{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T19:34:50Z","timestamp":1791056090541,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2009,6,1]],"date-time":"2009-06-01T00:00:00Z","timestamp":1243814400000},"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":[[2009,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leishmania donovani, a protozoan parasite, resides and replicates as amastigotes within macrophages. The parasite inflicts the disease visceral leishmaniasis by suppressing host cell function. Neither a therapeutic vaccine nor an effective anti-leishmanial drug to reverse the immunosuppression is available. Although miltefosine (hexadecylphosphocholine or HPC) is a promising orally bioavailable anti-leishmanial drug, its efficacy is seriously compromised by contra-indications in pregnant women. Further rational redesigning of the drug requires studies on its mechanism of action, which is unknown at present. Because miltefosine is proposed to have immunomodulatory functions, we examined whether miltefosine exerts its anti-leishmanial functions by activating macrophages. We observed that miltefosine\u2019s anti-leishmanial function was significantly compromised in IFN-\u03b3-deficient macrophages suggesting the importance of endogenous IFN-\u03b3 in miltefosine-induced anti-leishmanial functions of macrophages. Miltefosine induced IFN-\u03b3, neutralization of which reduced the anti-leishmanial functions of macrophages. IFN-\u03b3 responsiveness is reduced in L. donovani-infected macrophages but is significantly restored by miltefosine, as it enhances IFN-\u03b3 receptors and IFN-\u03b3 induced STAT-1 phosphorylation but reduced activation of SHP-1, the phosphatase implicated in the down-regulation of STAT-1 phosphorylation. Miltefosine induced protein kinase C-dependent and PI3K-dependent p38MAP kinase phosphorylation and anti-leishmanial function. Miltefosine promotes p38MAP kinase-dependent anti-leishmanial functions and IL-12-dependent Th1 response. Leishmania donovani-infected macrophages induced Th2 response but miltefosine treatment reversed the response to Th1-type. Thus, our data define for the first time the mechanistic basis of host cell-dependent anti-leishmanial function of miltefosine.<\/jats:p>","DOI":"10.4049\/jimmunol.0803859","type":"journal-article","created":{"date-parts":[[2009,5,19]],"date-time":"2009-05-19T21:00:29Z","timestamp":1242766829000},"page":"7146-7154","source":"Crossref","is-referenced-by-count":117,"title":["Miltefosine Promotes IFN-\u03b3-Dominated Anti-Leishmanial Immune Response"],"prefix":"10.1093","volume":"182","author":[{"given":"Pallavi","family":"Wadhone","sequence":"first","affiliation":[{"name":"National Centre for Cell Science , Ganeshkhind, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moitrayee","family":"Maiti","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science , Ganeshkhind, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reena","family":"Agarwal","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science , Ganeshkhind, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanita","family":"Kamat","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science , Ganeshkhind, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Martin","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science , Ganeshkhind, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaskar","family":"Saha","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science , Ganeshkhind, Pune,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,6,1]]},"reference":[{"key":"2025032715455838200_R1","first-page":"298","article-title":"Leishmania and human immunodeficiency virus co-infection: the first 10 years.","volume-title":"Clin. Microbiol. Rev.","year":"1997"},{"key":"2025032715455838200_R2","first-page":"91","article-title":"Leishmaniasis: recognition and management with a focus on the immuno-compromised patient.","volume-title":"Am. J. Clin. Dermatol.","year":"2002"},{"key":"2025032715455838200_R3","first-page":"1921","article-title":"HIV viral load and response to anti-leishmanial chemotherapy in co-infected patients.","volume-title":"AIDS","year":"1999"},{"key":"2025032715455838200_R4","first-page":"213","article-title":"Hexadecylphosphocholine, a new ether lipid analogue: studies on the anti-neoplastic activity in vitro and in vivo.","volume-title":"Acta Oncol.","year":"1989"},{"key":"2025032715455838200_R5","first-page":"2633","article-title":"The activity of alkyl phosphorylcholines and related derivatives against Leishmania donovani.","volume-title":"Biochem. Pharmacol.","year":"1987"},{"key":"2025032715455838200_R6","first-page":"795","article-title":"Visceral leishmanicidal activity of hexadecyl-phosphocholine (miltefosine) in mice deficient in T cells and activated macrophage microbicidal mechanisms.","volume-title":"J. Infect. Dis.","year":"2000"},{"key":"2025032715455838200_R7","first-page":"1821","article-title":"Trial of oral miltefosine for visceral leishmaniasis.","volume-title":"Lancet","year":"1998"},{"key":"2025032715455838200_R8","first-page":"85","article-title":"The inhibition of cell signaling pathways by anti-tumor ether lipids.","volume-title":"Biochim. Biophys. Acta","year":"1998"},{"key":"2025032715455838200_R9","first-page":"2080","article-title":"Effects of hexadecylphosphocholine on membrane phospholipid metabolism in human tumor cells.","volume-title":"Eur. J. Cancer","year":"1995"},{"key":"2025032715455838200_R10","first-page":"1872","article-title":"Activities of hexadecylphosphocholine (miltefosine), AmBisome, and sodium stibogluconate (Pentostam) against Leishmania donovani in immunodeficient scid mice.","volume-title":"Antimicrob. Agents Chemother.","year":"2001"},{"key":"2025032715455838200_R11","first-page":"69","article-title":"Influence of hexadecylphosphocholine on the release of tumor necrosis factor and nitroxide from peritoneal macrophages in vitro.","volume-title":"J. Cancer Res. Clin. Oncol.","year":"1995"},{"key":"2025032715455838200_R12","first-page":"403","article-title":"Investigation into the immunological effects of miltefosine, a new anticancer agent under development.","volume-title":"J. Cancer Res. Clin. Oncol.","year":"1991"},{"key":"2025032715455838200_R13","first-page":"161","article-title":"Hexadecylphosphocholine induces IFN-\u03b3 secretion and expression of GM-CSF mRNA in human mononuclear cells.","volume-title":"Cell Immunol.","year":"1992"},{"key":"2025032715455838200_R14","first-page":"333","article-title":"Hexadecylphosphocholine selectively up-regulates expression of intercellular adhesion molecule-1 and class-I major histocompatibility complex antigen in human monocytes.","volume-title":"J. Exp. Ther. Oncol.","year":"2002"},{"key":"2025032715455838200_R15","first-page":"2227","article-title":"The role of IL-12 in the maintenance of an established Th1 immune response in experimental leishmaniasis.","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2025032715455838200_R16","first-page":"17","article-title":"The role of nitric oxide in innate immunity.","volume-title":"Immunol. Rev.","year":"2000"},{"key":"2025032715455838200_R17","first-page":"75","article-title":"Leishmania inhibits STAT1-mediated IFN-\u03b3 signaling in macrophages: increased tyrosine phosphorylation of dominant negative STAT1\u03b2 by Leishmania mexicana.","volume-title":"Int. J. Parasitol.","year":"2005"},{"key":"2025032715455838200_R18","first-page":"577","article-title":"Immunobiological studies in experimental visceral leishmaniasis, I: changes in lymphoid organs and their possible roles in pathogenesis.","volume-title":"Eur. J. Immunol.","year":"1991"},{"key":"2025032715455838200_R19","first-page":"1037","article-title":"CD40 signaling is impaired in L. major-infected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response.","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2025032715455838200_R20","first-page":"2041","article-title":"Immunobiological studies in experimental visceral leishmaniasis, II: adherent cell-mediated down-regulation of delayed-type hypersensitivity response and up-regulation of B cell activation.","volume-title":"Eur. J. Immunol.","year":"1992"},{"key":"2025032715455838200_R21","first-page":"4636","article-title":"IL-2 is a key cytokine that regulates susceptibility to Leishmania infection.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032715455838200_R22","first-page":"2675","article-title":"Protection against lethal toxic shock by targeted disruption of the CD28 gene.","volume-title":"J. Exp. Med.","year":"1996"},{"key":"2025032715455838200_R23"},{"key":"2025032715455838200_R24","first-page":"6642","article-title":"Functional dichotomy in CD40 reciprocally regulates effector T cell functions.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032715455838200_R25","first-page":"2047","article-title":"Differential CD40\/CD40L expression results in counteracting anti-tumor immune responses.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032715455838200_R26","first-page":"2492","article-title":"Macrophage-T cell interaction in experimental visceral leishmaniasis: failure to express costimulatory molecules on Leishmania-infected macrophages and its implication in the suppression of cell-mediated immunity.","volume-title":"Eur. J. Immunol.","year":"1995"},{"key":"2025032715455838200_R27","first-page":"3737","article-title":"Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-\u03b3-triggered JAK2 activation.","volume-title":"Eur. J. Immunol.","year":"1999"},{"key":"2025032715455838200_R28","first-page":"936","article-title":"Identification of radicicol as an inhibitor of in vivo Ras\/Raf interaction with the yeast two-hybrid screening system.","volume-title":"J. Antibiot.","year":"1998"},{"key":"2025032715455838200_R29","first-page":"214","article-title":"Protein kinase C \u03b2 and \u03b4 isoenzymes mediate cholesterol accumulation in PMA-activated macrophages.","volume-title":"Biochem. Biophys. Res. Commun.","year":"2006"},{"key":"2025032715455838200_R30","first-page":"159","article-title":"Role of phosphatidylinositol 3-OH-kinase activity in the inhibition of apoptosis in haemopoietic cells: phosphatidylinositol 3-OH-kinase inhibitors reveal a difference in signalling between interleukin-3 and granulocyte-macrophage colony stimulating factor.","volume-title":"Biochem J.","year":"1995"},{"key":"2025032715455838200_R31","first-page":"1477","article-title":"Endogenous interleukin-12 regulates acquired resistance in experimental visceral leishmaniasis.","volume-title":"J. Infect. Dis.","year":"1997"},{"key":"2025032715455838200_R32","first-page":"669","article-title":"Neutralization of IL-12 demonstrates the existence of discrete organ-specific phases in the control of Leishmania donovani.","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2025032715455838200_R33","first-page":"890","article-title":"Dendritic cell (DC)-based anti-infective strategies: DCs engineered to secrete IL-12 are a potent vaccine in a murine model of an intracellular infection.","volume-title":"J. Immunol.","year":"1999"},{"key":"2025032715455838200_R34","first-page":"4378","article-title":"Leishmania major-parasitized macrophages augment Th2-type T cell activation.","volume-title":"J. Immunol.","year":"1994"},{"key":"2025032715455838200_R35","first-page":"763","article-title":"Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980\u20132004.","volume-title":"Lancet Infect. Dis.","year":"2005"},{"key":"2025032715455838200_R36","first-page":"1254","article-title":"Successful response to chemotherapy in experimental visceral leishmaniasis: requirement for T cells and effect of lymphokines.","volume-title":"J. Clin. Invest.","year":"1989"},{"key":"2025032715455838200_R37","first-page":"2821","article-title":"Treatment of visceral leishmaniasis.","volume-title":"Expert Opin. Pharmacother.","year":"2005"},{"key":"2025032715455838200_R38","first-page":"399","article-title":"Current scenario of drug development for leishmaniasis.","volume-title":"Indian J. Med. Res.","year":"2006"},{"key":"2025032715455838200_R39","first-page":"16","article-title":"CD4+ T-cell depletion in HIV infection: killed by friendly fire?.","volume-title":"Curr. HIV\/AIDS Rep.","year":"2005"},{"key":"2025032715455838200_R40","first-page":"253","article-title":"Cell-cycle dysregulation in the immunopathogenesis of AIDS.","volume-title":"Immunol. Res.","year":"2004"},{"key":"2025032715455838200_R41","first-page":"702","article-title":"Role of CD40 ligand dysregulation in HIV-associated dysfunction of antigen-presenting cells.","volume-title":"J. Leukocyte Biol.","year":"2003"},{"key":"2025032715455838200_R42","first-page":"852","article-title":"Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes.","volume-title":"Antimicrob. Agents Chemother.","year":"2004"},{"key":"2025032715455838200_R43","first-page":"22","article-title":"STAT1 and T-bet play distinct roles in determining outcome of visceral leishmaniasis caused by Leishmania donovani.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032715455838200_R44","first-page":"4460","article-title":"B7-2 blockade enhances T cell responses to Leishmania donovani.","volume-title":"J. Immunol.","year":"1997"},{"key":"2025032715455838200_R45","first-page":"4330","article-title":"Kinetics of \u03b3 interferon binding and induction of major histocompatibility complex class II mRNA in Leishmania-infected macrophages.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1988"},{"key":"2025032715455838200_R46","first-page":"1367","article-title":"CD4+ effector cells default to the Th2 pathway in interferon \u03b3-deficient mice infected with Leishmania major.","volume-title":"J. Exp. Med.","year":"1994"},{"key":"2025032715455838200_R47","first-page":"6355","article-title":"Essential role of platelet-activating factor in the control of Leishmania amazonensis infection.","volume-title":"Infect. Immun.","year":"2000"},{"key":"2025032715455838200_R48","first-page":"2569","article-title":"Platelet activating factor receptor-deficient mice present delayed interferon-\u03b3 upregualtion and high susceptibility to Leishmania amazonensis infection.","volume-title":"Microbes Infect.","year":"2006"},{"key":"2025032715455838200_R49","first-page":"20","article-title":"In vivo activity of perifosine against Leishmania amazonensis.","volume-title":"Acta Trop.","year":"2008"},{"key":"2025032715455838200_R50","first-page":"1","article-title":"Ether-lipid (alkyl-phospholipid) metabolism and the mechanism of action of ether-lipid analogues in Leishmania.","volume-title":"Mol. Biochem. Parasitol.","year":"2000"},{"key":"2025032715455838200_R51","first-page":"877","article-title":"Aspects of the cytological activity of edelfosine, miltefosine, and ilmofosine in Leishmania donovani.","volume-title":"J. Parasitol.","year":"2006"},{"key":"2025032715455838200_R52","first-page":"4658","article-title":"Parallel synthesis and anti-leishmanial activity of ether-linked phospholipids.","volume-title":"Bioorg. Med. Chem. Lett.","year":"2008"},{"key":"2025032715455838200_R53","first-page":"704","article-title":"Effects of the lysophospholipid analogue edelfosine, ilmofosine and miltefosine against Leishmania amazonensis.","volume-title":"J. Antimicrob. Chemother.","year":"2004"},{"key":"2025032715455838200_R54","first-page":"151","article-title":"Sensitivities of Leishmania species to hexadecylphosphocholine (miltefosine), ET-18-OCH(3) (edelfosine) and amphotericin B.","volume-title":"Acta Trop.","year":"2002"},{"key":"2025032715455838200_R55","first-page":"530","article-title":"The anti-tumor alkylphospholipid perifosine is internalized by an ATP-dependent translocase activity across plasma membrane of human KB carcinoma cells.","volume-title":"Biochim. Biophys. Acta","year":"2008"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/11\/7146\/62682360\/9047.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/11\/7146\/62682360\/9047.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T16:11:38Z","timestamp":1743351098000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/182\/11\/7146\/8006996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,6,1]]},"references-count":55,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2009,6,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0803859","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,6]]},"published":{"date-parts":[[2009,6,1]]}}}