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CCL20 Is an Inducible Product of Human Airway Epithelia with Innate Immune Properties

Department of Pediatrics, The University of Iowa College of Medicine, Iowa City, Iowa

Address correspondence to: Paul B. McCray Jr., M.D., Department of Pediatrics, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. E-mail: paul-mccray{at}uiowa.edu

Chemokine ligand 20 (CCL20) and human ß-defensins (HBDs) share structural and functional properties, including antiparallel ß-pleated sheet core structures, charge distribution, and signaling to adaptive immune cells via the highly selective CCR6 receptor. Because of their similarities, we hypothesized that in addition to its known adaptive immune signaling functions, CCL20 has antimicrobial properties and participates in pulmonary innate immunity. We found that primary cultures of human airway epithelial and cultured fetal lung explants expressed CCL20 mRNA. Expression of CCL20 transcripts were significantly induced by interleukin (IL)-1ß and tumor necrosis factor-, and inhibited by dexamethasone. Primary cultures of airway epithelia secreted CCL20 both apically and basolaterally, and CCL20 abundance was increased over 30-fold with IL-1ß stimulation, achieving an estimated concentration of 167 ng/ml in airway surface liquid. CCL20 abundance in bronchoalveolar lavage fluid from patients with cystic fibrosis was nearly 90-fold higher compared with bronchoalveolar lavage fluid from healthy volunteers. Interestingly, CCL20 exhibited salt-sensitive antimicrobial activity, mainly against Gram-negative bacteria in low µg/ml concentrations. Additionally, apical washings from IL-1ß–stimulated primary cultures of human airway epithelia had significantly more antimicrobial activity than unstimulated controls. CCL20 rapidly permeabilized bacterial membranes with a time course intermediate to HBD-2 and HBD-3. Thus, CCL20 is a bi-functional peptide with both innate and adaptive immune properties that is regulated by inflammatory mediators, expressed by airway epithelia, and increased in cystic fibrosis airway secretions.

Abbreviations: airway surface liquid, ASL • bronchoalveolar lavage fluid, BALF • chemokine ligand 20, CCL20 • chemokine receptor 6, CCR6 • cystic fibrosis, CF • enzyme-linked immunosorbent assay, ELISA • glyceraldehyde-3-phosphate dehydrogenase, GAPDH • human ß-defensin, HBD • interferon-, IFN- • interleukin, IL • minimal inhibitory concentration, MIC • o-nitrophenyl-ß-D-galactopyranoside, ONPG • polymerase chain reaction, PCR • reverse transcription, RT • tumor necrosis factor-, TNF-

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