Abstract
Virus infection induces the production of type I interferons (IFNs). IFNs bind to their heterodimeric receptors to initiate downstream cascade of signaling, leading to the up-regulation of interferon-stimulated genes (ISGs). ISGs play very important roles in innate immunity through a variety of mechanisms. Although hundreds of ISGs have been identified, it is commonly recognized that more ISGs await to be discovered. The aim of this study was to identify new ISGs and to probe their roles in regulating virus-induced type I IFN production. We used consensus interferon (Con-IFN), an artificial alpha IFN that was shown to be more potent than naturally existing type I IFN, to treat three human immune cell lines, CEM, U937 and Daudi cells. Microarray analysis was employed to identify those genes whose expressions were up-regulated. Six hundred and seventeen genes were up-regulated more than 3-fold. Out of these 617 genes, 138 were not previously reported as ISGs and thus were further pursued. Validation of these 138 genes using quantitative reverse transcription PCR (qRT-PCR) confirmed 91 genes. We screened 89 genes for those involved in Sendai virus (SeV)-induced IFN-β promoter activation, and PIM1 was identified as one whose expression inhibited SeV-mediated IFN-β activation. We provide evidence indicating that PIM1 specifically inhibits RIG-I- and MDA5-mediated IFN-β signaling. Our results expand the ISG library and identify PIM1 as an ISG that participates in the regulation of virus-induced type I interferon production.
Highlights
Viral infection activates host innate immune response (Schneider et al, 2014)
We used consensus interferon (Con-IFN), an artificial alpha IFN that was shown to be more potent than naturally existing type I IFN, to treat three human immune cell lines, CEM, U937 and Daudi cells
We screened 89 genes for those involved in Sendai virus (SeV)-induced IFN-β promoter activation, and PIM1 was identified as one whose expression inhibited SeV-mediated IFN-β activation
Summary
Viral infection activates host innate immune response (Schneider et al, 2014). The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), RIG-I and melanoma differentiation-associated gene 5 (MDA5), are important to initiate innate immune in response to RNA virus invasion (Wilkins and Gale, 2010). Following recognition of viral RNAs, RLRs are recruited to an adaptor protein VISA ( known as MAVS, IPS-1 and Cardif), which further triggers TBK1/IKKε and IKKα/β kinases-mediated activation of IRF3 and NF-κB (Xu et al, 2005; Seth et al, 2005; Meylan et al, 2005; Kawai et al, 2005). These events lead to the induction of the expressions of type I IFNs and pro-inflammatory cytokines. Type II IFN, IFN-γ, signals through the IFN-γ receptor complex (IFNGR) (Pestka et al, 1997) and type III IFNs signal through IFN-λ receptor 1 or IL-10R2 (Kotenko et al, 2003)
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