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

Mukherjee, Budhaditya and Mukhopadhyay, Rupkatha and Bannerjee, Bijoylaxmi and Chowdhury, Sayan and Mukherjee, Sandip and Naskar, Kshudiram and Allam, Uday Sankar and Chakravortty, Dipshikha and Sundar, Shyam 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. In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110 (7). E575-E582.

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

Abstract

The molecular mechanism of antimony-resistant Leishmania donovani ((SbLD)-L-R)-driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (M phi s) has been investigated. This study showed that both promastigote and amastigote forms of (SbLD)-L-R, 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 (SbLD)-L-R (KD (SbLD)-L-R), compromises the ability to induce the above effects. Infection of M phi s with KD (SbLD)-L-R enhanced the sensitivity toward antimonials compared with infection with (SbLD)-L-R, and infection of BALB/c mice with KD (SbLD)-L-R caused significantly less organ parasite burden compared with infection induced by (SbLD)-L-R. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by (SbLD)-L-R to activate ERK and nuclear translocation of NF-kappa B 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 (SbLD)-L-R up-regulate MDR1 in M. with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but M phi s derived from IL-10(-/-) mice are unable to show MDR1 up-regulation on infection with (SbLD)-L-R. 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-kappa B, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs.

Item Type: Journal Article
Additional Information: Copyright for this article belongs to the NATL ACAD SCIENCES,USA
Keywords: visceral leishmaniasis; antimony resistance;lycoconjugate; antimony efflux VISCERAL LEISHMANIASIS; DRUG-RESISTANCE; PHOSPHOINOSITIDE 3-KINASE; NITRIC-OXIDE; ACTIVATION; CELLS; MACROPHAGES; KINASE; LIPOPHOSPHOGLYCAN; CANCER
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Francis Jayakanth
Date Deposited: 03 Apr 2013 10:31
Last Modified: 03 Apr 2013 10:31
URI: http://eprints.iisc.ac.in/id/eprint/46248

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