Record Details

Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1

EPrints@IICB

View Archive Info
 
 
Field Value
 
Title Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1
 
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
 
Subject Infectious Diseases and Immunology
 
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.
 
Publisher National Academy of Sciences
 
Date 2013
 
Type Article
PeerReviewed
 
Format application/pdf
 
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.
 
Relation http://dx.doi.org/10.1073/pnas.1213839110/-/DCSupplemental.
http://www.eprints.iicb.res.in/1940/