Airway epithelial IL-15 transforms monocytes into dendritic cells.
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 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-1beta, IFN-gamma, or TNF-alpha. Airway epithelial cell supernatants induced an increase of IL-15Ralpha gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15Ralpha 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.
Regamey
Nicolas
N
Division of Respiratory Medicine, University Hospital of Berne, Freiburgstrasse 15, CH-3010 Berne, Switzerland.
Obregon
Carolina
C
Ferrari-Lacraz
Sylvie
S
van Leer
Coretta
C
Chanson
Marc
M
Nicod
Laurent P
LP
Geiser
Thomas
T
D000911:Antibodies, Monoclonal / Q000737:chemistry; D001980:Bronchi / Q000378:metabolism*; D002454:Cell Differentiation; D017077:Culture Media, Conditioned; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D004848:Epithelium / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000008:administration & dosage* / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma