Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium.
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.
Zheng
Shuo
S
Department of Pulmonary and Critical Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Xu
Weiling
W
Bose
Santanu
S
Banerjee
Amiya K
AK
Haque
S Jaharul
SJ
Erzurum
Serpil C
SC
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
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