Integrative genomic analyses on IL28RA, the common receptor of interferon-λ1, -λ2 and -λ3

Abstract

Abstract. Interferon (IFN)-Ïs, including INF-Ï1, -Ï2, and -Ï3, are a newly described group of cytokines distantly related to the type I IFNs and IL-10 family members. IFN-Ï1, -Ï2, and -Ï3 bind to the same receptor (known as IL28RA) to exert their antiviral, antitumor and immunomodulatory effects. Here, we identified IL28RA genes from the genome of human, chimpanzee, macaque, orangutan, mouse, horse, rat, dog, chicken, and found that only one IL28RA existed in each genome. All the identified IL28RAs are single-pass type I membrane proteins except chicken IL28RA. They belong to the type II cytokine receptor family and contain one fibronectin type-III domain. We found human IL28RA was expressed in lymphs, testes, lymphoma, teratocarcinoma, pediatric pre-B cell acute lymphoblastic leukemia, germinal center B cells, embryonic stem cells, fetal lung, and also expressed in bladder, blood and breast cancers, glioma, head and neck cancer and lung cancer tissues. Three tumor-related transcriptional factor binding sites (AP-2, c-Jun and P53) were identified within the 1.0-kb regions upstream of the transcriptional start site of human IL28RA. Meta-analysis of the prognostic value of IL28RA genes in various cancers found that the expression of IL28RA was indeed related to the cancer prognosis in certain cancers. The STAT1 binding sites in the promoter region of IL28RA implied a specific mechanism for the amplifying effects of IFN-Ïs. The LyF-1 binding sites in the promoter region of IL28RA imply that IFN-Ïs were involved in the differentiation of early B and T cells.

Dr Jekyll and Mr Hyde: From Two Branches of Immune Response to Three Types of Interferon Response

“…In 2010 this was clarified further when genomic analysis showed one gene for IL10RA (IFNLR1) was common to many animals including humans, monkeys, mice, horses and chickens. The gene transcript was subsequently found to be expressed by LNs, testis, but also by germinal centre B cells and in various types of cancer (lymphoma, acute lymphoblastic leukaemia, head and neck cancer); but expressed at high concentrations within tissue like the pancreas (thyroid, skeletal muscle, and heart tissues) indicating these could respond to type III IFN synthesis [195]. Interestingly, authors postulated that the three important adaptive arms of the immune system responsive were NK cells, and TC cells, through promoting the other phenotype by evoking a TH1 cellular response [195].…”

“…During early 2011 research, a gene regulator of B/T cell differentiation (LyF) was described as having a transcriptional binding site within the IFNLR1 domain encoding for one part of the type III IFN receptor. Furthermore, the activator protein 2 (AP-2), c-Jun and a p53 binding site within 1kb of the start of the transcription sequence on IFNLR1 in humans was described [195]. Conversely, the first report appeared after evidencing the other key gene transcript for type I IFN synthesis, ISG56, as well as RIG-I induced by synthetic IFN-λ2 in vitro in P. alecto bats [196].…”