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Previously we showed that MDR-1 upregulation in SbRLD infection is IL-10\u2013dependent. Imipramine, a drug in use for the treatment of depression and nocturnal enuresis in children, inhibits IL-10 production from SbRLD-infected macrophages (SbRLD-M\u03d5s) and favors accumulation of surrogates of antimonials. It inhibits IL-10\u2013driven nuclear translocation of c-Fos\/c-Jun, critical for enhanced MDR-1 expression. The drug upregulates histone deacetylase 11, which inhibits acetylation of IL-10 promoter, leading to a decrease in IL-10 production from SbRLD-M\u03d5s. It abrogates SbRLD-mediated p50\/c-Rel binding to IL-10 promoter and preferentially recruits p65\/RelB to IL-12 p35 and p40 promoters, causing a decrease in IL-10 and overproduction of IL-12 in SbRLD-M\u03d5s. Histone deacetylase 11 per se does not influence IL-12 promoter activity. Instead, a imipramine-mediated decreased IL-10 level allows optimal IL-12 production in SbRLD-M\u03d5s. Furthermore, exogenous rIL-12 inhibits intracellular SbRLD replication, which can be mimicked by the presence of Ab to IL-10. This observation indicated that reciprocity exists between IL-10 and IL-12 and that imipramine tips the balance toward an increased IL-12\/IL-10 ratio in SbRLD-M\u03d5s. Oral treatment of infected BALB\/c mice with imipramine in combination with sodium stibogluconate cleared organ SbRLD parasites and caused an expansion of the antileishmanial T cell repertoire where sodium stibogluconate alone had no effect. Our study deciphers a detailed molecular mechanism of imipramine-mediated regulation of IL-10\/IL-12 reciprocity and its impact on SbRLD clearance from infected hosts.<\/jats:p>","DOI":"10.4049\/jimmunol.1400710","type":"journal-article","created":{"date-parts":[[2014,9,13]],"date-time":"2014-09-13T06:59:41Z","timestamp":1410591581000},"page":"4083-4094","source":"Crossref","is-referenced-by-count":40,"title":["Imipramine Exploits Histone Deacetylase 11 To Increase the IL-12\/IL-10 Ratio in Macrophages Infected with Antimony-Resistant <i>Leishmania donovani<\/i> and Clears Organ Parasites in Experimental Infection"],"prefix":"10.1093","volume":"193","author":[{"given":"Sandip","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Budhaditya","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupkatha","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kshudiram","family":"Naskar","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam","family":"Sundar","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, Benaras Hindu University , Varanasi 221005 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"Dujardin","sequence":"additional","affiliation":[{"name":"Institute of Tropical Medicine , 2000 Antwerp ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syamal","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,10,15]]},"reference":[{"key":"2025030707410442500_r1","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1046\/j.1365-3156.2001.00778.x","article-title":"Drug resistance in Indian visceral leishmaniasis","volume":"6","author":"Sundar","year":"2001","journal-title":"Trop. 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