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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Th17 Cells
Inflammation
Colitis
Interleukin-17
Inflammatory Bowel Diseases
Trinitrobenzenes
T-Lymphocytes
Dextran Sulfate
Sulfonic Acids
Interleukins
interleukin-21
Mucous Membrane
Cytokines
Transforming Growth Factors

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Fina, D., Sarra, M., Fantini, M. C., Rizzo, A., Caruso, R., Caprioli, F., ... 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

Regulation of Gut Inflammation and Th17 Cell Response by Interleukin-21. / Fina, Daniele; Sarra, Massimiliano; Fantini, Massimo C.; Rizzo, Angelamaria; Caruso, Roberta; Caprioli, Flavio; Stolfi, Carmine; Cardolini, Iris; Dottori, Marta; Boirivant, Monica; Pallone, Francesco; MacDonald, Thomas T.; Monteleone, Giovanni.

In: Gastroenterology, Vol. 134, No. 4, 04.2008.

Research output: Contribution to journalArticle

Fina, D, Sarra, M, Fantini, MC, Rizzo, A, Caruso, R, Caprioli, F, Stolfi, C, Cardolini, I, Dottori, M, Boirivant, M, Pallone, F, MacDonald, TT & Monteleone, G 2008, 'Regulation of Gut Inflammation and Th17 Cell Response by Interleukin-21', Gastroenterology, vol. 134, no. 4. https://doi.org/10.1053/j.gastro.2008.01.041
Fina, Daniele ; Sarra, Massimiliano ; Fantini, Massimo C. ; Rizzo, Angelamaria ; Caruso, Roberta ; Caprioli, Flavio ; Stolfi, Carmine ; Cardolini, Iris ; Dottori, Marta ; Boirivant, Monica ; Pallone, Francesco ; MacDonald, Thomas T. ; Monteleone, Giovanni. / Regulation of Gut Inflammation and Th17 Cell Response by Interleukin-21. In: Gastroenterology. 2008 ; Vol. 134, No. 4.
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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, na{\"i}ve 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.",
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AU - Sarra, Massimiliano

AU - Fantini, Massimo C.

AU - Rizzo, Angelamaria

AU - Caruso, Roberta

AU - Caprioli, Flavio

AU - Stolfi, Carmine

AU - Cardolini, Iris

AU - Dottori, Marta

AU - Boirivant, Monica

AU - Pallone, Francesco

AU - MacDonald, Thomas T.

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N2 - 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.

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