{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T15:28:51Z","timestamp":1774020531843,"version":"3.50.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T00:00:00Z","timestamp":1259625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Immediate early response gene X-1 (IEX-1) is a stress-inducible gene abundantly expressed in macrophages and T cells following various stimuli. To explore a potential role for IEX-1 in control of the susceptibility to Leishmania major infection, the inflammatory response during cutaneous leishmaniasis was evaluated in 129Sv\/C57BL\/6-resistant mice in the presence or absence of IEX-1. Null mutation of IEX-1 enhanced the susceptibility of the mice to L. major infection, and aggravated inflammatory responses in comparison with wild-type control mice. The excessive inflammation was not ascribed to a Th2-biased immune response or a defect in Th1 polarization, but rather to an elevated level of IL-17 production by both \u03b3\u03b4 T and CD4+ cells, concomitant with an increase of the neutrophil recruitment early in the infection. The lack of IEX-1 also suppressed TNF-\u03b1 production in both macrophages and T cells, resulting in a high intralesional load of parasites and delayed healing of the lesion, both of which were reversed by TNF-\u03b1 treatment. These findings indicate the crucial role of IL-17 and TNF-\u03b1 in determining the outcome of L. major infection beyond a balance between Th1- and Th2-mediated immune responses.<\/jats:p>","DOI":"10.4049\/jimmunol.0900866","type":"journal-article","created":{"date-parts":[[2009,11,18]],"date-time":"2009-11-18T22:22:55Z","timestamp":1258582975000},"page":"7994-8003","source":"Crossref","is-referenced-by-count":21,"title":["Enhanced Susceptibility to\n                    <i>Leishmania<\/i>\n                    Infection in Resistant Mice in the Absence of Immediate Early Response Gene X-1"],"prefix":"10.1093","volume":"183","author":[{"given":"Oleg E","family":"Akilov","sequence":"first","affiliation":[{"name":"Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School , Boston, MA 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina V","family":"Ustyugova","sequence":"additional","affiliation":[{"name":"Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School , Boston, MA 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhi","sequence":"additional","affiliation":[{"name":"Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School , Boston, MA 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tayyaba","family":"Hasan","sequence":"additional","affiliation":[{"name":"Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School , Boston, MA 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei X","family":"Wu","sequence":"additional","affiliation":[{"name":"Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School , Boston, MA 02114"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,12,15]]},"reference":[{"key":"2026012811214383600_R1","first-page":"225","article-title":"Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice.","volume-title":"Immunol. Rev.","year":"2004"},{"key":"2026012811214383600_R2","first-page":"187","article-title":"Macrophage-parasite interactions in Leishmania infections.","volume-title":"J. Leukocyte Biol.","year":"1990"},{"key":"2026012811214383600_R3","first-page":"143","article-title":"Cytokine profile and pathology in human leishmaniasis.","volume-title":"Braz. J. Med. Biol. Res.","year":"1998"},{"key":"2026012811214383600_R4","first-page":"413","article-title":"Immunology of leishmaniasis.","volume-title":"Curr. Opin. Immunol.","year":"1992"},{"key":"2026012811214383600_R5","first-page":"6132","article-title":"IL-4- and IL-4 receptor-deficient BALB\/c mice reveal differences in susceptibility to Leishmania major parasite substrains.","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012811214383600_R6","first-page":"1499","article-title":"Mechanism of transforming growth factor \u03b2-induced inhibition of T helper type 1 differentiation.","volume-title":"J. Exp. Med.","year":"2002"},{"key":"2026012811214383600_R7","first-page":"974","article-title":"Anti-TGF-\u03b2 treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production.","volume-title":"J. Immunol.","year":"1999"},{"key":"2026012811214383600_R8","first-page":"744","article-title":"Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.","volume-title":"Nature","year":"2003"},{"key":"2026012811214383600_R9","first-page":"207","article-title":"TGF-\u03b2 indirectly favors the development of human Th17 cells by inhibiting Th1 cells.","volume-title":"Eur. J. Immunol.","year":"2009"},{"key":"2026012811214383600_R10","first-page":"3039","article-title":"IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice.","volume-title":"J. Immunol.","year":"2009"},{"key":"2026012811214383600_R11","first-page":"603","article-title":"IEX-1 targets mitochondrial F1Fo-ATPase inhibitor for degradation.","volume-title":"Cell Death Differ.","year":"2008"},{"key":"2026012811214383600_R12","first-page":"878","article-title":"Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2002"},{"key":"2026012811214383600_R13","first-page":"97","article-title":"A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation.","volume-title":"Exp. Parasitol.","year":"2001"},{"key":"2026012811214383600_R14","first-page":"1941","article-title":"Development of a natural model of cutaneous leishmaniasis: powerful effects of vector saliva and saliva preexposure on the long-term outcome of Leishmania major infection in the mouse ear dermis.","volume-title":"J. Exp. Med.","year":"1998"},{"key":"2026012811214383600_R15","first-page":"1064","article-title":"Enhanced cloning efficiency of mouse bone marrow macrophage progenitors correlates with increased content of CSF-1 receptor of their progeny at low oxygen tension.","volume-title":"Microbes Infect.","year":"2003"},{"key":"2026012811214383600_R16","first-page":"875","article-title":"Regulatory T cells and infection: a dangerous necessity.","volume-title":"Nat. Rev. Immunol.","year":"2007"},{"key":"2026012811214383600_R17","first-page":"394","article-title":"CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice.","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012811214383600_R18","first-page":"6369","article-title":"Macrophage synthesis of nitrite, nitrate, and N-nitrosamines: precursors and role of the respiratory burst.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1987"},{"key":"2026012811214383600_R19","first-page":"87","article-title":"Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens.","volume-title":"Immunol. Lett.","year":"1994"},{"key":"2026012811214383600_R20","first-page":"98","article-title":"Leishmania spp.: mechanisms of toxicity of nitrogen oxidation products.","volume-title":"Exp. Parasitol.","year":"1997"},{"key":"2026012811214383600_R21","first-page":"278","article-title":"Activated macrophages destroy intracellular Leishmania major amastigotes by an l-arginine-dependent killing mechanism.","volume-title":"J. Immunol.","year":"1990"},{"key":"2026012811214383600_R22","first-page":"672","article-title":"Production of nitric oxide and superoxide by activated macrophages and killing of Leishmania major.","volume-title":"Eur. J. Immunol.","year":"1994"},{"key":"2026012811214383600_R23","first-page":"1331","article-title":"Effective clearance of intracellular Leishmania major in vivo requires Pten in macrophages.","volume-title":"Eur. J. Immunol.","year":"2008"},{"key":"2026012811214383600_R24","first-page":"4306","article-title":"Tumor necrosis factor-\u03b1 synergizes with IFN-\u03b3 in mediating killing of Leishmania major through the induction of nitric oxide.","volume-title":"J. Immunol.","year":"1990"},{"key":"2026012811214383600_R25","first-page":"1414","article-title":"Tumor necrosis factor \u03b1 (TNF-\u03b1) and TNF-\u03b2 and their receptors in experimental cutaneous leishmaniasis.","volume-title":"Infect. Immun.","year":"1994"},{"key":"2026012811214383600_R26","first-page":"720","article-title":"An essential role for transmembrane TNF in the resolution of the inflammatory lesion induced by Leishmania major infection.","volume-title":"Eur. J. Immunol.","year":"2008"},{"key":"2026012811214383600_R27","first-page":"1587","article-title":"Interferon-\u03b3 and tumor necrosis factor induce the l-arginine-dependent cytotoxic effector mechanism in murine macrophages.","volume-title":"Eur. J. Immunol.","year":"1988"},{"key":"2026012811214383600_R28","first-page":"707","article-title":"Elevated blood pressure and cardiac hypertrophy after ablation of the gly96\/IEX-1 gene.","volume-title":"J. Appl. Physiol.","year":"2006"},{"key":"2026012811214383600_R29","first-page":"6845","article-title":"Development of T-cell lymphomas in Emu-IEX-1 mice.","volume-title":"Oncogene","year":"2003"},{"key":"2026012811214383600_R30","first-page":"502","article-title":"CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.","volume-title":"Nature","year":"2002"},{"key":"2026012811214383600_R31","first-page":"969","article-title":"A natural model of Leishmania major infection reveals a prolonged \u201csilent\u201d phase of parasite amplification in the skin before the onset of lesion formation and immunity.","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012811214383600_R32","first-page":"3232","article-title":"The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB\/c mice are subject to the control of regulatory CD4+CD25+ T cells.","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012811214383600_R33","first-page":"201","article-title":"Leishmania amazonensis: participation of regulatory T and B cells in the in vitro priming (PIV) of CBA\/J spleen cells susceptible response.","volume-title":"Exp. Parasitol.","year":"2006"},{"key":"2026012811214383600_R34","first-page":"135","article-title":"Differences in the onset of the inflammatory response to cutaneous leishmaniasis in resistant and susceptible mice.","volume-title":"J. Leukocyte Biol.","year":"1992"},{"key":"2026012811214383600_R35","first-page":"2636","article-title":"Induction, function and regulation of IL-17-producing T cells.","volume-title":"Eur. J. Immunol.","year":"2008"},{"key":"2026012811214383600_R36","first-page":"2628","article-title":"An immunomodulatory function for neutrophils during the induction of a CD4+ Th2 response in BALB\/c mice infected with Leishmania major.","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012811214383600_R37","first-page":"4454","article-title":"Macrophage interactions with neutrophils regulate Leishmania major infection.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811214383600_R38","first-page":"2097","article-title":"Tumor necrosis factor plays a protective role in experimental murine cutaneous leishmaniasis.","volume-title":"J. Exp. Med.","year":"1989"},{"key":"2026012811214383600_R39","first-page":"4290","article-title":"Leishmania major amastigotes initiate the l-arginine-dependent killing mechanism in IFN-\u03b3-stimulated macrophages by induction of tumor necrosis factor-\u03b1.","volume-title":"J. Immunol.","year":"1990"},{"key":"2026012811214383600_R40","first-page":"235","article-title":"[Leishmaniasis in rheumatoid arthritis.].","volume-title":"Reumatismo","year":"2007"},{"key":"2026012811214383600_R41","first-page":"1920","article-title":"Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major.","volume-title":"Infect. Immun.","year":"2004"},{"key":"2026012811214383600_R42","first-page":"2822","article-title":"MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor 2 signaling.","volume-title":"Eur. J. Immunol.","year":"2003"},{"key":"2026012811214383600_R43","first-page":"11380","article-title":"Oxidoreductive regulation of nuclear factor \u03baB: involvement of a cellular reducing catalyst thioredoxin.","volume-title":"J. Biol. Chem.","year":"1993"},{"key":"2026012811214383600_R44","first-page":"4328","article-title":"Modulation of transcription factor NF-\u03baB binding activity by oxidation-reduction in vitro.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1991"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/12\/7994\/62688780\/9887.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/12\/7994\/62688780\/9887.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:22:16Z","timestamp":1769617336000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/12\/7994\/8053012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2009,12,15]]},"published-print":{"date-parts":[[2009,12,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0900866","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,12]]},"published":{"date-parts":[[2009,12]]}}}