title: Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium.
abstract: Cystic fibrosis (CF) airway epithelial cells are more susceptible to viral infection due to impairment of the innate host defense pathway of nitric oxide (NO). NO synthase-2 (NOS2) expression is absent, and signal transducer and activator of transcription (STAT) 1 activation is reduced in CF. We hypothesized that the IFN-gamma signaling pathway, which leads to NOS2 gene induction in CF airway epithelial cells, is defective. In contrast to a lack of NOS2 induction, the major histocompatibility complex class 2, an IFN-gamma-regulated delayed-responsive gene, is similarly induced in CF and non-CF airway epithelial (NL) cells, suggesting an NOS2-specific defect in the IFN-gamma signaling pathway. STAT1 and activator protein-1, both required for NOS2 gene expression, interact normally in CF cells. Protein inhibitor of activated STAT1 is not increased in CF cells. IFN-gamma induces NOS2 expression in airway epithelial cells through an autocrine mechanism involving synthesis and secretion of IFN-gamma-inducible mediator(s), which activates STAT1. Here, CF cells secrete IFN-gamma-inducible factor(s), which stimulate NOS2 expression in NL cells, but not in CF cells. In contrast, IFN-gamma-inducible factor(s) similarly inhibit virus in CF and NL cells. Thus autocrine activation of NOS2 is defective in CF cells, but IFN-gamma induction of antiviral host defense is intact.
authors.affiliation: Department of Pulmonary and Critical Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Zheng
authors.forename: Weiling
authors.initials: W
authors.lastname: Xu
authors.forename: Santanu
authors.initials: S
authors.lastname: Bose
authors.forename: Amiya K
authors.initials: AK
authors.lastname: Banerjee
authors.forename: S Jaharul
authors.initials: SJ
authors.lastname: Haque
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar; D000970:Antineoplastic Agents / Q000494:pharmacology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008175:Lung Neoplasms; D011401:Promoter Regions, Genetic / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; D029742:Caenorhabditis elegans Proteins; D017077:Culture Media, Conditioned; D000949:Histocompatibility Antigens Class II; C400703:nos-2 protein, C elegans; D007371:Interferon-gamma