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
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| 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
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| Creator |
Mukherjee, Sandip
Mukherjee, Budhaditya Mukhopadhyay, Rupkatha Naskar, Kshudiram Sundar, Shyam Dujardin, Jean-Claude Roy, Syamal |
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| Subject |
Infectious Diseases and Immunology
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| Description |
The efflux of antimony through multidrug resistance protein (MDR)-1 is the key factor in the failure of metalloid treatment in kalaazar patients infected with antimony-resistant Leishmania donovani (SbRLD). Previously we showed that MDR-1 upregulation in SbRLD 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 SbRLD-infected macrophages (SbRLD-Mfs) 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 upregulateshistone deacetylase 11, which inhibits acetylation of IL-10 promoter, leading to a decrease in IL-10 production from SbRLDMfs. 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-Mfs. 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-Mfs. 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-Mfs. 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.
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| Publisher |
American Association of Immunologists
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| Date |
2014
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2155/1/JOURNAL_OF_IMMUNOLOGY__V_193(_8)_4083%2D4094;2014[25].pdf
Mukherjee, Sandip and Mukherjee, Budhaditya and Mukhopadhyay, Rupkatha and Naskar, Kshudiram and Sundar, Shyam and Dujardin, Jean-Claude and Roy, Syamal (2014) 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. The Journal of Immunology, 193 (8). pp. 4083-4094. ISSN 0022-1767 |
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| Relation |
http://dx.doi.org//10.4049/jimmunol.1400710
http://www.eprints.iicb.res.in/2155/ |
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