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Selective Transcriptional Down-Regulation of Human Rhinovirus-Induced Production of CXCL10 from Airway Epithelial Cells via the MEK1 Pathway ¹

Airway Inflammation Group, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada

Human rhinovirus (HRV) infections can trigger exacerbations of lower airway diseases. Infection of airway epithelial cells induces production of a number of proinflammatory chemokines that may exacerbate airway inflammation, including CXCL10, a chemoattractant for type 1 lymphocytes and NK cells. Primary human bronchial epithelial cells and the BEAS-2B human bronchial epithelial cell line were used to examine the role of MAPK pathways in HRV-16-induced production of CXCL10. Surprisingly, PD98059 and U0126, two inhibitors of the MEK1/2-ERK MAPK pathway, significantly enhanced HRV-16-induced CXCL10 mRNA and protein. This enhancement was not seen with IFN-β-induced production of CXCL10. Studies using small interfering RNA revealed that knockdown of MEK1, but not MEK2, was associated with enhanced HRV-induced CXCL10 production. Promoter construct studies revealed that PD98059 and U0126 enhanced HRV-16-induced transcriptional activation of CXCL10. HRV-16-induced promoter activation was regulated by two NF-B binding sites, B1 and B2, and by an IFN-stimulated response element. Inhibitors of the MEK1/2-ERK pathway did not alter HRV-16-induced activation of tandem repeat B1 or B2 constructs, nor did they alter HRV-16-induced nuclear translocation/binding of NF-B to either B1 or B2 recognition sequences. Furthermore, PD98059 and U0126 did not alter phosphorylation or degradation of IB. In contrast, inhibitors of the MEK1/2-ERK pathway, and small interfering RNA knockdown of MEK1, enhanced nuclear translocation/binding of IFN regulatory factor (IRF)-1 to the IFN-stimulated response element recognition sequence in HRV-16 infected cells. We conclude that activation of MEK1 selectively down-regulates HRV-16-induced expression of CXCL10 via modulation of IRF-1 interactions with the gene promoter in human airway epithelial cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funding from Canadian Institutes of Health Research Grant 43923. David Proud is the recipient of a Canada Research Chair in Inflammatory Airway Diseases. Raza Zaheer and Rommy Koetzler are recipients of studentship awards from the Lung Association of Alberta and Northwest Territories.

² Address correspondence and reprint requests to Dr. David Proud, Airway Inflammation Group, Institute of Infection, Immunity and Inflammation, University of Calgary, 3330 Hospital Drive, NW, Calgary, Alberta T2N 4N1, Canada. E-mail address: dproud{at}ucalgary.ca

³ Abbreviations used in this paper: HRV, human rhinovirus; BEBM, bronchial epithelial cell basal medium; BEGM, bronchial epithelial cell growth medium; COPD, chronic obstructive pulmonary disease; HBE, human bronchial epithelial cell; IRF, IFN regulatory factor; ISGF, IFN-stimulated gene factor; ISRE, IFN-stimulated response element; MOI, multiplicity of infection; siRNA, small interfering RNA; TCID₅₀, 50% tissue culture-infective dose.