Down-regulation of E-cadherin in human bronchial epithelial cells leads to epidermal growth factor receptor-dependent Th2 cell-promoting activity.
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.
Heijink
Irene H
IH
Department of Allergology, University Medical Center, University of Groningen, Groningen, The Netherlands. h.i.heijink@int.umcg.nl
Kies
P Marcel
PM
Kauffman
Henk F
HF
Postma
Dirkje S
DS
van Oosterhout
Antoon J M
AJ
Vellenga
Edo
E
D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000276:immunology* / Q000378:metabolism; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
C106230:CCL17 protein, human; D015820:Cadherins; D054414:Chemokine CCL17; D019742:Chemokines, CC; D016207:Cytokines; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D000094632:Thymic Stromal Lymphopoietin