title: Regulation of gut inflammation and th17 cell response by interleukin-21.
abstract: OBJECTIVE
  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.affiliation: Dipartimento di Medicina Interna e Centro di Eccellenza per lo studio delle malattie complesse e multifattoriali, Università Tor Vergata, Rome.
authors.forename: Daniele
authors.initials: D
authors.lastname: Fina
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Sarra
authors.forename: Massimo C
authors.initials: MC
authors.lastname: Fantini
authors.forename: Angelamaria
authors.initials: A
authors.lastname: Rizzo
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Iris
authors.initials: I
authors.lastname: Cardolini
authors.forename: Marta
authors.initials: M
authors.lastname: Dottori
authors.forename: Monica
authors.initials: M
authors.lastname: Boirivant
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Macdonald
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D016176:T-Lymphocyte Subsets; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D000098546:Interleukin-21
chemical_list: D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D012313:RNA; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D000098546:Interleukin-21