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Published ahead of print on March 15, 2007, doi:10.1165/rcmb.2006-0235OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 1, July 2007, 75-84

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Submitted on June 30, 2006
Revised on March 13, 2007

Airway Epithelial Interleukin-15 Transforms Monocytes into Dendritic Cells

Nicolas Regamey1, Carolina Obregon2, Sylvie Ferrari-Lacraz3, Coretta van Leer2, Marc Chanson4, Laurent P Nicod2*, and Thomas Geiser2

1 Pediatric Respiratory Medicine, University Children's Hospital of Berne, Berne, Switzerland, 2 Respiratory Medicine, University Hospital of Berne, Berne, Switzerland, 3 Division of Immunology and Allergy, University Hospitals, Geneva, Switzerland, 4 Department of Paediatrics, Laboratory of Clinical Investigation III, University Hospitals, Geneva, Switzerland

* To whom correspondence should be addressed. E-mail: Laurent.Nicod{at}insel.ch.

IL-15 has recently been shown to induce the differentiation of functional dendritic cells (DCs) from human peripheral blood monocytes. Since DCs lay in close proximity to epithelial cells in the airway mucosa, we investigated whether airway epithelial cells could release IL-15 in response to inflammatory stimuli and thereby induce differentiation and maturation of DCs. Alveolar (A549) and bronchial (BEAS-2B) epithelial cells produced IL-15 spontaneously and in a time- and dose-dependent manner after stimulation with IL-1{beta}, IFN-{gamma} or TNF-{alpha}. Airway epithelial cell supernatants induced an increase of IL-15R{alpha} gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15R{alpha} gene expression up to 300 fold. Airway epithelial cell-conditioned media induced the differentiation of ex vivo monocytes into partially mature DCs (HLA-DR+, DC-SIGN+, CD14+, CD80-, CD83+, CD86+, CCR3+, CCR6+, CCR7-). Based on their phenotypic (CD123+, BDCA2+, BDCA4+, BDCA1-, CD1a-) and functional properties (limited maturation upon stimulation with LPS and limited capacity to induce T cell proliferation), these DCs resembled plasmacytoid DCs. The effects of airway epithelial cell supernatants were largely blocked by a neutralizing monoclonal antibody to IL-15. Thus, our results demonstrate that airway epithelial cell-conditioned media have the capacity to differentiate monocytes into functional DCs, a process substantially mediated by epithelial-derived IL-15.




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