Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells

Koetzler, Rommy and Zaheer, Raza S. and Wiehler, Shahina and Holden, Neil S. and Giembycz, Mark A. and Proud, David (2009) Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells. The Journal of Allergy and Clinical Immunology, 123 (1). 201-208.e9. ISSN 0091-6749

Full content URL: http://dx.doi.org/10.1016/j.jaci.2008.09.041

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Item Type:Article
Item Status:Live Archive

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.

Additional Information:Published online: November 5, 2008
Keywords:Human rhinovirus, asthma, airway epithelial cell, CXCL10, IFN-?–inducible protein of 10 kd, nitric oxide, IFN response factors, nuclear factor ?B
Subjects:B Subjects allied to Medicine > B990 Subjects Allied to Medicine not elsewhere classified
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
C Biological Sciences > C500 Microbiology
Divisions:College of Science > School of Life Sciences
ID Code:15136
Deposited On:21 Oct 2014 15:15

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