Alternative and Accessory Pathways in the Regulation of IFN-β-Mediated Gene Expression

Abstract

Type I interferons (IFNs) induce the transcription of IFN-stimulated genes (ISGs) through activation of the Jak-Stat pathway. Although some determinants of specificity are dictated by the Jak-Stat components, recent observations indicate that the system incorporates other components for selectivity and flexibility, whose mechanisms remain to be defined. We identified a gene, β-R1, which was induced relatively selectively by IFN-β as compared with numerous IFN-α subtypes. Because all type I IFNs equally activate Jak-Stat signaling to IFN-stimulated gene factor 3 (ISGF3), this observation implied the existence of accessory signals for IFN-induced gene expression. We have used β-R1 as a model system to examine this accessory signaling. In addition to Jak-Stat signaling for mediating IFN-induced cellular responses, p38 mitogen-activated protein kinase(p38 MAPK), phosphoinositol 3-kinase (PI3K), the IκB kinases (IKKs), and nuclear factor-κB (NF-κB) are some of the accessory components identified as required for the induction of certain IFN-β-induced genes. This review focuses on the roles of accessory components in IFN-β-mediated signaling, mechanisms of accessory signal generation, and how they modulate gene induction.