title: Imipramine exploits histone deacetylase 11 to increase the IL-12/IL-10 ratio in macrophages infected with antimony-resistant Leishmania donovani and clears organ parasites in experimental infection.
abstract: The efflux of antimony through multidrug resistance protein (MDR)-1 is the key factor in the failure of metalloid treatment in kala-azar patients infected with antimony-resistant Leishmania donovani (Sb(R)LD). Previously we showed that MDR-1 upregulation in Sb(R)LD infection is IL-10-dependent. Imipramine, a drug in use for the treatment of depression and nocturnal enuresis in children, inhibits IL-10 production from Sb(R)LD-infected macrophages (Sb(R)LD-Mϕs) and favors accumulation of surrogates of antimonials. It inhibits IL-10-driven 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 Sb(R)LD-Mϕs. It abrogates Sb(R)LD-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 Sb(R)LD-Mϕs. 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 Sb(R)LD-Mϕs. Furthermore, exogenous rIL-12 inhibits intracellular Sb(R)LD 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 Sb(R)LD-Mϕs. Oral treatment of infected BALB/c mice with imipramine in combination with sodium stibogluconate cleared organ Sb(R)LD 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 Sb(R)LD clearance from infected hosts.
authors.affiliation: Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India;
authors.forename: Sandip
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India;
authors.forename: Budhaditya
authors.initials: B
authors.lastname: Mukherjee
authors.affiliation: Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India;
authors.forename: Rupkatha
authors.initials: R
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India;
authors.forename: Kshudiram
authors.initials: K
authors.lastname: Naskar
authors.affiliation: Institute of Medical Sciences, Benaras Hindu University, Varanasi 221005, India; and.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: Institute of Tropical Medicine, 2000 Antwerp, Belgium.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.affiliation: Department of Infectious Diseases and Immunology, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India; sroy@iicb.res.in.
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000965:Antimony / Q000494:pharmacology; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D004351:Drug Resistance; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000096:biosynthesis; D007099:Imipramine / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D007893:Leishmania donovani / Q000187:drug effects* / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051996:Transcription Factor RelA / Q000378:metabolism; D014344:Trypanocidal Agents / Q000627:therapeutic use*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000906:Antibodies; C556062:IL10 protein, mouse; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D052002:NF-kappa B p50 Subunit; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014344:Trypanocidal Agents; D016753:Interleukin-10; D018664:Interleukin-12; D000965:Antimony; C528111:Hdac11 protein, mouse; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D007099:Imipramine; D000967:Antimony Sodium Gluconate