House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium.
The molecular basis of airway remodeling and loss of epithelial integrity in asthma is still undefined. We aimed to establish if exposure of human bronchial epithelium (16HBE cells) to asthma-related stimuli can induce epithelial-to-mesenchymal transition (EMT), a key process in tissue repair and remodeling associated with loss of intercellular contacts. We studied the effects of fibrogenic cytokine TGF-beta and protease-containing aeroallergen house dust mite (HDM) on mesenchymal and epithelial markers, cytoskeleton organization, and activation of beta-catenin-driven reporter TopFLASH. TGF-beta alone up-regulated vimentin and fibronectin, modestly down-regulated E-cadherin, but did not affect cytokeratin. HDM alone did not affect these markers, but promoted stress fibers. Importantly, when added to TGF-beta-primed epithelium, HDM induced E-cadherin internalization, enhanced beta-catenin-dependent transcription, and down-regulated cytokeratin. Regarding the underlying mechanisms, the stimuli together induced sustained myosin light chain phosphorylation, which was crucial for E-cadherin internalization and beta-catenin-dependent transcription. Previously, we showed that HDM signals through the epidermal growth factor receptor (EGFR). Accordingly, inhibition of EGFR prevented TGF-beta/HDM-induced mesenchymalization. TGF-beta facilitated uncoupling of EGFR from E-cadherin, its negative regulator, and prolonged EGFR signaling. Thus, we show that HDM promotes EMT in TGF-beta-primed epithelium. Analysis of primary epithelium appears consistent with this phenotypic change. We propose that TGF-beta secretion and dysregulated EGFR signaling may increase epithelial vulnerability to allergens and trigger the induction of EMT, a hitherto unrecognized contributor to airway remodeling in asthma.
Department of Allergology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, The Netherlands. h.i.heijink@int.umcg.nl
Irene H
IH
Heijink
Dirkje S
DS
Postma
Jacobien A
JA
Noordhoek
Martine
M
Broekema
Andras
A
Kapus
D000485:Allergens; D000818:Animals; D001980:Bronchi / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010641:Phenotype; D039981:Pyroglyphidae / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000485:Allergens; D015820:Cadherins; D016207:Cytokines; D018994:Myosin Light Chains; D016212:Transforming Growth Factor beta; D007633:Keratins; D066246:ErbB Receptors