Regulation of gut inflammation and th17 cell response by interleukin-21

Gastroenterology. 2008 Apr;134(4):1038-48. doi: 10.1053/j.gastro.2008.01.041. Epub 2008 Jan 17.


Background & aims: Interleukin (IL)-21, a T-cell-derived cytokine, is overproduced in inflammatory bowel diseases (IBD), but its role in the pathogenesis of gut inflammation remains unknown. We here examined whether IL-21 is necessary for the initiation and progress of experimental colitis and whether it regulates specific pathways of inflammation.

Methods: Both dextran sulfate sodium colitis and trinitrobenzene sulfonic acid-relapsing colitis were induced in wild-type and IL-21-deficient mice. CD4(+)CD25(-) T cells from wild-type and IL-21-deficient mice were differentiated in T helper cell (Th)17-polarizing conditions, with or without IL-21 or an antagonistic IL-21R/Fc. We also examined whether blockade of IL-21 by anti-IL-21 antibody reduced IL-17 in cultures of IBD lamina propria CD3(+) T lymphocytes. Cytokines were evaluated by real-time polymerase chain reaction and/or enzyme-linked immunosorbent assay.

Results: High IL-21 was seen in wild-type mice with dextran sulfate sodium- and trinitrobenzene sulfonic acid-relapsing colitis. IL-21-deficient mice were largely protected against both colitides and were unable to up-regulate Th17-associated molecules during gut inflammation, thus suggesting a role for IL-21 in controlling Th17 cell responses. Indeed, naïve T cells from IL-21-deficient mice failed to differentiate into Th17 cells. Treatment of developing Th17 cells from wild-type mice with IL-21R/Fc reduced IL-17 production. Moreover, in the presence of transforming growth factor-beta1, exogenous IL-21 substituted for IL-6 in driving IL-17 induction. Neutralization of IL-21 reduced IL-17 secretion by IBD lamina propria lymphocytes.

Conclusions: These results indicate that IL-21 is a critical regulator of inflammation and Th17 cell responses in the gut.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colitis / metabolism
  • Dextran Sulfate / toxicity
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression
  • Humans
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukins / deficiency
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polymerase Chain Reaction
  • RNA / genetics
  • T-Lymphocyte Subsets
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Trinitrobenzenesulfonic Acid / toxicity


  • Interleukin-17
  • Interleukin-2 Receptor alpha Subunit
  • Interleukins
  • RNA
  • Trinitrobenzenesulfonic Acid
  • Dextran Sulfate
  • interleukin-21