Human rhinovirus-induced epithelial production of CXCL10 is dependent upon IFN regulatory factor-1.

Human rhinovirus (HRV) infections are associated with exacerbations of lower-airway diseases. HRV-induced production of proinflammatory chemokines, such as CXCL10, from infected airway epithelial cells may play a role in the pathogenesis of exacerbations. We have previously shown that the MAP/ERK kinase (MEK) pathway selectively down-regulates HRV-16-induced epithelial production of CXCL10 by modulating nuclear translocation and/or binding of IFN regulatory factor (IRF)-1 with the CXCL10 promoter. Using primary human bronchial epithelial cells (HBEs) and the BEAS-2B bronchial epithelial cell line, we have further evaluated the role of IRF-1 in HRV-16-induced epithelial CXCL10 production. We demonstrate that HRV-16 induced the expression of both IRF-1 mRNA and protein in a time-dependent manner. Interestingly, MEK1 pathway inhibition with PD98059 or U0126 significantly enhanced HRV-16-induced IRF-1 mRNA levels in BEAS-2B cells and HBEs, although IRF-1 protein expression was only enhanced in HBEs. Using short interfering RNA (siRNA), we both inhibited HRV-16-induced IRF-1 expression and reduced nuclear translocation and/or binding of IRF-1 to the CXCL10 promoter. Knockdown of IRF-1 also led to a significant reduction in HRV-16-induced CXCL10 production, confirming that IRF-1 is directly involved in HRV-16-induced CXCL10 expression in epithelial cells. Moreover, pronounced IRF-1 knockdown abrogated the enhancement of CXCL10 normally induced by inhibitors of the MEK1 pathway. Phosphatase experiments indicate that IRF-1 binding to the CXCL10 promoter is not dependent upon its phosphorylation state. We conclude that HRV-16-induced CXCL10 production is dependent upon IRF-1, and that the MEK1 pathway-dependent suppression of CXCL10 expression is also mediated via effects on IRF-1.

[1]  D. Proud,et al.  Selective Transcriptional Down-Regulation of Human Rhinovirus-Induced Production of CXCL10 from Airway Epithelial Cells via the MEK1 Pathway 1 , 2009, The Journal of Immunology.

[2]  D. Proud,et al.  Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells. , 2009, The Journal of allergy and clinical immunology.

[3]  R. Garofalo,et al.  Cigarette smoke condensate enhances respiratory syncytial virus-induced chemokine release by modulating NF-kappa B and interferon regulatory factor activation. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[4]  W. Busse,et al.  Host immune responses to rhinovirus: mechanisms in asthma. , 2008, The Journal of allergy and clinical immunology.

[5]  Kyoungsook Park,et al.  Elevated level of SUMOylated IRF-1 in tumor cells interferes with IRF-1-mediated apoptosis , 2007, Proceedings of the National Academy of Sciences.

[6]  D. Proud,et al.  Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[7]  S. Johnston,et al.  IFN-γ–induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations , 2007, Journal of Allergy and Clinical Immunology.

[8]  B. Celli,et al.  Exacerbations of chronic obstructive pulmonary disease , 2007, European Respiratory Journal.

[9]  D. Proud,et al.  Viral-associated exacerbations of asthma and COPD , 2007, Current Opinion in Pharmacology.

[10]  E. May,et al.  Single-stranded RNA viruses inactivate the transcriptional activity of p53 but induce NOXA-dependent apoptosis via post-translational modifications of IRF-1, IRF-3 and CREB , 2007, Oncogene.

[11]  W. Teague,et al.  Prevalence of viral respiratory tract infections in children with asthma , 2006, Journal of Allergy and Clinical Immunology.

[12]  P. Österlund,et al.  TNF-α and IFN-α enhance influenza-A-virus-induced chemokine gene expression in human A549 lung epithelial cells , 2006 .

[13]  K. Melén,et al.  TNF-alpha and IFN-alpha enhance influenza-A-virus-induced chemokine gene expression in human A549 lung epithelial cells. , 2006, Virology.

[14]  Xiaojing Ma,et al.  Interferon Regulatory Factor 1 Is an Essential and Direct Transcriptional Activator for Interferon γ-induced RANTES/CCl5 Expression in Macrophages* , 2005, Journal of Biological Chemistry.

[15]  D. Proud,et al.  Human airway epithelial cells produce IP-10 (CXCL10) in vitro and in vivo upon rhinovirus infection. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[16]  N. Siafakas,et al.  Changes in sputum T-lymphocyte subpopulations at the onset of severe exacerbations of chronic obstructive pulmonary disease. , 2005, Respiratory medicine.

[17]  W. Busse,et al.  Quantitative and qualitative analysis of rhinovirus infection in bronchial tissues. , 2005, American journal of respiratory and critical care medicine.

[18]  D. Graham,et al.  Role of interferon-stimulated responsive element-like element in interleukin-8 promoter in Helicobacter pylori infection. , 2004, Gastroenterology.

[19]  J. Hiscott,et al.  A role for casein kinase II phosphorylation in the regulation of IRF-1 transcriptional activity , 2004, Molecular and Cellular Biochemistry.

[20]  R. Atmar,et al.  Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. , 2003, American journal of respiratory and critical care medicine.

[21]  H. Yokosawa,et al.  PIAS3 induces SUMO‐1 modification and transcriptional repression of IRF‐1 , 2002, FEBS letters.

[22]  B. Medoff,et al.  IFN-γ-Inducible Protein 10 (CXCL10) Contributes to Airway Hyperreactivity and Airway Inflammation in a Mouse Model of Asthma1 , 2002, The Journal of Immunology.

[23]  W. Busse,et al.  Similar frequency of rhinovirus-infectible cells in upper and lower airway epithelium. , 2002, The Journal of infectious diseases.

[24]  Y. Seo,et al.  Tumour necrosis factor-alpha and interferon-gamma synergistically activate the RANTES promoter through nuclear factor kappaB and interferon regulatory factor 1 (IRF-1) transcription factors. , 2000, The Biochemical journal.

[25]  M. Matthay,et al.  Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance. , 2000, American journal of respiratory and critical care medicine.

[26]  H. Yokosawa,et al.  Degradation of transcription factor IRF-1 by the ubiquitin-proteasome pathway. The C-terminal region governs the protein stability. , 2000, European journal of biochemistry.

[27]  S. Johnston,et al.  Asthma and natural colds. Inflammatory indices in induced sputum: a feasibility study. , 1998, American journal of respiratory and critical care medicine.

[28]  D. Proud,et al.  Nitric Oxide Inhibits Rhinovirus-Induced Cytokine Production and Viral Replication in a Human Respiratory Epithelial Cell Line , 1998, Journal of Virology.

[29]  M. Shin,et al.  Induction of IP-10 chemokine promoter by measles virus: comparison with interferon-γ shows the use of the same response element but with differential DNA–protein binding profiles , 1997, Journal of Neuroimmunology.

[30]  E. Petricoin,et al.  Phosphorylation Events Modulate the Ability of Interferon Consensus Sequence Binding Protein to Interact with Interferon Regulatory Factors and to Bind DNA* , 1997, The Journal of Biological Chemistry.

[31]  W. Busse,et al.  Rhinovirus enters but does not replicate inside monocytes and airway macrophages. , 1996, Journal of immunology.

[32]  D. Proud,et al.  Infection of a human respiratory epithelial cell line with rhinovirus. Induction of cytokine release and modulation of susceptibility to infection by cytokine exposure. , 1995, The Journal of clinical investigation.

[33]  T. Taniguchi,et al.  Activation of IFN-beta element by IRF-1 requires a posttranslational event in addition to IRF-1 synthesis. , 1991, Nucleic acids research.

[34]  J. Darnell,et al.  Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either , 1990, Molecular and cellular biology.

[35]  T. Taniguchi,et al.  Induction of the transcription factor IRF-1 and interferon-beta mRNAs by cytokines and activators of second-messenger pathways. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Takashi Miyata,et al.  Structurally similar but functionally distinct factors, IRF-1 and IRF-2, bind to the same regulatory elements of IFN and IFN-inducible genes , 1989, Cell.

[37]  J. Resau,et al.  Cyclooxygenase metabolism of endogenous arachidonic acid by cultured human tracheal epithelial cells. , 1989, The American review of respiratory disease.