A Functional Role for Interleukin-21 in Promoting the Synthesis of the T-Cell Chemoattractant, MIP-3α, by Gut Epithelial Cells

Roberta Caruso, Daniele Fina, Ilaria Peluso, Carmine Stolfi, Massimo Claudio Fantini, Valentina Gioia, Flavio Caprioli, Giovanna Del Vecchio Blanco, Omero Alessandro Paoluzi, Thomas T. MacDonald, Francesco Pallone, Giovanni Monteleone

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Abstract

Background & Aims: 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-3α 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-3α), a T-cell chemoattractant. Inhibition of ERK1/2 but not p38 suppressed IL-21-induced MIP-3α production. IL-21-treated cell culture supernatants enhanced in vitro lymphocyte migration, and this effect was inhibited by anti-MIP-3α antibody. Treatment of IBD explants with anti-IL-21 reduced MIP-3α 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.

Original languageEnglish
Pages (from-to)166-175
Number of pages10
JournalGastroenterology
Volume132
Issue number1
DOIs
Publication statusPublished - Jan 2007

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ASJC Scopus subject areas

  • Gastroenterology

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Caruso, R., Fina, D., Peluso, I., Stolfi, C., Fantini, M. C., Gioia, V., Caprioli, F., Del Vecchio Blanco, G., Paoluzi, O. A., MacDonald, T. T., Pallone, F., & Monteleone, G. (2007). A Functional Role for Interleukin-21 in Promoting the Synthesis of the T-Cell Chemoattractant, MIP-3α, by Gut Epithelial Cells. Gastroenterology, 132(1), 166-175. https://doi.org/10.1053/j.gastro.2006.09.053