Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13.
Expulsion of the gastrointestinal nematode Trichuris muris is mediated by a T helper (Th) 2 type response involving interleukin (IL)-4 and IL-13. Here we show that Th1 response-associated susceptibility involves prior activation of IL-18 and caspase-1 followed by IL-12 and interferon (IFN)-gamma in the intestine. IL-18-deficient mice are highly resistant to chronic T. muris infection and in vivo treatment of normal mice with recombinant (r)IL-18 suppresses IL-13 and IL-4 secretion but does not affect IFN-gamma. In vivo treatment of T. muris-infected IFN-gamma-deficient mice with rIL-18 demonstrated that the inhibitory effect of IL-18 on IL-13 secretion is independent of IFN-gamma. Hence, IL-18 does not function as an IFN-gamma-inducing cytokine during chronic T. muris infection but rather as a direct regulator of Th2 cytokines. These results provide the first demonstration of the critical role of IL-18 in regulating Th cell responses during gastrointestinal nematode infection.
Helmby
H
H
School of Biological Sciences, Stopford Building 3.239, The University of Manchester, Manchester M13 9PT, UK. helena.e.helmby@man.ac.uk
Takeda
K
K
Akira
S
S
Grencis
R K
RK
D000818:Animals; D020170:Caspase 1 / Q000235:genetics; D002908:Chronic Disease; D015536:Down-Regulation; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014257:Trichuriasis / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation
D018793:Interleukin-13; D020382:Interleukin-18; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D020170:Caspase 1