A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells

Gastroenterology. 2007 Jan;132(1):166-75. doi: 10.1053/j.gastro.2006.09.053. Epub 2006 Oct 1.


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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • Caco-2 Cells
  • Cell Communication / immunology
  • Cell Movement / immunology
  • Chemokine CCL20
  • Chemokines, CC / metabolism*
  • Colon / cytology
  • Colon / immunology
  • Colon / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • HT29 Cells
  • Humans
  • Inflammatory Bowel Diseases / immunology*
  • Inflammatory Bowel Diseases / metabolism
  • Inflammatory Bowel Diseases / pathology
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Interleukins / pharmacology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism
  • Macrophage Inflammatory Proteins / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Organ Culture Techniques
  • Receptors, Interleukin-21 / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*


  • Antibodies
  • CCL20 protein, human
  • Chemokine CCL20
  • Chemokines, CC
  • Interleukins
  • Macrophage Inflammatory Proteins
  • Receptors, Interleukin-21
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • interleukin-21