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Down-Regulation of E-Cadherin in Human Bronchial Epithelial Cells Leads to Epidermal Growth Factor Receptor-Dependent Th2 Cell-Promoting Activity¹

Irene H. Heijink^2,*,, P. Marcel Kies^*,, Henk F. Kauffman^*, Dirkje S. Postma, Antoon J. M. van Oosterhout^*, and Edo Vellenga

^* Department of Allergology, Department of Pulmonology, and Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Grant 3.2.03.34 from the Netherlands Asthma Foundation.

² Address correspondence and reprint requests to Dr. I. H. Heijink, Department of Allergology and Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. E-mail address: h.i.heijink{at}int.umcg.nl

³ Abbreviations used in this paper: TARC, thymus- and activation-regulated chemokine; ECIS, electric cell-substrate impedance sensing; EGF, epidermal growth factor; EGFR, EGF receptor; TSLP, thymic stromal lymphopoietin; siRNA, small interference RNA; 16HBE, human bronchial epithelial cell line 16HBE 14o–; BEGM, bronchial epithelium growth medium; ₂m, ₂-microglobulin; rh, recombinant human.