Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-{kappa}B

Tacon, Claire E., Wiehler, Shahina, Holden, Neil S. , Newton, Robert, Proud, David and Leigh, Richard (2010) Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-{kappa}B. American Journal of Respiratory Cell and Molecular Biology, 43 (2). pp. 201-209. ISSN 1044-1549

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Human rhinovirus (HRV) infections up-regulate proinflammatory mediators and growth factors that are associated with exacerbations of inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Matrix metalloproteinase (MMP)-9 was shown to be increased in the airways of patients with asthma and COPD. We sought to determine whether HRV infection modulated the expression of MMP-9 and its highest-affinity inhibitor, the tissue inhibitor of metalloproteinase (TIMP)-1, and we explored the mechanism by which this modulation occurs. In vitro studies, using RT-PCR, ELISA, zymography, and a fluorescent activity assay, demonstrated that MMP-9 mRNA, protein, and activity were increased upon infection with HRV, whereas TIMP-1 mRNA and protein remained unchanged. These results were verified in vivo, using nasal lavage samples obtained from subjects with confirmed rhinovirus infections. Human rhinovirus infections were shown to up-regulate NF-kappaB, and NF-kappaB has also been reported to play a role in the expression of MMP-9. We therefore investigated the role of NF-kappaB in HRV-induced MMP-9 expression. Using two inhibitors of IkappaBalpha kinase beta, we observed a concentration-dependent decrease in HRV-induced MMP-9 expression. The role of NF-kappaB in HRV-induced MMP-9 expression was further confirmed using MMP-9 promoter luciferase constructs, which demonstrated that an NF-kappaB site at -620/-607 base pairs was necessary for HRV-induced MMP-9 expression. Electrophoretic mobility shift assays and supershift assays confirmed the nuclear translocation and binding of p50/p65 NF-kappaB subunits to an MMP-9-specific NF-kappaB oligonucleotide. This increase in MMP-9 may be a mechanism by which rhinovirus infections contribute to airway inflammation and, potentially, to airway remodeling.

Additional Information:Accepted August 27, 2009
Keywords:Matrix metalloproteinase-9, Airway epithelial cell, Airway remodeling, Airway inflammation, Human rhinovirus
Subjects:B Subjects allied to Medicine > B132 Pathobiology
Divisions:College of Science > School of Life Sciences
ID Code:15121
Deposited On:18 Nov 2014 16:39

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