Alternative and accessory pathways in the regulation of IFN-beta-mediated gene expression.
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, beta-R1, which was induced relatively selectively by IFN-beta as compared with numerous IFN-alpha 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 beta-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 IkappaB kinases (IKKs), and nuclear factor-kappaB (NF-kappaB) are some of the accessory components identified as required for the induction of certain IFN-beta-induced genes. This review focuses on the roles of accessory components in IFN-beta-mediated signaling, mechanisms of accessory signal generation, and how they modulate gene induction.
Rani
M R Sandhya
MR
Department of Neurosciences/NC30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Ransohoff
Richard M
RM
D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016328:NF-kappa B; D017471:Receptors, Interferon; D050791:STAT Transcription Factors; D016899:Interferon-beta; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases