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 language | English |
|---|---|
| Journal | Gastroenterology |
| Volume | 134 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2008 |
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ASJC Scopus subject areas
- Gastroenterology
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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 journal › Article
}
TY - JOUR
T1 - Regulation of Gut Inflammation and Th17 Cell Response by Interleukin-21
AU - Fina, Daniele
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.
AU - Monteleone, Giovanni
PY - 2008/4
Y1 - 2008/4
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=41349121555&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41349121555&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2008.01.041
DO - 10.1053/j.gastro.2008.01.041
M3 - Article
C2 - 18395085
AN - SCOPUS:41349121555
VL - 134
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 4
ER -