{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T08:46:58Z","timestamp":1792572418487,"version":"4.5.0"},"reference-count":37,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,8,6]]},"abstract":"<jats:p>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\u2013associated susceptibility involves prior activation of IL-18 and caspase-1 followed by IL-12 and interferon (IFN)-\u03b3 in the intestine. IL-18\u2013deficient 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-\u03b3.<\/jats:p>\n               <jats:p>In vivo treatment of T. muris\u2013infected IFN-\u03b3\u2013deficient mice with rIL-18 demonstrated that the inhibitory effect of IL-18 on IL-13 secretion is independent of IFN-\u03b3. Hence, IL-18 does not function as an IFN-\u03b3\u2013inducing 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.<\/jats:p>","DOI":"10.1084\/jem.194.3.355","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:48:33Z","timestamp":1027702113000},"page":"355-364","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":80,"title":["Interleukin (Il)-18 Promotes the Development of Chronic Gastrointestinal Helminth Infection by Downregulating IL-13"],"prefix":"10.1084","volume":"194","author":[{"given":"Helena","family":"Helmby","sequence":"first","affiliation":[{"name":"aSchool of Biological Sciences, The University of Manchester, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Takeda","sequence":"additional","affiliation":[{"name":"bDepartment of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizuo","family":"Akira","sequence":"additional","affiliation":[{"name":"bDepartment of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard K.","family":"Grencis","sequence":"additional","affiliation":[{"name":"aSchool of Biological Sciences, The University of Manchester, Manchester M13 9PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2001,8,6]]},"reference":[{"key":"2023072509530484800_R1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0169-4758(97)90019-3","article-title":"This wormy world - then and now","volume":"13","author":"Bundy","year":"1997","journal-title":"Parasitology Today."},{"key":"2023072509530484800_R2","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1365-3024.1992.tb00018.x","article-title":"Modulation of cytokine production and response phenotypes in murine trichuriasis","volume":"14","author":"Else","year":"1992","journal-title":"Parasite Immunol."},{"key":"2023072509530484800_R3","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1084\/jem.179.1.347","article-title":"Cytokine-mediated regulation of intestinal helminth infection","volume":"179","author":"Else","year":"1994","journal-title":"J. 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Immunol."},{"key":"2023072509530484800_R6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/378088a0","article-title":"Cloning of a new cytokine that induces IFN-\u03b3 production by T cells","volume":"378","author":"Okamura","year":"1995","journal-title":"Nature."},{"key":"2023072509530484800_R7","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.4049\/jimmunol.159.5.2125","article-title":"A mechanism underlying synergy between IL-12 and IFN-\u03b3-inducing factor in enhanced production of IFN-\u03b3","volume":"159","author":"Ahn","year":"1997","journal-title":"J. Immunol."},{"key":"2023072509530484800_R8","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S1074-7613(00)80378-7","article-title":"IGIF does not drive Th1 development but synergizes with IL-12 for interferon-\u03b3 production and activates IRAK and NF\u03baB","volume":"7","author":"Robinson","year":"1997","journal-title":"Immunity."},{"key":"2023072509530484800_R9","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.4049\/jimmunol.158.4.1541","article-title":"IFN-\u03b3-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12","volume":"158","author":"Kohno","year":"1997","journal-title":"J. Immunol."},{"key":"2023072509530484800_R10","doi-asserted-by":"crossref","first-page":"3948","DOI":"10.1073\/pnas.94.8.3948","article-title":"Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-\u03b3 production from activated B cells","volume":"94","author":"Yoshimoto","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072509530484800_R11","doi-asserted-by":"crossref","first-page":"3400","DOI":"10.4049\/jimmunol.161.7.3400","article-title":"IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cellssynergism with IL-18 for IFN-\u03b3 production","volume":"161","author":"Yoshimoto","year":"1998","journal-title":"J. Immunol."},{"key":"2023072509530484800_R12","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1084\/jem.187.12.2103","article-title":"Murine macrophages secrete interferon-\u03b3 upon combined stimulation with interleukin (IL)-12 and IL-18a novel pathway of autocrine macrophage activation","volume":"187","author":"Munder","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072509530484800_R13","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1084\/jem.185.6.1005","article-title":"Interleukin-18 (interferon-\u03b3\u2013inducing factor) is produced by osteoblasts and acts via granulocyte\/macrophage colony-stimulating factor and not via interferon-\u03b3 to inhibit osteoclast formation","volume":"185","author":"Udagawa","year":"1997","journal-title":"J. Exp. 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Chem."},{"key":"2023072509530484800_R15","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/386619a0","article-title":"Caspase-1 processes IFN-\u03b3-inducing factor and regulates LPS-induced IFN \u03b3 production","volume":"386","author":"Ghayur","year":"1997","journal-title":"Nature"},{"key":"2023072509530484800_R16","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1126\/science.275.5297.206","article-title":"Activation of interferon-\u03b3 inducing factor mediated by interleukin-1\u03b2 converting enzyme","volume":"275","author":"Gu","year":"1997","journal-title":"Science."},{"key":"2023072509530484800_R17","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S1074-7613(00)80543-9","article-title":"Defective NK cell activity and Th1 response in IL-18-deficient mice","volume":"8","author":"Takeda","year":"1998","journal-title":"Immunity."},{"key":"2023072509530484800_R18","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4049\/jimmunol.163.1.143","article-title":"Bioactive IL-18 expression is up-regulated in Crohn's disease","volume":"163","author":"Monteleone","year":"1999","journal-title":"J. Immunol."},{"key":"2023072509530484800_R19","doi-asserted-by":"crossref","first-page":"6829","DOI":"10.4049\/jimmunol.162.11.6829","article-title":"IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's diseaseexpression and localization in intestinal mucosal cells","volume":"162","author":"Pizarro","year":"1999","journal-title":"J. Immunol."},{"key":"2023072509530484800_R20","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1002\/1521-4141(200007)30:7<1998::AID-IMMU1998>3.0.CO;2-U","article-title":"In vivo administration of IL-18 can induce IgE production through Th2 cytokine induction and up-regulation of CD40 ligand (CD154) expression on CD4+ T cells","volume":"30","author":"Hoshino","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"2023072509530484800_R21","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/77811","article-title":"IL-18 induction of IgEdependence on CD4+ T cells, IL-4 and STAT 6","volume":"1","author":"Yoshimoto","year":"2000","journal-title":"Nat. Immunol."},{"key":"2023072509530484800_R22","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S1074-7613(00)80413-6","article-title":"IL-12-deficient mice are defective in IFN-\u03b3 production and type 1 cytokine responses","volume":"4","author":"Magram","year":"1996","journal-title":"Immunity"},{"key":"2023072509530484800_R23","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1002\/eji.1830241230","article-title":"Low-level infection with Trichuris muris significantly affects the polarization of the CD4 response","volume":"24","author":"Bancroft","year":"1994","journal-title":"Eur. J. Immunol."},{"key":"2023072509530484800_R24","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.4049\/jimmunol.156.3.1207","article-title":"Regulation of bioactive IL-12 production in lipopolysaccharide-stimulated human monocytes is determined by the expression of the p35 subunit","volume":"156","author":"Snijders","year":"1996","journal-title":"J. Immunol."},{"key":"2023072509530484800_R25","doi-asserted-by":"crossref","first-page":"2919","DOI":"10.4049\/jimmunol.158.6.2919","article-title":"Bacterial lipopolysaccharide stimulates the production of cytokines and the expression of costimulatory molecules by human peripheral blood dendritic cellsevidence for a soluble CD14-dependent pathway","volume":"158","author":"Verhasselt","year":"1997","journal-title":"J. Immunol."},{"key":"2023072509530484800_R26","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1084\/jem.186.11.1819","article-title":"In vivo microbial stimulation induces rapid CD40 ligand-independent production of IL-12 by dendritic cells and their redistribution to T cell areas","volume":"186","author":"Reis e Sousa","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023072509530484800_R27","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1073\/pnas.96.5.2256","article-title":"Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1\u03b2 are differentially regulated in human blood mononuclear cells and mouse spleen cells","volume":"96","author":"Puren","year":"1999","journal-title":"Proc. Natl. Acad. Sci. 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Immunol."},{"key":"2023072509530484800_R30","doi-asserted-by":"crossref","first-page":"3818","DOI":"10.1128\/IAI.66.8.3818-3824.1998","article-title":"Differential regulation of the interleukin-12 receptor during the innate immune response to Leishmania major","volume":"66","author":"Jones","year":"1998","journal-title":"Infect. Immun."},{"key":"2023072509530484800_R31","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.4049\/jimmunol.165.3.1463","article-title":"Chlamydia trachomatis infection of epithelial cells induces the activation of caspase-1 and release of mature IL-18","volume":"165","author":"Lu","year":"2000","journal-title":"J. Immunol."},{"key":"2023072509530484800_R32","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.4049\/jimmunol.163.5.2821","article-title":"Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice","volume":"163","author":"Wei","year":"1999","journal-title":"J. Immunol."},{"key":"2023072509530484800_R33","doi-asserted-by":"crossref","first-page":"5890","DOI":"10.4049\/jimmunol.164.11.5890","article-title":"Genetically resistant mice lacking IL-18 gene develop Th1 response and control cutaneous Leishmania major infection","volume":"164","author":"Monteforte","year":"2000","journal-title":"J. Immunol."},{"key":"2023072509530484800_R34","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1128\/IAI.68.5.2449-2456.2000","article-title":"Potentiality of interleukin-18 as a useful reagent for treatment and prevention of Leishmania major infection","volume":"68","author":"Ohkusu","year":"2000","journal-title":"Infect. Immun."},{"key":"2023072509530484800_R35","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.4049\/jimmunol.156.11.4274","article-title":"Cloning of the cDNA for human IFN-\u03b3-inducing factor, expression in Escherichia coli, and studies on the biological activities of the protein","volume":"156","author":"Ushio","year":"1996","journal-title":"J. Immunol."},{"key":"2023072509530484800_R36","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1084\/jem.180.5.1587","article-title":"Transforming growth factor \u03b2the good, the bad, and the ugly","volume":"180","author":"Wahl","year":"1994","journal-title":"J. Exp. Med."},{"key":"2023072509530484800_R37","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.4049\/jimmunol.161.4.1664","article-title":"Low dose TGF-\u03b2 attenuates IL-12 responsiveness in murine Th cells","volume":"161","author":"Gorham","year":"1998","journal-title":"J. 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