{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:06:19Z","timestamp":1791421579238,"version":"4.3.3"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2013,9,17]],"date-time":"2013-09-17T00:00:00Z","timestamp":1379376000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2013,11,1]],"date-time":"2013-11-01T00:00:00Z","timestamp":1383264000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>During visceral leishmaniasis, the control of hepatic parasite burden is mainly due to granuloma assembly in a microenvironment consisting of both Th1 and Th2 components. Using enzyme-linked immunosorbent assay (ELISA) dosages, quantitative PCR (qPCR), immunohistochemistry, and flow cytometry, we studied the role of interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, during visceral leishmaniasis. We showed that a higher level of IL-33 was detected in the serum of patients with visceral leishmaniasis than in that from healthy donors and demonstrated the presence of IL-33<jats:sup>+<\/jats:sup>cells in a liver biopsy specimen from a patient. Similarly, in BALB\/c mice experimentally infected with<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>, a higher level of IL-33 was detected in the serum, as well as the presence of IL-33<jats:sup>+<\/jats:sup>cells and ST2<jats:sup>+<\/jats:sup>cells in the mouse liver. In ST2<jats:sup>\u2212\/\u2212<\/jats:sup>BALB\/c mice, better control of the hepatic parasite burden and reduced hepatomegaly were observed. This was associated with strong induction of Th1 cytokines (gamma interferon [IFN-\u03b3] and IL-12) compared to the level in wild-type (WT) mice and better recruitment of myeloid cells associated with strongly induced chemokines (CCL2 and CXCL2) and receptors (CCR2 and CXCR2). Conversely, BALB\/c mice treated twice weekly with recombinant IL-33 showed a dramatically reduced induction of Th1 cytokines and delayed inhibition of monocyte and neutrophil recruitment in the liver, which was associated with reduced KC\/CXCL1 and CXCR2 expression. Taken together, our results suggest that IL-33 could be a new deleterious regulator of the hepatic immune response against<jats:named-content content-type=\"genus-species\">Leishmania donovani<\/jats:named-content>, via the repression of the Th1 response and myeloid cell recruitment.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Visceral leishmaniasis is a life-threatening systemic disease due to the<jats:italic>Leishmania<\/jats:italic>protozoa<jats:named-content content-type=\"genus-species\">L. infantum<\/jats:named-content>and<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>and is ranked by the World Health Organization as the second most important protozoan parasitic disease after malaria for its grave morbidity, high mortality, and global distribution.<jats:italic>Leishmania<\/jats:italic>parasites subvert the host\u2019s immune response to propagate to target organs, including the spleen, the bone marrow, and the liver. Control of hepatic parasite burdens depends on a delicate and poorly understood Th1\/Th2 immune balance. To better understand this complex immune response, new cytokines are interesting targets for research studies. IL-33 is a newly described cytokine usually associated with Th2 response and involved in different diseases, including infectious diseases and hepatitis. Our results suggest that IL-33 could be a new factor of susceptibility and a potential prognostic marker during visceral leishmaniasis.<\/jats:p>","DOI":"10.1128\/mbio.00383-13","type":"journal-article","created":{"date-parts":[[2013,9,18]],"date-time":"2013-09-18T01:48:41Z","timestamp":1379468921000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":59,"title":["The IL-33\/ST2 Axis Is Associated with Human Visceral Leishmaniasis and Suppresses Th1 Responses in the Livers of BALB\/c Mice Infected with Leishmania donovani"],"prefix":"10.1128","volume":"4","author":[{"given":"Octavie","family":"Rostan","sequence":"first","affiliation":[{"name":"Inserm U1085, IRSET, Rennes, France"},{"name":"BIOSIT, Structure F\u00e9d\u00e9rative UMS3480 CNRS\u2013US18 Inserm, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Gangneux","sequence":"additional","affiliation":[{"name":"Inserm U1085, IRSET, Rennes, France"},{"name":"Laboratoire de Parasitologie-Mycologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Rennes 1, Rennes, France"},{"name":"Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Ponchaillou, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Piquet-Pellorce","sequence":"additional","affiliation":[{"name":"Inserm U1085, IRSET, Rennes, France"},{"name":"BIOSIT, Structure F\u00e9d\u00e9rative UMS3480 CNRS\u2013US18 Inserm, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christelle","family":"Manuel","sequence":"additional","affiliation":[{"name":"Laboratoire de Parasitologie-Mycologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Rennes 1, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N. J.","family":"McKenzie","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Guiguen","sequence":"additional","affiliation":[{"name":"Laboratoire de Parasitologie-Mycologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Rennes 1, Rennes, France"},{"name":"Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Ponchaillou, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Samson","sequence":"additional","affiliation":[{"name":"Inserm U1085, IRSET, Rennes, France"},{"name":"BIOSIT, Structure F\u00e9d\u00e9rative UMS3480 CNRS\u2013US18 Inserm, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Robert-Gangneux","sequence":"additional","affiliation":[{"name":"Inserm U1085, IRSET, Rennes, France"},{"name":"Laboratoire de Parasitologie-Mycologie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Rennes 1, Rennes, France"},{"name":"Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Ponchaillou, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63631-0"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.09.015"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.04.005"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2692"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.2332\/allergolint.10-RAI-0186"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24305"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801898105"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.21175"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2011.02735.x"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.7.4780"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071868"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.218867"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2011.02.005"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2156"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-3983"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2443"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.6.1069"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939705"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200209)32:9<2450::AID-IMMU2450>3.0.CO;2-O"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.4.1961-1971.2003"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.11.6294-6299.2000"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","first-page":"4623","DOI":"10.4049\/jimmunol.154.9.4623","article-title":"IL-12 enhances Th1-type responses in human Leishmania donovani infections","volume":"154","author":"Ghalib HW","year":"1995","unstructured":"GhalibHW WhittleJA KubinM HashimFA el-HassanAM GrabsteinKH TrinchieriG ReedSG . 1995. IL-12 enhances Th1-type responses in human Leishmania donovani infections. J. Immunol. 154:4623\u20134629.","journal-title":"J. Immunol."},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000703"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0399-8320(06)73378-4"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.8.4804-4807.2003"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2009.00801.x"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2010.02316.x"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200589"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-012-8283-9"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2011.53"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25893"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201041332"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1590\/S0036-46651987000300003"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2660"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-011-1760-5"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003331"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0769-2625(87)80030-2"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1250436"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2011.22"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2004.02.004"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112209"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/0001-706X(94)90103-1"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1177\/039463200702000302"},{"key":"e_1_3_2_45_2","first-page":"245","article-title":"Immune responses in kala-azar","volume":"123","author":"Saha S","year":"2006","unstructured":"SahaS MondalS BanerjeeA GhoseJ BhowmickS AliN . 2006. Immune responses in kala-azar. Indian J. Med. Res. 123:245\u2013266.","journal-title":"Indian J. Med. Res."},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(90)90038-R"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2004.00188.x"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.icb7100011"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/173.6.1515"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/0008-8749(85)90274-6"},{"key":"e_1_3_2_51_2","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1172\/JCI114654","article-title":"Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1","volume":"85","author":"Reiner NE","year":"1990","unstructured":"ReinerNE NgW WilsonCB McMasterWR BurchettSK . 1990. Modulation of in vitro monocyte cytokine responses to Leishmania donovani. Interferon-gamma prevents parasite-induced inhibition of interleukin 1 production and primes monocytes to respond to Leishmania by producing both tumor necrosis factor-alpha and interleukin 1. J. Clin. Invest. 85:1914\u20131924.","journal-title":"J. Clin. Invest."},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.7.1231"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2012.84"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033413"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2010.11.005"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-12-162"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103564"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25768"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30634"},{"key":"e_1_3_2_60_2","first-page":"799","article-title":"The Th2 transcription factor c-Maf inhibits IL-12p35 gene expression in activated macrophages by targeting NF-kappaB nuclear translocation","volume":"27","author":"Homma Y","year":"2007","unstructured":"HommaY CaoS ShiX MaX . 2007. The Th2 transcription factor c-Maf inhibits IL-12p35 gene expression in activated macrophages by targeting NF-kappaB nuclear translocation. J. Interferon Cytokine Res. 27:799\u2013808.","journal-title":"J. Interferon Cytokine Res."},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.10.5258"},{"key":"e_1_3_2_62_2","first-page":"89","article-title":"The regulation of beta-interferon gene expression","volume":"1","author":"Goodbourn S","year":"1990","unstructured":"GoodbournS . 1990. The regulation of beta-interferon gene expression. Semin. Cancer Biol. 1:89\u201395.","journal-title":"Semin. Cancer Biol."},{"key":"e_1_3_2_63_2","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.4049\/jimmunol.155.7.3593","article-title":"Two structurally distinct kappa B sequence motifs cooperatively control LPS-induced KC gene transcription in mouse macrophages","volume":"155","author":"Ohmori Y","year":"1995","unstructured":"OhmoriY FukumotoS HamiltonTA . 1995. Two structurally distinct kappa B sequence motifs cooperatively control LPS-induced KC gene transcription in mouse macrophages. J. Immunol. 155:3593\u20133600.","journal-title":"J. Immunol."},{"key":"e_1_3_2_64_2","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.4049\/jimmunol.153.5.2052","article-title":"NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene","volume":"153","author":"Ueda A","year":"1994","unstructured":"UedaA OkudaK OhnoS ShiraiA IgarashiT MatsunagaK FukushimaJ KawamotoS IshigatsuboY OkuboT . 1994. NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. J. Immunol. 153:2052\u20132063.","journal-title":"J. Immunol."},{"key":"e_1_3_2_65_2","doi-asserted-by":"crossref","first-page":"4996","DOI":"10.4049\/jimmunol.150.11.4996","article-title":"Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1alpha, and MIP-1beta, members of the chemokine superfamily of proinflammatory cytokines","volume":"150","author":"Widmer U","year":"1993","unstructured":"WidmerU ManogueKR CeramiA SherryB . 1993. Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1alpha, and MIP-1beta, members of the chemokine superfamily of proinflammatory cytokines. J. Immunol. 150:4996\u20135012.","journal-title":"J. Immunol."},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210536"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200737586"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.08.016"},{"key":"e_1_3_2_69_2","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.4049\/jimmunol.138.7.2290","article-title":"Experimental visceral leishmaniasis: production of interleukin 2 and interferon-gamma, tissue immune reaction, and response to treatment with interleukin 2 and interferon-gamma","volume":"138","author":"Murray HW","year":"1987","unstructured":"MurrayHW SternJJ WelteK RubinBY CarrieroSM NathanCF . 1987. Experimental visceral leishmaniasis: production of interleukin 2 and interferon-gamma, tissue immune reaction, and response to treatment with interleukin 2 and interferon-gamma. J. Immunol. 138:2290\u20132297.","journal-title":"J. Immunol"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00383-13","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00383-13","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T16:48:11Z","timestamp":1688489291000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.00383-13"}},"subtitle":[],"editor":[{"given":"Louis M.","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2013,11]]},"references-count":68,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2013,11]]}},"alternative-id":["10.1128\/mBio.00383-13"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00383-13","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,11]]},"assertion":[{"value":"2013-05-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-08-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-09-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00383-13"}}