outcome of HCV infection and response to treatment (e.g. rs12980275, p=2.84×10-27, OR=17.7; 95% CI=10.0-31.3, Tanaka, Nat. Gen. 2009). This region harbors the highly homologous IL29, IL28A, IL28B genes and a pseudogene IL28-like (IL28L), also known as interferon-lambda-1, interferon-lambda-2, interferon-lambda-3 and interferon-lambda-4-pseudo, respectively. We hypothesized that the associated genetic variants might affect mRNA expression of one or more of these genes. We performed mRNA expression analysis of IL28A, IL28B, IL29 and IL28L in human peripheral blood mononuclear cells (PBMCs) and primary hepatocytes using highly specific custom-designed assays to overcome the up to 97% sequence homology between these genes. In PBMCs and hepatocytes, mRNA transcripts were not expressed under baseline conditions, but activation of these cells with IFN-alpha or IFN-lambda did moderately induce expression of some transcripts after 24 hours of activation. However, when IL28A, IL28B, IL29 and IL28L were activated with the immunostimulant poly I:C, a Toll-like receptor-3 agonist that mimics infection by RNA viruses, expression of all transcripts was strongly increased. Gene expression was measured at 0, 1, 2, 4, 8 and 24 hours and was compared to the 2-hour point, at which expression was first stably seen. We observed a suggestive association between time-specific activation of all transcripts and genetic variants correlated with HCV infection and treatment outcome. In hepatocytes, mRNA levels of all transcripts were increased in carriers of risk alleles associated with poor treatment outcome at 24 hours compared to 2 hours (60-fold for IL28A, 85-fold for IL28B, 222-fold for IL29 and 5-fold for IL28L) suggesting that under certain circumstances increased baseline interferon production in carriers of risk variants could be deleterious. The clinical relevance of our in vitro findings should be validated by similar studies in primary liver and blood samples derived from HCV-infected individuals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3751. doi:10.1158/1538-7445.AM2011-3751