Rhinovirus infection induces expression of type 2 nitric oxide synthase in human respiratory epithelial cells in vitro and in vivo

Sanders, Scherer P.; Siekierski, Edward S.; Richards, Stephen M.; Porter, Jacqueline D.; Imani, Farhad; Proud, David

doi:10.1067/mai.2001.112028

Cited by 74 publications

(75 citation statements)

References 44 publications

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“…Analysis of the housekeeping gene GAPDH was performed on each sample using a primer and probe kit obtained from Applied Biosystems. For each gene of interest, we confirmed that the efficiency of amplification was comparable to that of GAPDH (data not shown), permitting us to assess fold induction of genes as previously described (41).…”

Section: Methodsmentioning

confidence: 56%

“…Thus it is reasonable to hypothesize that increased airway inflammation in exacerbations of asthma and COPD is triggered by viral-induced alterations in epithelial cell biology. In support of this, numerous studies have demonstrated that HRV infection of epithelial cells in vitro leads to the generation of a wide variety of proinflammatory chemokines and cytokines, including IL-8, ENA-78 (CXCL5), IP-10 (CXCL10), RANTES (CCL5), IL-1, and IL-6 (8, 40, 43, 46 -48), as well as host defense molecules, including human ␤-defensin-2 (HBD-2) and nitric oxide (38,41). Several of these products also have been detected in nasal lavages during HRV infections of normal subjects in vivo, but, to date, there have been few studies examining the presence of these molecules in lower airway secretions during viral exacerbations of asthma or COPD.…”

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confidence: 99%

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Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection

Wiehler

Proud²

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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109

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Human rhinovirus (HRV) infections are associated with exacerbations of asthma and chronic obstructive pulmonary disease that are characterized by a selective neutrophil infiltration. IL-17A, a cytokine derived primarily from activated T cells, has been linked to neutrophilic inflammation of the airways. We hypothesized that IL-17A alters the response of HRV-infected epithelial cells to modulate airway inflammatory cell populations. IL-17A synergistically enhanced HRV-16-induced epithelial production of the neutrophil chemoattractant, IL-8, as well as human β-defensin-2 (HBD-2), a chemoattractant for immature dendritic cells and memory T cells, but suppressed viral production of the eosinophil chemoattractant, RANTES. These effects were not due to alterations of viral uptake or replication by IL-17A. The synergy between HRV-16 and IL-17A for IL-8 protein production was both dose- and time-dependent. IL-8 induction by IL-17A or HRV-16, alone and in combination, was reduced by inhibitors of the p38 and p44/42 MAPK pathways. By contrast, induction of HBD-2 depended on the activation of the p38 and JNK pathways. The ability of IL-17A to synergistically enhance HRV-induced IL-8 is mediated posttranscriptionally, since IL-8 promoter activation by the combination of the two stimuli was merely additive, whereas the combination of IL-17A and HRV-16 led to stabilization of IL-8 mRNA. Similarly, stimulation of HBD-2 promoter constructs by the combination of IL-17A and HRV-16 was no more than the sum of the individual responses. Further studies are needed to examine HBD-2 mRNA stability. Taken together, these data represent the first demonstration that IL-17A can modify epithelial responses to HRV in a manner that would be expected to favor the recruitment of neutrophils, immature dendritic cells, and memory T cells to the airways.

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Section: Methodsmentioning

confidence: 56%

mentioning

confidence: 99%

Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection

Wiehler

Proud²

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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109

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“…In support of this, IRF-1 and NF-B have been shown to physically interact on the long terminal repeat enhancer of HIV (48). Moreover, cooperation between IRF-1 and NF-B has been described in the transcriptional activation of CCL5 and inducible NO synthase (34,49), genes that can also be induced by HRV (10,50). Our demonstration that inhibitors of the MEK1/2 pathway also enhance HRV-16-induced production of CCL5 provides evidence that other IRF-1 responsive genes can be regulated via the MEK1/2 pathway.…”

Section: Discussionmentioning

confidence: 96%

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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“…Analysis of the housekeeping gene GAPDH was performed on each sample, using a primer and probe kit obtained from Applied Biosystems (catalogue number 4326317E). Both MMP-9 and TIMP-1 mRNA concentrations were calculated using the comparative C T method, as previously described (16), and are expressed relative to GAPDH.…”

Section: Real-time Rt-pcrmentioning

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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Rhinovirus infection induces expression of type 2 nitric oxide synthase in human respiratory epithelial cells in vitro and in vivo

Cited by 74 publications

References 44 publications

Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection

Interleukin-17A modulates human airway epithelial responses to human rhinovirus infection

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

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

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