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

Zaheer, Raza S.; Koetzler, Rommy; Holden, Neil S.; Wiehler, Shahina; Proud, David

doi:10.4049/jimmunol.0802401

Cited by 39 publications

(36 citation statements)

References 59 publications

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“…In addition, we have shown chronic activation of this MAPK pathway upon HRV infection (12,33). As reported earlier, Fra-1 expression is induced upon HRV infection of BEAS-2B cells but is constitutively present in primary HBE cells.…”

Section: Activation Of Mek Is Necessary For Fra-1 Expression and Dna supporting

confidence: 83%

“…Thus, we next sought to determine whether the MEK/ERK MAPK pathway was playing a role in Fra-1 expression and consequently in HRV-induced MMP-9 expression. The pharmacological inhibitors of MEK1/2, PD98059 (1-30 mM) and U0126 (0.3-10 mM), which have been shown to inhibit HRV-induced ERK phosphorylation (33), both decreased HRV-induced Fra-1 expression in BEAS-2B cells in a concentration-dependent manner (Fig. 3A, 3B).…”

Section: Activation Of Mek Is Necessary For Fra-1 Expression and Dna mentioning

confidence: 94%

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Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Tacon

Newton

Leigh

2012

The Journal of Immunology

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Matrix metalloproteinase-9 is implicated in airway inflammation and airway remodeling in asthma. We have previously confirmed that human rhinovirus-16 (HRV-16) infection increases MMP-9 expression both in vivo and in vitro. However, the role of the AP-1 sites within the MMP-9 promoter and the effect of commonly used asthma pharmacotherapies in modulating human rhinovirus (HRV)-induced MMP-9 production have not yet been elucidated. Experiments were performed in vitro in the human bronchial epithelial (HBE) cell line BEAS-2B and in primary HBE cells obtained from non-transplanted lungs. Using site-directed mutagenesis approaches, AP-1 sites were found to be necessary for HRV-induced MMP-9 promoter drive. EMSAs and supershift assays identified complexes consisting of Fos-related Ag-1 (Fra-1) in addition to other AP-1 subunits. Small interfering RNA approaches indicated that Fra-1 was induced upon HRV-16 infection in BEAS-2B cells and was necessary for MMP-9 expression in both BEAS-2B and primary HBE cells. Inhibition of MEK1/2 activity using PD98059 and U0126 reduced Fra-1 expression, DNA binding, MMP-9 promoter drive, and MMP-9 protein production. The long-acting β2-agonist formoterol and the glucocorticoid dexamethasone significantly reduced HRV-induced ERK phosphorylation, Fra-1, and MMP-9 expression in BEAS-2B cells. These data indicate that HRV-induced activation of the MEK/ERK MAPK pathway and Fra-1 expression are necessary for the upregulation of MMP-9 and can be modulated by two distinct but commonly used asthma pharmacotherapies. Together, these results offer insights into the mechanisms by which long-acting β2-agonists and glucocorticoids might reduce HRV-related asthma exacerbations.

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Section: Activation Of Mek Is Necessary For Fra-1 Expression and Dna supporting

confidence: 83%

Section: Activation Of Mek Is Necessary For Fra-1 Expression and Dna mentioning

confidence: 94%

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Tacon

Newton

Leigh

2012

The Journal of Immunology

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“…This is particularly interesting in view of a recent publication showing that activation of the MAP kinase kinase (MEK)-ERK pathway by HRV-16 actually inhibits CXCL10 production (30). Thus, after exposure to cigarette smoke, HRV-16 can still effectively induce the MEK-ERK pathway, exerting an inhibitory effect on the expression of CXCL10.…”

Section: Discussionmentioning

confidence: 83%

“…Activation of the mitogen-activated protein (MAP) kinase kinases SAPK/JNK and ERK was shown to be involved in the regulation of virally induced gene expression (29)(30)(31). SAPK/JNK is involved in the regulation of b-defensin and activates activating transcription factor 2 (ATF2), a component of the Type I IFN response, whereas ERK is involved in the regulation of RV-induced CXCL10 and respiratory syncytial virus (RSV)-induced CCL5.…”

Section: Effects Of Cse On Poly I:c-induced and Hrv-16-induced Activamentioning

confidence: 99%

Cigarette Smoke Decreases Innate Responses of Epithelial Cells to Rhinovirus Infection

Eddleston¹,

Lee²,

Doerner³

et al. 2011

Am J Respir Cell Mol Biol

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Exposure to cigarette smoke is associated with a significant increase in the risk for respiratory viral infections. The airway epithelium is the primary target for both cigarette smoke and respiratory viral infection. We investigated the effects of cigarette smoke on the response of airway epithelial cells to rhinovirus infection. We found that pre-exposure of BEAS-2B cells or primary normal human bronchial epithelial cells (NHBEs) to cigarette smoke extract (CSE) reduced the induction of mRNA of the chemokines CXCL10 and CCL5 by either the viral mimic polyinosine-polycytidylic acid (Poly I:C) or human rhinovirus 16 (HRV-16) infection. The HRV-16-induced release of CXCL10 and CCL5 was also significantly suppressed by CSE. Activation of the IFN mediator STAT-1 and the activation of JNK by poly I:C and HRV-16 were partially suppressed by pre-exposure to CSE. In contrast, the poly I:C-induced and HRV-16-induced phosphorylation of ERK1/2 was unaffected by CSE. HRV-16-stimulated IFN-b mRNA was also significantly reduced by CSE. Because suppression of the IFN response to viral infection was associated with increased viral production, we assessed HRV-16 RNA concentrations. Exposure to CSE resulted in an increase in HRV-16 RNA at 48 hours after the infection of BEAS-2B cells. These data demonstrate that exposure to CSE alters the response of airway epithelial cells to HRV infection, leading to decreased activation of the IFN-STAT-1 and SAP-JNK pathways, the suppression of CXCL10 and CCL5 production, and increased viral RNA. A diminished, early epithelial-initiated antiviral response to rhinovirus infection could contribute to the increased susceptibility of subjects to prolonged respiratory viral infections after exposure to cigarette smoke.

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“…The 5ϫNF-B sequence reporter construct was kindly donated by Robert Newton (University of Calgary, Alberta, Canada) and was described previously (1); the 5ϫISER sequence reporter construct was kindly provided by David Proud (University of Calgary, Alberta, Canada) and was described previously (48). The internal control Renilla luciferase reporter construct pRL-SV40 was obtained from Promega (Southampton, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis

Coward

Watts

Feghali‐Bostwick

et al. 2010

Molecular and Cellular Biology

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Targeted repression of a subset of key genes involved in tissue remodeling is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The mechanism is unclear but is potentially important in disease pathogenesis and therapeutic targeting. We have previously reported that defective histone acetylation is responsible for the repression of the antifibrotic cyclooxygenase-2 gene. Here we extended our study to the repression of another antifibrotic gene, the potent angiostatic chemokine gamma interferon (IFN-␥)-inducible protein of 10 kDa (IP-10), in lung fibroblasts from patients with IPF. We revealed that this involved not only histone deacetylation, as with cyclooxygenase-2 repression, but also histone H3 hypermethylation, as a result of decreased recruitment of histone acetyltransferases and increased presence of histone deacetylase (HDAC)-containing repressor complexes, histone methyltransferases G9a and SUV39H1, and heterochromatin protein 1 at the IP-10 promoter, leading to reduced transcription factor binding. More importantly, treatment of diseased cells with HDAC or G9a inhibitors similarly reversed the repressive histone deacetylation and hypermethylation and restored IP-10 expression. These findings strongly suggest that epigenetic dysregulation involving interactions between histone deacetylation and hypermethylation is responsible for targeted repression of IP-10 and potentially other antifibrotic genes in fibrotic lung disease and that this is amenable to therapeutic targeting.

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

Cited by 39 publications

References 59 publications

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Rhinovirus-Induced MMP-9 Expression Is Dependent on Fra-1, Which Is Modulated by Formoterol and Dexamethasone

Cigarette Smoke Decreases Innate Responses of Epithelial Cells to Rhinovirus Infection

Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis

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