The role of transposable elements in the regulation of IFN-[lambda]1 gene expression

IFNs [lambda]1, [lambda]2, and [lambda]3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-[beta] gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-[lambda] gene expression. Studies of virus induction of IFN-[lambda]1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-[lambda]1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-[kappa]B binding sites. Remarkably, these sites, which bind efficiently to NF-[kappa]B and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-[kappa]B RelA protein significantly reduces the level of the IFN-[lambda]1 gene expression. We conclude that IFN-[lambda]1 gene expression requires NF-[kappa]B, and we propose a model for IFN-[lambda]1 gene regulation, in which IRF and NF-[kapppa]B activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-[lambda]1 and IFN-[beta] promoters and directly implicate transposable elements in the regulation of the IFN-[lambda]1 gene by NF-[kappa]B. gene regulation | interferon | transcription enhancer | NF-[kappa]B | Alu repeats