Selective transcriptional down-regulation of human rhinovirus-induced production of cxcl10 in airway epithelian cells via mek1 pathway effects on interferon regulatory factor-1

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dc.contributor.advisorProud, David
dc.contributor.authorZaheer, Raza Syed
dc.date.accessioned2017-12-18T22:05:45Z
dc.date.available2017-12-18T22:05:45Z
dc.date.issued2010
dc.descriptionBibliography: p. 187-225en
dc.description.abstractHuman rhinovirus (HRV) infections can trigger exacerbations of lower airway diseases. Infection of airway epithelial cells induces production of a number of pro-inflammatory chemokines that may exacerbate airway inflammation, including interferony-inducible protein of lOkDa (CXCLIO), a chemoattractant for type 1 lymphocytes and Natural Killer cells. Primary human bronchial epithelial (HBE) cells and the BEAS-2B human bronchial epithelial cell line were used to examine the role of the mitogen-activated protein kinase (MAPK) pathways in HRV-16-induced production of CXCLlO. Infection with HRV-16 induced the activation of the major MAPK pathways, including chronic activation of ERKl/2. Inhibitors of the MEKl/2 pathway, PD98059 and U0126, significantly enhanced HRV-16, but not interferon (IFN)-~, induced production of CXCLIO mRNA and protein. Inhibitor effects were not due to changes in cell viability or viral replication. Studies using siRNA revealed that knockdown of MEKl was primarily associated with the enhancement of HRV-16-induced CXCLlO production. Promoter construct studies revealed that PD98059 and UO 126 enhanced HR V -16-induced transcriptional activation of CXCLlO. Inhibitors of the MEKl/2 pathway did not alter NF-KB translocation and/or binding to the CXCLlO promoter. In contrast, inhibitors of the MEKl/2 pathway and siRNA knockdown of MEKl enhanced translocation and/or binding of HRV-16-induced IFN regulatory factor (IRF)-1 to the CXCLlO promoter. Further examination revealed that HRV -16 induced the expression of both IRF-1 mRN A and protein in a time-dependent manner. Both PD98059 and U0126 significantly enhanced HRV-16-induced IRF-1 mRNA levels in BEAS-2B and HBE, although IRF-1 protein expression was only enhanced in HBE. Using siRNA targeting IRF-1 , both HRV-16-induced IRF-1 expression and nuclear translocation and/or binding of IRF-1 to the CXCLlO promoter was substantially reduced. Knockdown of IRF-1 also led to a significant reduction in HRV-16-induced CXCLlO production, confirming that IRF-1 is directly involved in HRV-16-induced CXCLlO expression. Moreover, pronounced IRF- 1 knockdown abrogated the enhancement of CXCLlO normally induced by the loss of MEKl function. Phosphatase experiments indicate that IRF-1 binding to the CXCLlO promoter may not be dependent upon its phosphorylation state. In conclusion, these studies demonstrate that activation of MEKl selectively down-regulates HRV-16- induced expression of CXCLlO by modulating IRF-1 interactions with the gene promoter in human airway epithelial cells.
dc.format.extentxx, 227 leaves : ill. ; 30 cm.en
dc.identifier.citationZaheer, R. S. (2010). Selective transcriptional down-regulation of human rhinovirus-induced production of cxcl10 in airway epithelian cells via mek1 pathway effects on interferon regulatory factor-1 (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/3417en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/3417
dc.identifier.urihttp://hdl.handle.net/1880/104418
dc.language.isoeng
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.titleSelective transcriptional down-regulation of human rhinovirus-induced production of cxcl10 in airway epithelian cells via mek1 pathway effects on interferon regulatory factor-1
dc.typedoctoral thesis
thesis.degree.disciplineCardiovascular & Respiratory Sciences
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
ucalgary.thesis.accessionTheses Collection 58.002:Box 1981 627942824
ucalgary.thesis.notesUARCen
ucalgary.thesis.uarcreleaseyen
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