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

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-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.

• Authors: 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
• Journal: Gastroenterology (Gastroenterology) Vol. 134 Issue 4 Pg. 1038-48 (Apr 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18395085 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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