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

Mukherjee, B. ; Mukhopadhyay, R. ; Bannerjee, B. ; Chowdhury, S. ; Mukherjee, S. ; Naskar, K. ; Allam, U. S. ; Chakravortty, D. ; Sundar, S. ; Dujardin, J.-C. ; Roy, S. (2013) Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1 PNAS, 110 (7). E575-E582. ISSN 0027-8424

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Official URL: http://doi.org/10.1073/pnas.1213839110

Related URL: http://dx.doi.org/10.1073/pnas.1213839110

Abstract

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 (KD SbRLD), compromises the ability to induce the above effects. Infection of Mϕs with KD SbRLD enhanced the sensitivity toward antimonials 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.

Item Type:Article
Source:Copyright of this article belongs to National Academy of Sciences.
Keywords:Visceral Leishmaniasis; Antimony Resistance; Glycoconjugate; Antimony Efflux.
ID Code:118336
Deposited On:20 May 2021 09:18
Last Modified:02 Feb 2023 05:42

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