Title
Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Washington, D.C. ,
Subject
Engineering sciences. Technology
Source (journal)
Proceedings of the National Academy of Sciences of the United States of America. - Washington, D.C.
Volume/pages
110(2013) :7 , p. 575-582
ISSN
0027-8424
1091-6490
ISI
000315812800006
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
E-info
https://repository.uantwerpen.be/docman/iruaauth/986b9a/4393767.pdf
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