Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1
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| Creator |
Mukherjee, Budhaditya
Mukhopadhyay, Rupkatha Bannerjee, Bijoylaxmi Chowdhury, Sayan Chowdhury Mukherjee, Sandip Naskar, Kshudiram Allam, Uday Sankar Chakravortty, Dipshikha Nandi, Shyam Sundar Dujardin, Jean-Claude Roy, Syamal |
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| Subject |
Infectious Diseases and Immunology
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| Description |
The molecular mechanism of antimony-resistant Leishmania donovani (SbRLD)–driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (Mϕs) has been investigated. This study showed that both promastigote and amastigote forms of SbRLD, but not the antimony-sensitive form of LD,express a unique glycan with N-acetylgalactosamine as a terminal
sugar. Removal of it either by enzyme treatment or by knocking down the relevant enzyme, galactosyltransferase in SbRLD (KDSbRLD), compromises the ability to induce the above effects. Infection of Mϕs with KD SbRLD enhanced the sensitivity towardantimonials compared with infection with SbRLD, and infection of BALB/c mice with KD SbRLD caused significantly less organ parasite burden compared with infection induced by SbRLD. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by SbRLD to activate ERK and nuclear translocation of NF-κB involving p50/c-Rel leading to IL-10 induction, whereas
MDR1 up-regulation is mediated by PI3K/Akt and the JNK pathway.Interestingly both recombinant IL-10 and SbRLD up-regulate MDR1 in Mϕ with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but Mϕs derived from IL-10−/− mice are unable to show MDR1 up-regulation on infection with SbRLD. Thus, it is very likely that an IL-10 surge is a prerequisite for MDR1 up-regulation. The transcription factor important for IL-10–driven MDR1 up-regulation is c-Fos/c-Jun and
not NF-κB, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs.
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| Publisher |
National Academy of Sciences
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| Date |
2013
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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/1940/1/PROCEEDINGS_OF_THE_NATIONAL_ACADEMY_OF_SCIENCES_OF_THE_UNITED_STATES_OF_AMERICA__110_(7)_E575%2DE582;2013[75].pdf
Mukherjee, Budhaditya and Mukhopadhyay, Rupkatha and Bannerjee, Bijoylaxmi and Chowdhury, Sayan Chowdhury and Mukherjee, Sandip and Naskar, Kshudiram and Allam, Uday Sankar and Chakravortty, Dipshikha and Nandi, Shyam Sundar and Dujardin, Jean-Claude and Roy, Syamal (2013) Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1. Proceedings of the National Academy of Sciences of the United States of America (PNAS) ISSN 1091-6490, 110 (7). E575-E582. |
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| Relation |
http://dx.doi.org/10.1073/pnas.1213839110/-/DCSupplemental.
http://www.eprints.iicb.res.in/1940/ |
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