Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the IFNL4 gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable in vitro from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4 This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans.IMPORTANCE Recent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the IFNL4 gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the IFNL4 gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the IFNL4 gene and found it to be poorly induced by viral infections. A thorough investigation of the IFNL4 promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the IFNL4 gene is related to its noncanonical transcriptional regulation.

中文翻译：

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IFNL4基因是具有独特但在进化上保守的调控的非经典干扰素基因。

干扰素λ4（IFN-λ4）是最近发现的干扰素（IFN）λ家族的神秘成员。遗传数据表明，IFNL4基因在患者中以前病毒和抗炎的方式起作用。但是，该蛋白在体外与干扰素λ家族的其他成员没有区别。我们已经详细研究了IFNL4的基因调控，发现它与典型的抗病毒干扰素完全不同。被病毒感染诱导是干扰素的定义特征，但是病毒感染或干扰素调节因子（IRF）转录因子家族成员的过表达仅导致IFNL4的微小诱导。这种行为在进化上是保守的，可以通过插入来逆转一个功能性IRF3结合位点进入IFNL4启动子。从而，IFNL4基因的调控有根本不同，可能解释了人类中与IFNL4基因相关的一些非典型表型。重要的最新遗传证据突出了IFNL4基因如何以违反直觉的方式起作用，因为具有无功能IFNL4基因的患者表现出增加清除丙型肝炎病毒（HCV）还会增加肝脏炎症。这表明IFNL4基因以前病毒和抗炎的方式起作用。这些令人惊讶但非常清楚的遗传数据促使人们对IFNL4基因及其基因产物干扰素λ4（IFN-λ4）的基本特征进行了广泛的研究。我们已经研究了IFNL4基因的表达，发现它被病毒感染诱导较弱。对IFNL4启动子的彻底研究表明，它是一种高度保守且功能强大的启动子，但也缺乏干扰素（IFN）的定义特征，即不能被病毒感染有效诱导的启动子。我们建议，IFNL4基因的独特功能与其非规范的转录调控有关。