Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling

Leigh, Richard; Oyelusi, Wale; Wiehler, Shahina; Koetzler, Rommy; Zaheer, Raza S.; Newton, Robert; Proud, David

doi:10.1016/j.jaci.2008.01.067

Cited by 119 publications

(105 citation statements)

References 34 publications

(39 reference statements)

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“…Our earlier studies on HRV-16-induced activation of the p38, JNK, and MEK1/2-ERK MAPK pathways in human airway epithelial cells focused on short-term activation (19,20). We have extended these studies to show that, consistent with an earlier report (25), HRV-16 induces chronic activation of ERK1/2 in BEAS-2B cells, with phosphorylation detected up to 24 h postinfection (data not shown).…”

Section: Enhancement Of Hrv-16-induced Cxcl10 Expression Occurs Throusupporting

confidence: 84%

“…We have previously shown that infection of epithelial cells with HRV-16 activates the p38, MEK1/2-ERK, and JNK MAPK pathways (19,20). To define the role of each of these pathways in viral induction of CXCL10, we initially used selective pharmacologic inhibitors.…”

Section: Inhibition Of the Mek1/2-erk Pathway Enhances Hrv-16-inducedmentioning

confidence: 99%

“…We have previously shown that infection of epithelial cells with HRV-16 leads to activation of all three major MAPK pathways (19,20). Both the p38 and MEK1/2-ERK MAPK pathways have been reported to be involved in the adenoviral induction of CXCL10 expression in murine kidney epithelial cells (21), and the MEK1/2-ERK pathway mediates CXCL10 expression in murine macrophages in response to rabies virus infection (22).…”

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confidence: 99%

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

Zaheer

Koetzler

Holden

et al. 2009

The Journal of Immunology

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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-κB binding sites, κB1 and κB2, and by an IFN-stimulated response element. Inhibitors of the MEK1/2-ERK pathway did not alter HRV-16-induced activation of tandem repeat κB1 or κB2 constructs, nor did they alter HRV-16-induced nuclear translocation/binding of NF-κB to either κB1 or κB2 recognition sequences. Furthermore, PD98059 and U0126 did not alter phosphorylation or degradation of IκBα. 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.

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Section: Enhancement Of Hrv-16-induced Cxcl10 Expression Occurs Throusupporting

confidence: 84%

Section: Inhibition Of the Mek1/2-erk Pathway Enhances Hrv-16-inducedmentioning

confidence: 99%

mentioning

confidence: 99%

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

Zaheer

Koetzler

Holden

et al. 2009

The Journal of Immunology

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“…CCL5 is the dominant chemoattractant present in HRV-15 CM, although CXCL8 may also contribute. These data, together with earlier reports that HRV infected epithelial cells show expression of genes related to airway remodeling (33), and release a number of growth factors and matrix proteins linked to airway remodeling (34)(35)(36), further support the concept that recurrent HRV infections may contribute to the initiation and progression of airway remodeling in asthma. Future studies will need to determine if the current observations are relevant to cells obtained from asthmatic subjects (both children and adults), while clinical studies of either naturally-acquired or experimental HRV infections will confirm whether these observations occur in vivo.…”

Section: Hrv-induced Asmc Migration Is Mediated At Least In Part VIsupporting

confidence: 81%

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

Shariff

Shelfoon

Holden

et al. 2017

Am J Respir Cell Mol Biol

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Rationale: Airway remodeling, a characteristic feature of asthma, begins in early life. Recurrent human rhinovirus (HRV) infections are a potential inciting stimulus for remodeling. One component of airway remodeling is an increase in airway smooth muscle cell mass with a greater proximity of the airway smooth muscle cells (ASMC) to the airway epithelium. We asked whether human bronchial epithelial cells infected with HRV produced mediators that are chemotactic for ASMC.Methods: ASMC migration was investigated using the modified Boyden Chamber and the xCELLigence Real-Time Cell Analyzer. Multiplex bead analysis was used to measure HRVinduced epithelial chemokine release. The chemotactic effects of CCL5, CXCL8 and CXCL10 were also examined.Results: Supernatants from HRV-infected epithelial cells caused ASMC chemotaxis. Pretreatment of ASMC with pertussis toxin abrogated chemotaxis, as did treatment with formoterol, forskolin, or 8-bromo-cAMP. CCL5, CXCL8, and CXCL10 were most up-regulated chemokines produced by HRV-infected airway epithelial cells. When recombinant CCL5, CXCL8 and CXCL10 were used at levels found in epithelial supernatants they induced ASMC chemotaxis similar to that seen with epithelial cell supernatants. When examined individually, CCL5 was the most effective chemokine in causing ASMC migration and treatment of supernatant from HRVinfected epithelial cells with anti-CCL5 antibodies significantly attenuated ASMC migration. Conclusion:These findings suggest that HRV-induced CCL5 can induce ASMC chemotaxis, and thus may contribute to the pathogenesis of airway remodeling in asthmatic patients.3

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“…It was demonstrated that the HRV infection of airway epithelial cells in vitro induces the production of various cytokines, chemokines, growth factors, and host defense proteins, several of which are also detected in airway secretions during in vivo HRV infections (5,6). According to the current paradigm, these cellular products serve as chemoattractants and activators for the inflammatory cells that are recruited to the airways during disease exacerbations.…”

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confidence: 99%

Human Rhinovirus Infection Up-Regulates MMP-9 Production in Airway Epithelial Cells via NF-κB

Tacon¹,

Wiehler²,

Holden³

et al. 2010

Am J Respir Cell Mol Biol

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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-kB, and NF-kB has also been reported to play a role in the expression of MMP-9. We therefore investigated the role of NF-kB in HRV-induced MMP-9 expression. Using two inhibitors of IkBa kinase b, we observed a concentration-dependent decrease in HRVinduced MMP-9 expression. The role of NF-kB in HRV-induced MMP-9 expression was further confirmed using MMP-9 promoter luciferase constructs, which demonstrated that an NF-kB site at 2620/2607 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-kB subunits to an MMP-9-specific NF-kB oligonucleotide. This increase in MMP-9 may be a mechanism by which rhinovirus infections contribute to airway inflammation and, potentially, to airway remodeling.Keywords: airway epithelial cell; airway inflammation; airway remodeling; human rhinovirus; matrix metalloproteinase-9Human rhinovirus (HRV) infections are associated with exacerbations of lower airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (1). More than 100 serotypes of HRV exist, and they may be grouped according to the cell surface receptor used to gain entry into airway epithelial cells, which are their primary site of infection (2, 3). More than 90% of these HRV serotypes belong to the major group that attaches to the host cell via intercellular adhesion molecule-1, whereas at least 10 serotypes belong to the minor group and use members of the low-density lipoprotein receptor family for attachment (4).Although HRV infections are strongly linked to exacerbations of asthma and COPD, the mechanisms by which such infections cause these exacerbations are not yet fully characterized. It was demonstrated that the HRV infection of airway epithelial cells in vitro induces the production of various cytokines, chemokines, growth factors, and host defense proteins, several of which are also detected in airway secretions during in vivo HRV infections (5, 6). According to the current paradigm, these cellular products s...

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Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling

Cited by 119 publications

References 34 publications

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

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

Human Rhinovirus Infection of Epithelial Cells Modulates Airway Smooth Muscle Migration

Human Rhinovirus Infection Up-Regulates MMP-9 Production in Airway Epithelial Cells via NF-κB

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