Critical role of IL-25 in nematode infection-induced alterations in intestinal function.
IL-25 (IL-17E) is a member of the IL-17 cytokine family. IL-25-deficient mice exhibit impaired Th2 immunity against nematode infection, implicating IL-25 as a key component in mucosal immunity. The sources of IL-25 and mechanisms responsible for the induction of Th2 immunity by IL-25 in the gastrointestinal tract remain poorly understood. There is also little information on the regulation of IL-25 during inflammation or its role in gut function. In the current study, we investigated the regulation of IL-25 during Nippostrongylus brasiliensis infection and the contribution of IL-25 to the infection-induced alterations in intestinal function. We found that epithelial cells, but not immune cells, are the major source of IL-25 in the small intestine. N. brasiliensis infection-induced upregulation of IL-25 depends upon IL-13 activation of STAT6. IL-25(-/-) mice had diminished intestinal smooth muscle and epithelial responses to N. brasiliensis infection that were associated with an impaired Th2 protective immunity. Exogenous IL-25 induced characteristic changes similar to those after nematode infection but was unable to restore the impaired host immunity against N. brasiliensis infection in IL-13(-/-) mice. These data show that IL-25 plays a critical role in nematode infection-induced alterations in intestinal function that are important for host protective immunity, and IL-13 is the major downstream Th2 cytokine responsible for the IL-25 effects.
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. azhao@mbrc.umaryland.edu
Aiping
A
Zhao
Joseph F
JF
Urban
Rex
R
Sun
Jennifer
J
Stiltz
Motoko
M
Morimoto
Luigi
L
Notari
Kathleen B
KB
Madden
Zhonghan
Z
Yang
Viktoriya
V
Grinchuk
Thirumalai R
TR
Ramalingam
Thomas A
TA
Wynn
Terez
T
Shea-Donohue
D000818:Animals; D018928:Immunity, Mucosal; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007378:Interleukins / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000469:parasitology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009130:Muscle, Smooth / Q000276:immunology / Q000469:parasitology / Q000503:physiopathology; D009559:Nippostrongylus / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D017206:Strongylida Infections / Q000276:immunology* / Q000469:parasitology / Q000503:physiopathology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D015854:Up-Regulation / Q000276:immunology
D018793:Interleukin-13; D007378:Interleukins; C442281:Mydgf protein, mouse; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4