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Am J Physiol Lung Cell Mol Physiol (April 23, 2004). doi:10.1152/ajplung.00039.2004
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Submitted on February 9, 2004
Accepted on April 21, 2004

Impaired nitric oxide synthase (NOS)2 signaling pathway in cystic fibrosis airway epithelium

Shuo Zheng1, Weiling Xu1, Santanu Bose2, Amiya K. Banerjee2, S. Jaharul Haque3, and Serpil C. Erzurum1*

1 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic, Cleveland, Ohio, USA; Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio, USA
2 Department of Virology, Cleveland Clinic, Cleveland, Ohio, USA
3 Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio, USA; Department of Pulmonary and Critical Care Medicine, Cleveland Clinic, Cleveland, Ohio, USA

* To whom correspondence should be addressed. E-mail: erzurus{at}ccf.org.

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 lack of NOS2 induction, the major histocompatibility complex, class 2 (MHCII), an IFN- {gamma} regulated delayed-responsive gene is similarly induced in CF and non-CF airway epithelial cells (NL), suggesting a NOS2 specific defect in the IFN-{gamma} signaling pathway. STAT1 and activator protein 1 (AP-1), both required for NOS2 gene expression, interact normally in CF cells. Protein inhibitor of activated STAT1 (PIAS1) is not increased in CF cells. Interferon-{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.




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