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Am J Physiol Cell Physiol (October 13, 2004). doi:10.1152/ajpcell.00171.2004
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Submitted on April 1, 2004
Accepted on September 22, 2004

The Chemokine Receptor CCR6 Transduces Signals that Activate p130Cas and Alter cAMP-Stimulated Ion Transport in Human Intestinal Epithelial Cells

Charles C Yang1, Hiroyuki Ogawa1, Michael B Dwinell1, Declan F McCole1, Lars Eckmann1, and Martin F Kagnoff1*

1 Laboratory of Mucosal Immunology, Departments of Medicine and Pediatrics, University of California at San Diego, La Jolla, CA, USA

* To whom correspondence should be addressed. E-mail: mkagnoff{at}ucsd.edu.

Human colon epithelial cells express the G-protein-coupled receptor CCR6, the sole receptor for the chemokine CCL20 (also termed MIP-3{alpha}). CCL20 produced by intestinal epithelial cells is upregulated in response to proinflammatory stimuli and microbial infection, and chemoattracts leukocytes, including CCR6 expressing immature myeloid dendritic cells (DC), into sites of inflammation. The aim of this study was to determine if CCR6 expressed by intestinal epithelial cells acts as a functional receptor for CCL20 and if stimulation with CCL20 alters intestinal epithelial cell functions. The human colon epithelial cell lines T84, Caco-2, HT-29, and HCA-7 were used to model colonic epithelium. Polarized intestinal epithelial cells constitutively expressed CCR6, predominately on the apical side. Consistent with this, apical stimulation of polarized intestinal epithelial cells resulted in tyrosine phosphorylation of the p130 Crk-associated substrate (Cas), an adaptor/scaffolding protein that localizes in focal adhesions and has a role in regulating cytoskeletal elements important for cell attachment and migration. In addition, CCL20 stimulation inhibited agonist-stimulated production of the second messenger cAMP and cAMP-mediated chloride secretory responses by intestinal epithelial cells. Inhibition was abrogated by pertussis toxin, consistent with signaling through G{alpha}i-proteins that negatively regulate adenylyl cyclases and cAMP production. These data indicate that signaling events, occurring via the activation of the apically expressed chemokine receptor CCR6 on polarized intestinal epithelial cells, alter specialized intestinal epithelial cell functions, including electrogenic ion secretion and possibly epithelial cell adhesion and migration.




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