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Am J Physiol Lung Cell Mol Physiol 287: L374-L381, 2004. First published April 23, 2004; doi:10.1152/ajplung.00039.2004
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Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium

Shuo Zheng,1 Weiling Xu,1 Santanu Bose,2 Amiya K. Banerjee,2 S. Jaharul Haque,1 and Serpil C. Erzurum1,2

1Departments of Pulmonary and Critical Care Medicine, Cancer Biology, and 2Virology, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, Ohio 44195

Submitted 9 February 2004 ; accepted in final form 21 April 2004

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.

IFN-{gamma}-inducible factor; antiviral host defense; signal transducer and activator of transcription 1


Address for reprint requests and other correspondence: S. C. Erzurum, Lung Biology Program, Cleveland Clinic Foundation, Lerner Research Inst., 9500 Euclid Ave/NB40, Cleveland, OH 44195 (E-mail erzurus{at}ccf.org)




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