Kim, S., Lewis, C. & Nadel, J.A. CCL20/CCR6 feedback exaggerates epidermal growth factor receptor-dependent MUC5AC mucin production in human airway epithelial (NCI-H292) cells. J. Immunol. 186, 3392-3400

Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
The Journal of Immunology (Impact Factor: 4.92). 02/2011; 186(6):3392-400. DOI: 10.4049/jimmunol.1003377
Source: PubMed


Mucous hypersecretion is an important feature of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Multiple stimuli induce mucin production via activation of an epidermal growth factor receptor (EGFR) cascade, but the mechanisms that exaggerate mucin production in obstructive airway diseases remain unknown. In this study, we show that binding of CCL20, a G protein-coupled receptor (GPCR) ligand that is upregulated in the airways of subjects with obstructive airway diseases, to its unique GPCR CCR6 induces MUC5AC mucin production in human airway epithelial (NCI-H292) cells via metalloprotease TNF-α-converting enzyme (TACE)-dependent EGFR activation. We also show that EGFR activation by its potent ligand TGF-α induces reactivation of EGFR via binding of endogenously produced CCL20 to its receptor CCR6 in NCI-H292 cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating mucin production in the NCI-H292 cells. In NCI-H292 cells, TGF-α stimulation induced two phases of EGFR phosphorylation (EGFR-P). The second EGFR-P was TACE-dependent and was responsible for most of the total mucin induced by TGF-α. Binding of endogenously produced CCL20 to CCR6 increased the second EGFR-P and subsequent mucin production induced by TGF-α. In NHBE cells, TGF-α-induced EGFR activation did not lead to significant CCL20 production or to EGFR rephosphorylation, and less mucin was produced. We conclude that NCI-H292 cells but not NHBE cells produce CCL20 in response to EGFR activation, which leads to a second phase of EGFR-P and subsequent exaggerated mucin production. These findings have potentially important therapeutic implications in obstructive airway diseases.

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    • "Its activation could play a potential role in innate immune response. Especially, the EGFR pathway is also involved in the production of chemokine CCL20 by airway ECs [48]. We showed that nasal passage DCs can sense a CCL20 gradient from ECs after H9N2 WIV challenge, then quickly migrate to the subepithelial regions and send TEDs for viral uptake. "
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    • "Although there are contradictory reports concerning the expression of CXCR1 and CXCR2 on bronchial epithelial cells (38,39), we found that IL-8 release is increased in ZZ primary bronchial epithelial cells, which potentially might provide an autocrine inflammatory signal in the absence of sufficient α1-antitrypsin. Alternatively, C-C chemokine ligand20 (also known as MIP-3α) and its receptor C-C chemokine receptor6 have been shown to activate ADAM17 causing transactivation of EGFR (40,41). "
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    • "Multiple endogenous epithelial cell products have been shown to activate the TACE-EGFR cascade [30], [47]. We focused on IL-1 for several reasons: First, IL-1 is a well known stimulus of IL-8 production [44]; second, binding of IL-1 to IL-1R activates the TACE-EGFR cascade [42], [43]; third, proteins in the IL-1R signaling pathway are upregulated in CF airway epithelial cells [15], [41]; and fourth, IL-1R blockade has been previously reported to suppress exaggerated IL-8 production in CF airway epithelial cells [41]. "
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