Role of NF-κB in Cytokine Production Induced from Human Airway Epithelial Cells by Rhinovirus Infection

Kim, Jean; Sanders, Scherer P.; Siekierski, Edward S.; Casolaro, Vincenzo; Proud, David

doi:10.4049/jimmunol.165.6.3384

Cited by 97 publications

(98 citation statements)

References 56 publications

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“…This analysis showed that the upper band was shifted by Abs to both p65 and p50, suggesting it represents the canonical p65-p50 heterodimer, which we have previously reported to be induced in HRV-16-infected cells (31). In contrast, the lower band was shifted only by Abs to p50, suggesting it may represent p50 homodimers.…”

Section: Evaluation Of the Role Of Nf-b In Mek1/2-mediated Modulationmentioning

confidence: 70%

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: Evaluation Of the Role Of Nf-b In Mek1/2-mediated Modulationmentioning

confidence: 70%

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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“…IL-8 gene regulation requires activation of nuclear factor (NF)-kB [28]. A. fumigatus proteases can induce IL-8 gene expression by transcription mechanisms involving enhanced DNA binding of NF-kB [29,30].…”

Section: Discussionmentioning

confidence: 99%

Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis

Gibson¹,

Wark²,

Simpson³

et al. 2003

Eur Respir J

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Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus, causing severe asthma that may progress to bronchiectasis. Sputum neutrophilia can occur in association with sputum eosinophilia and correlates with the degree of bronchiectasis. The mechanisms of sputum neutrophilia in ABPA are not known. The aim of this study was to investigate the role of the chemokine interleukin (IL)-8 in sputum neutrophilia in ABPA.Induced sputum was obtained from subjects with ABPA (n=29), and compared to nonsensitised asthma (n=9) and healthy controls (n=21). Semiquantitative polymerase chain reaction was used to assess IL-8 gene expression in induced sputum and IL-8 protein was measured by enzyme-linked immunosorbent assay.Sputum IL-8 protein was significantly higher in ABPA compared to asthma and controls. IL-8 messenger ribonucleic acid/glyceraldehyde-3-phosphate dehydrogenase ratio was elevated in ABPA compared to asthma and controls. Sputum IL-8 correlated with sputum neutrophils, matrix metalloproteinase-9 levels and forced expiratory volume in one second.Interleukin-8 gene expression and protein release were increased in allergic bronchopulmonary aspergillosis and correlated with airway neutrophilia and airway obstruction. The interleukin-8-mediated neutrophil influx in allergic bronchopulmonary aspergillosis may induce lung damage via release of matrix metalloproteinase-9, potentially leading to bronchiectasis. Eur Respir J 2003; 21: 582-588.

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“…Little is known about the events initiating RV-induced cytokine expression in airway epithelium. The IL-8 response to RV serotype 16 infection in BEAS-2B human respiratory epithelial cells is inhibited by antibodies to ICAM-1, implying that integrinmediated signal transduction pathways play a role in RVinduced responses (29). On the other hand, in primary bronchial epithelial cells, anti-ICAM-1 attenuates RANTES but not IL-8 secretion (30).…”

Section: Discussionmentioning

confidence: 99%

“…Down-regulation of the RV-induced cytokine response from one of the other RV16 proteins could serve to attenuate the impact of 3C. As noted above, effects of virus attachment (29) and entry (31) could also play a role.…”

Section: Discussionmentioning

confidence: 99%

Rhinovirus 16 3C Protease Induces Interleukin-8 and Granulocyte-Macrophage Colony-Stimulating Factor Expression in Human Bronchial Epithelial Cells

et al. 2004

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Rhinovirus (RV), a member of the Picornaviridae family, accounts for many virus-induced asthma exacerbations. RV induces airway cell chemokine expression both in vivo and in vitro. Because of the known interactions of proteases with cellular functions, we hypothesized that RV 3C protease is sufficient for cytokine up-regulation. A cDNA encoding RV16 3C protease was constructed by PCR amplification and transfected into 16HBE14oϪ human bronchial epithelial cells. 3C protease induced expression of both IL-8 and GM-CSF, as well as transcription from both the IL-8 and GM-CSF promoters. 3C expression also induced activator protein 1 and NF-B transcriptional activation. Finally, mutation of IL-8 promoter AP-1 and NF-B promoter sequences significantly reduced 3C-induced responses. Together, these data suggest expression of RV16 3C protease is RVs are the most common upper respiratory pathogens, inducing the majority of common colds worldwide. Viral infections trigger asthma in 80 to 85% of asthma exacerbations in children and 44% in adults (1, 2) RV, a member of the Picornaviridae family of small, positive-stranded RNA viruses, accounts for much of virus-induced asthma exacerbations (1, 2). Cytokines are elaborated in vivo in the nasal mucosa, and most likely also from bronchial epithelium, after RV infection. Neutrophils, eosinophils, and lymphocytes increase in the nasal secretions of RV-infected patients compared with uninfected controls (3, 4).The cytokines IL-8 and GM-CSF have been implicated in the pathogenesis of asthma. IL-8 is a potent activator and chemoattractant of neutrophils (5) and eosinophils (6), and GM-CSF promotes the differentiation and survival of recruited eosinophils (7). Increased levels of IL-8, GM-CSF (8), and ICAM-1 (9), the receptor of 90% of RV serotypes, as well as IL-1 and IL-6, have been found in the nasal secretions of individuals infected with RVs (10 -12). In bronchial mucosal biopsies obtained after experimental infection with RV, Bardin and colleagues (13) noted a significant increase in submucosal lymphocytes and epithelial eosinophils, which, in asthmatics, persisted into convalescence. Although increases in cytokine secretion in the nasal mucosa does not prove increased expression in the epithelium in the lower airways, taken together the above data strongly suggest that cytokine elaboration is increased in the RV-infected lower airway epithelium.RV infection also induces cytokine production and adhesion molecule expression in cell culture. Divergent findings regard-

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Role of NF-κB in Cytokine Production Induced from Human Airway Epithelial Cells by Rhinovirus Infection

Cited by 97 publications

References 56 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

Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis

Rhinovirus 16 3C Protease Induces Interleukin-8 and Granulocyte-Macrophage Colony-Stimulating Factor Expression in Human Bronchial Epithelial Cells

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