A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells.
OBJECTIVE
Interleukin (IL)-21, a T-cell-derived cytokine, is produced in excess in inflammatory bowel diseases (IBD). The IL-21 receptor (IL-21R) is expressed by immune and nonimmune cells, raising the possibility that IL-21 has broad effects in gut inflammation. In this study we examined whether intestinal epithelial cells express IL-21R and respond to IL-21 in IBD.


METHODS
IL-21R was evaluated in intestinal samples of IBD patients and controls by immunohistochemistry and Western blotting. Intestinal epithelial cells were stimulated with IL-21, and cell-free supernatants were evaluated by a protein array and enzyme-linked immunosorbent assay. The effect of IL-21-treated epithelial cell supernatants on blood lymphocyte migration was assessed using a chemotaxis assay. Finally, we evaluated the effect of a neutralizing IL-21 antibody on MIP-3alpha synthesis in ex vivo organ cultures of IBD mucosal explants.


RESULTS
Constitutive expression of IL-21R was seen in intestinal epithelial cells, but was higher in IBD patients than in controls. Stimulation of intestinal epithelial cells with IL-21 resulted in enhanced phosphorylation of ERK1/2 and p38 and increased synthesis of macrophage inflammatory protein-3 alpha (MIP-3alpha), a T-cell chemoattractant. Inhibition of ERK1/2 but not p38 suppressed IL-21-induced MIP-3alpha production. IL-21-treated cell culture supernatants enhanced in vitro lymphocyte migration, and this effect was inhibited by anti-MIP-3alpha antibody. Treatment of IBD explants with anti-IL-21 reduced MIP-3alpha production.


CONCLUSIONS
These data show that intestinal epithelial cells are a target of IL-21 and that IL-21 is involved in the cross-talk between epithelial and immune cells in the gut.
Caruso
Roberta
R
Dipartimento di Medicina Interna e Centro di Eccellenza, Studio delle Malattie Complesse e Multifattoriali, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Fina
Daniele
D
Peluso
Ilaria
I
Stolfi
Carmine
C
Fantini
Massimo Claudio
MC
Gioia
Valentina
V
Caprioli
Flavio
F
Del Vecchio Blanco
Giovanna
G
Paoluzi
Omero Alessandro
OA
Macdonald
Thomas T
TT
Pallone
Francesco
F
Monteleone
Giovanni
G
D000906:Antibodies / Q000494:pharmacology; D018938:Caco-2 Cells; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009924:Organ Culture Techniques; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D000098546:Interleukin-21
D000906:Antibodies; C108355:CCL20 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D007378:Interleukins; D019402:Macrophage Inflammatory Proteins; D053655:Receptors, Interleukin-21; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000098546:Interleukin-21