Regulation of Gut Inflammation and Th17 Cell Response by Interleukin-21

Daniele Fina, Massimiliano Sarra, Massimo C. Fantini, Angelamaria Rizzo, Roberta Caruso, Flavio Caprioli, Carmine Stolfi, Iris Cardolini, Marta Dottori, Monica Boirivant, Francesco Pallone, Thomas T. MacDonald, Giovanni Monteleone

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Abstract

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-β1, 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.

Original languageEnglish
JournalGastroenterology
Volume134
Issue number4
DOIs
Publication statusPublished - Apr 2008

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ASJC Scopus subject areas

  • Gastroenterology

Cite this

Fina, D., Sarra, M., Fantini, M. C., Rizzo, A., Caruso, R., Caprioli, F., Stolfi, C., Cardolini, I., Dottori, M., Boirivant, M., Pallone, F., MacDonald, T. T., & Monteleone, G. (2008). Regulation of Gut Inflammation and Th17 Cell Response by Interleukin-21. Gastroenterology, 134(4). https://doi.org/10.1053/j.gastro.2008.01.041