Expression of c-erbB Receptors and Ligands in Human Bronchial Mucosa

Polosa, Riccardo; Prosperini, G; Leir, Shih Hsing; Holgate, Stephen T.; Lackie, Peter M.; Davies, Donna E.

doi:10.1165/ajrcmb.20.5.3308

Cited by 113 publications

(119 citation statements)

References 50 publications

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“…We observed basal activation and phosphorylation of EGFR in the 16HBE cells, possibly due to autocrine release of EGFR ligands (e.g., EGF, TGF-␣, human bronchial EGF, which are expressed by 16HBE cells; Ref. 32). When the cells were transfected with siRNA Ecadherin for 3 days, a marked increase in basal EGFR phosphorylation occurred when compared with cells transfected with nontargeting siRNA (Fig.…”

Section: Increased Egfr Phosphorylation After E-cadherin Silencingmentioning

confidence: 80%

Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity

Heijink

Kies

Kauffman³

et al. 2007

The Journal of Immunology

153

133

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Airway epithelial cells are well-known producers of thymus- and activation-regulated chemokine (TARC), a Th2 cell-attracting chemokine that may play an important role in the development of allergic airway inflammation. However, the mechanism responsible for up-regulation of TARC in allergy is still unknown. In the asthmatic airways, loss of expression of the cell-cell contact molecule E-cadherin and reduced epithelial barrier function has been observed, which may be the result of an inadequate repair response. Because E-cadherin also suppressed multiple signaling pathways, we studied whether disruption of E-cadherin-mediated cell contact may contribute to increased proallergic activity of epithelial cells, e.g., production of the chemokine TARC. We down-regulated E-cadherin in bronchial epithelial cells by small interference RNA and studied effects on electrical resistance, signaling pathways, and TARC expression (by electric cell-substrate impedance sensing, immunodetection, immunofluorescent staining, and real-time PCR). Small interference RNA silencing of E-cadherin resulted in loss of E-cadherin-mediated junctions, enhanced phosphorylation of epidermal growth factor receptor (EGFR), and the downstream targets MEK/ERK-1/2 and p38 MAPK, finally resulting in up-regulation of TARC as well as thymic stromal lymphopoietin expression. The use of specific inhibitors revealed that the effect on TARC is mediated by EGFR-dependent activation of the MAPK pathways. In contrast to TARC, expression of the Th1/Treg cell-attracting chemokine RANTES was unaffected by E-cadherin down-regulation. In summary, we show that loss of E-cadherin-mediated epithelial cell-cell contact by damaging stimuli, e.g., allergens, may result in reduced suppression of EGFR-dependent signaling pathways and subsequent induction of Th2 cell-attracting molecule TARC. Thus, disruption of intercellular epithelial contacts may specifically promote Th2 cell recruitment in allergic asthma.

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Section: Increased Egfr Phosphorylation After E-cadherin Silencingmentioning

confidence: 80%

Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity

Heijink

Kies

Kauffman³

et al. 2007

The Journal of Immunology

153

133

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“…ERBB3 was expressed in primary proliferating cultures of human bronchial epithelium. 364 In scrape-wounded adult lung epithelial monolayers, tyrosine phosphorylation of EGFR, ERBB2 and ERBB3 occurred immediately. 365 Smoking was associated with significant increases in EGFR and especially in ERBB3 in bronchial epithelial cells compared to nonsmokers.…”

Section: Respiratory Tissuesmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…For example, HB-EGF, amphiregulin and EGF have a widespread tissue distribution pattern, although TGF-a is expressed mainly in epithelial cells, macrophages and eosinophils. Immunolocalisation studies have revealed that EGF is primarily expressed in bronchial glands [218,219], although there is weak expression in the bronchial epithelium and smooth muscle [220]. Interestingly, stronger EGF immunoreactivity has been demonstrated in the bronchial epithelium, glands, smooth muscle [220] and submucosa [165] of asthmatic subjects compared with nonasthmatics.…”

Section: A Question Of Balancementioning

confidence: 99%

“…EPIDERMAL GROWTH FACTORS AND ASTHMA EGFR, ErbB2 and ErbB3 receptors are expressed in the epithelium of the upper and lower airways, as well as in primary cultures of human bronchial epithelial cells and human bronchial epithelial derived cell lines, such as H292 and 16HBE 14o- [217,219]. In asthma, it has been observed that the expression of EGFR is increased on the remaining epithelial cells around the site of damage, and on the apical side of the exposed basal cells [219].…”

Section: Functions Of Egfr Ligandsmentioning

confidence: 99%

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The contribution of transforming growth factor- and epidermal growth factor signalling to airway remodelling in chronic asthma

Boxall

Holgate²,

Davies³

2006

European Respiratory Journal

225

187

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Asthma is increasing in prevalence in the developing world, affecting ,10% of the world's population. It is characterised by chronic lung inflammation and airway remodelling associated with wheezing, shortness of breath, acute bronchial hyperresponsiveness to a variety of innocuous stimuli and a more rapid decline in lung function over time.Airway remodelling, involving proliferation and differentiation of mesenchymal cells, particularly myofibroblasts and smooth muscle cells, is generally refractory to corticosteroids and makes a major contribution to disease chronicity. Transforming growth factor-b is a potent profibrogenic factor whose expression is increased in the asthmatic airways and is a prime candidate for the initiation and persistence of airway remodelling in asthma.This review highlights the role of transforming growth factor-b in the asthmatic lung, incorporating biosynthesis, signalling pathways and functional outcome. In vivo, however, it is the balance between transforming growth factor-b and other growth factors, such as epidermal growth factor, which will determine the extent of fibrosis in the airways.A fuller comprehension of the actions of transforming growth factor-b, and its interaction with other signalling pathways, such as the epidermal growth factor receptor signalling cascade, may enable development of therapies that control airway remodelling where there is an unmet clinical need.

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Expression of c-erbB Receptors and Ligands in Human Bronchial Mucosa

Cited by 113 publications

References 50 publications

Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity

Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity

The ERBB3 receptor in cancer and cancer gene therapy

The contribution of transforming growth factor- and epidermal growth factor signalling to airway remodelling in chronic asthma

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