Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract.
The cytokine interleukin (IL) 25 has been implicated in the initiation of type 2 immunity by driving the expression of type 2 cytokines such as IL-5 and IL-13, although its role in the regulation of immunity and infection-induced inflammation is unknown. Here, we identify a dual function for IL-25: first, in promoting type 2 cytokine-dependent immunity to gastrointestinal helminth infection and, second, in limiting proinflammatory cytokine production and chronic intestinal inflammation. Treatment of genetically susceptible mice with exogenous IL-25 promoted type 2 cytokine responses and immunity to Trichuris. IL-25 was constitutively expressed by CD4+ and CD8+ T cells in the gut of mouse strains that are resistant to Trichuris, and IL-25-deficient mice on a genetically resistant background failed to develop a type 2 immune response or eradicate infection. Furthermore, chronically infected IL-25(-/-) mice developed severe infection-induced intestinal inflammation associated with heightened expression of interferon-gamma and IL-17, identifying a role for IL-25 in limiting pathologic inflammation at mucosal sites. Therefore, IL-25 is not only a critical mediator of type 2 immunity, but is also required for the regulation of inflammation in the gastrointestinal tract.
Owyang
Alexander M
AM
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Zaph
Colby
C
Wilson
Emma H
EH
Guild
Katherine J
KJ
McClanahan
Terrill
T
Miller
Hugh R P
HR
Cua
Daniel J
DJ
Goldschmidt
Michael
M
Hunter
Christopher A
CA
Kastelein
Robert A
RA
Artis
David
D
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000145:classification* / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D007249:Inflammation / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D007378:Interleukins / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D014257:Trichuriasis / Q000188:drug therapy / Q000276:immunology*; D014258:Trichuris / Q000276:immunology
D016207:Cytokines; D007378:Interleukins; C442281:Mydgf protein, mouse; D011994:Recombinant Proteins