Abstract
Abstract Respiratory virus infection is one of the leading causes of death in the world. Activation of the Jak-Stat pathway by Interferon-alpha/beta (IFN-α/β) in lung epithelial cells is critical for innate immunity to respiratory viruses. Transcriptional factor profiling in the transcriptome and RNA analysis revealed that Early growth response-1 (EGR1/Egr-1) was rapidly induced by IFN-α/β and Toll-like receptor (TLR) ligands in multiple cell types. Studies in mutant cell lines lacking components of the interferon-stimulated gene factor complex (ISGF-3) revealed that IFN-β induction of Egr-1 was independent of Stat1, Stat2, or Irf9. Activation of the Mek/Erk-1/2 pathway was implicated in the rapid induction of Egr-1 by IFN-β in serum-starved mouse lung epithelial cells. Interrogation of multiple microarray datasets revealed that respiratory viruses including coronaviruses induced IFN-β and regulated Egr-1 expression in human lung cell lines. Furthermore, bioinformatic analysis revealed that type I interferon-stimulated genes and Egr-1 inducible genes including transcription factors, mediators of cell growth, and chemokines were differentially regulated in the human lung cell lines after coronavirus infection, and in the lung biopsies of COVID-19 patients.
Highlights
Interferons (IFNs) are pleiotropic cytokines that play a central role in innate and adaptive immunity [1, 2]
Time-course experiments in bone marrow derived-macrophages (BMDM) revealed distinct Early growth response-1 (Egr-1) gene expression pro les for each treatment (Figures 3B-3D). These studies revealed that cytokines and Toll-like receptor (TLR) ligands use multiple and distinct signal transduction pathways to induce Egr-1 gene expression
Studies in mutant cells lacking Stat1 (U3A), Stat2 (U6A), and Irf9 (U2A) demonstrated that IFN-β induction of Egr-1 was independent of ISGF-3 components (Figure 4B)
Summary
Interferons (IFNs) are pleiotropic cytokines that play a central role in innate and adaptive immunity [1, 2]. Type I IFN signaling involves the binding of IFN-α/β to its receptor (IFNAR) and activation of receptor-associated Janus protein tyrosine kinases Jak and Tyk and the phosphorylation of Stat and Stat to form a heterodimer. This heterodimer associate with the Interferon responsive factor 9 (Irf9) to form the interferon-stimulated gene factor-3 (ISGF-3) complex on interferon-stimulated response elements (ISRE) in the promoters of type I IFN responsive genes to regulate transcription [1, 2, 4]. Stat homodimer or heterodimer of Stat1/Stat can bind to Gamma activated sequence (GAS) in the promoter and regulate transcription of
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