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Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells.
J Allergy Clin Immunol 2009; 123(1):201-208.e9JA

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.

Authors+Show Affiliations

Airway Inflammation Group, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18986693

Citation

Koetzler, Rommy, et al. "Nitric Oxide Inhibits Human Rhinovirus-induced Transcriptional Activation of CXCL10 in Airway Epithelial Cells." The Journal of Allergy and Clinical Immunology, vol. 123, no. 1, 2009, pp. 201-208.e9.
Koetzler R, Zaheer RS, Wiehler S, et al. Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells. J Allergy Clin Immunol. 2009;123(1):201-208.e9.
Koetzler, R., Zaheer, R. S., Wiehler, S., Holden, N. S., Giembycz, M. A., & Proud, D. (2009). Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells. The Journal of Allergy and Clinical Immunology, 123(1), pp. 201-208.e9. doi:10.1016/j.jaci.2008.09.041.
Koetzler R, et al. Nitric Oxide Inhibits Human Rhinovirus-induced Transcriptional Activation of CXCL10 in Airway Epithelial Cells. J Allergy Clin Immunol. 2009;123(1):201-208.e9. PubMed PMID: 18986693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells. AU - Koetzler,Rommy, AU - Zaheer,Raza S, AU - Wiehler,Shahina, AU - Holden,Neil S, AU - Giembycz,Mark A, AU - Proud,David, Y1 - 2008/11/04/ PY - 2008/07/01/received PY - 2008/08/25/revised PY - 2008/09/29/accepted PY - 2008/11/7/pubmed PY - 2009/1/28/medline PY - 2008/11/7/entrez SP - 201 EP - 208.e9 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 123 IS - 1 N2 - 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. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/18986693/Nitric_oxide_inhibits_human_rhinovirus_induced_transcriptional_activation_of_CXCL10_in_airway_epithelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(08)01738-7 DB - PRIME DP - Unbound Medicine ER -