NFκB Negatively Regulates Interferon-induced Gene Expression and Anti-influenza Activity*

Interferons (IFNs) are antiviral cytokines that selectively regulate gene expression through several signaling pathways including nuclear factor κB(NFκB). To investigate the specific role of NFκB in IFN signaling, we performed gene expression profiling after IFN treatment of embryonic fibroblasts derived from normal mice or mice with targeted deletion of NFκB p50 and p65 genes. Interestingly, several antiviral and immunomodulatory genes were induced higher by IFN in NFκB knock-out cells. Chromatin immunoprecipitation experiments demonstrated that NFκB was basally bound to the promoters of these genes, while IFN treatment resulted in the recruitment of STAT1 and STAT2 to these promoters. However, in NFκB knock-out cells IFN induced STAT binding as well as the binding of the IFN regulatory factor-1 (IRF1) to the IFN-stimulated gene (ISG) promoters. IRF1 binding closely correlated with enhanced gene induction. Moreover, NFκB suppressed both antiviral and immunomodulatory actions of IFN against influenza virus. Our results identify a novel negative regulatory role of NFκB in IFN-induced gene expression and biological activities and suggest that modulating NFκB activity may provide a new avenue for enhancing the therapeutic effectiveness of IFN.

[1]  M. Holtzman,et al.  Modification of the Stat1 SH2 Domain Broadly Improves Interferon Efficacy in Proportion to p300/CREB-binding Protein Coactivator Recruitment*♦ , 2005, Journal of Biological Chemistry.

[2]  R. Webster,et al.  Neuraminidase Inhibitor-Rimantadine Combinations Exert Additive and Synergistic Anti-Influenza Virus Effects in MDCK Cells , 2004, Antimicrobial Agents and Chemotherapy.

[3]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[4]  L. Staudt,et al.  Active NF-kappaB signalling is a prerequisite for influenza virus infection. , 2004, The Journal of general virology.

[5]  D. J. Carrigan,et al.  Role of Nuclear Factor-κB in the Antiviral Action of Interferon and Interferon-regulated Gene Expression* , 2004, Journal of Biological Chemistry.

[6]  B. Domon,et al.  Expression, purification, and characterization of rat interferon-beta, and preparation of an N-terminally PEGylated form with improved pharmacokinetic parameters. , 2004, Protein expression and purification.

[7]  A. Sher,et al.  p47 GTPases: regulators of immunity to intracellular pathogens , 2004, Nature Reviews Immunology.

[8]  Douglas A. Hosack,et al.  Identifying biological themes within lists of genes with EASE , 2003, Genome Biology.

[9]  Christopher K. Glass,et al.  Exchange of N-CoR Corepressor and Tip60 Coactivator Complexes Links Gene Expression by NF-κB and β-Amyloid Precursor Protein , 2002, Cell.

[10]  S. Vidal,et al.  Functional diversity of Mx proteins: variations on a theme of host resistance to infection. , 2002, Genome research.

[11]  P. Pitha,et al.  On the role of IRF in host defense. , 2002, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[12]  Jonathan W. Yewdell,et al.  A novel influenza A virus mitochondrial protein that induces cell death , 2001, Nature Medicine.

[13]  M. Karin,et al.  Inhibition of JNK activation through NF-κB target genes , 2001, Nature.

[14]  Francesca Zazzeroni,et al.  Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling , 2001, Nature.

[15]  L. Pfeffer,et al.  Interferon α/β Promotes Cell Survival by Activating Nuclear Factor κB through Phosphatidylinositol 3-Kinase and Akt* , 2001, The Journal of Biological Chemistry.

[16]  L. Pfeffer,et al.  IFNα/β promotes cell survival by activating NF-κB , 2000 .

[17]  J. Altman,et al.  A Previously Unrecognized H-2Db-Restricted Peptide Prominent in the Primary Influenza A Virus-Specific CD8+T-Cell Response Is Much Less Apparent following Secondary Challenge , 2000, Journal of Virology.

[18]  J. Carton,et al.  Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. , 1999, Virology.

[19]  G. Kochs,et al.  Mx proteins: mediators of innate resistance to RNA viruses. , 1998, Revue scientifique et technique.

[20]  J. Darnell,et al.  The state of the STATs: recent developments in the study of signal transduction to the nucleus. , 1997, Current opinion in cell biology.

[21]  B. Barber,et al.  Presentation of an influenza nucleoprotein epitope incorporated into the H-2Db signal sequence requires the transporter-associated with antigen presentation. , 1997, Journal of immunology.

[22]  David Baltimore,et al.  An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death , 1996, Science.

[23]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[24]  R. Pine,et al.  Constitutive expression of an ISGF2/IRF1 transgene leads to interferon-independent activation of interferon-inducible genes and resistance to virus infection , 1992, Journal of virology.