title: Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells.
abstract: BACKGROUND
  Human rhinovirus (HRV) infections trigger exacerbations of asthma and chronic obstructive pulmonary disease. Nitric oxide (NO) inhibits HRV replication in human airway epithelial cells and suppresses HRV-induced epithelial production of several cytokines and chemokines.
  
  
  OBJECTIVE
  We sought to delineate the mechanisms by which NO inhibits HRV-induced epithelial production of CXCL10, a chemoattractant for type 1 T cells and natural killer cells.
  
  
  METHODS
  Primary human bronchial epithelial cells or cells of the BEAS-2B human bronchial epithelial cell line were exposed to HRV-16 in the presence or absence of the NO donor 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPA NONOate). A cGMP analogue and an inhibitor of soluble guanylyl cyclase were used to examine the role of the cyclic guanosine monophosphate (cGMP) pathway in the actions of NO. BEAS-2B cells were transfected with CXCL10 promoter-luciferase constructs and the effects of PAPA NONOate were examined to study mechanisms of transcriptional regulation. Electrophoretic mobility shift assays were also used.
  
  
  RESULTS
  PAPA NONOate inhibited HRV-16-induced increases in CXCL10 mRNA and protein. Inhibition of CXCL10 production occurred through a cGMP-independent pathway. PAPA NONOate inhibited HRV-16-induced CXCL10 transcription by blocking nuclear translocation, binding, or both of both nuclear factor kappaB and IFN response factors (IRFs) to their respective recognition elements in the CXCL10 promoter.
  
  
  CONCLUSIONS
  NO inhibits HRV-16-induced production of CXCL10 by inhibiting viral activation of nuclear factor kappaB and of IRFs, including IRF-1, through a cGMP-independent pathway. The broad-ranging inhibition of HRV-induced epithelial cytokine and chemokine production by NO suggests a potential therapeutic utility of NO donors in viral exacerbations of asthma and chronic obstructive pulmonary disease.
authors.affiliation: Airway Inflammation Group, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Rommy
authors.initials: R
authors.lastname: Koetzler
authors.forename: Raza S
authors.initials: RS
authors.lastname: Zaheer
authors.forename: Shahina
authors.initials: S
authors.lastname: Wiehler
authors.forename: Neil S
authors.initials: NS
authors.lastname: Holden
authors.forename: Mark A
authors.initials: MA
authors.lastname: Giembycz
authors.forename: David
authors.initials: D
authors.lastname: Proud
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D001249:Asthma / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology*; D006152:Cyclic GMP / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology / Q000627:therapeutic use; D050856:Interferon Regulatory Factor-1 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D010850:Picornaviridae Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000821:virology; D020218:Response Elements / Q000276:immunology; D012229:Rhinovirus / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology*; D014775:Virus Activation / Q000187:drug effects / Q000276:immunology
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D006834:Hydrazines; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D020030:Nitric Oxide Donors; C112653:PAPA NONOate; D009569:Nitric Oxide; D006152:Cyclic GMP