Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1
Data(s) |
2013
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Resumo |
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. |
Formato |
application/pdf |
Identificador |
http://eprints.iisc.ernet.in/46248/1/PNASUSA_110_7_E575_2013.pdf 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. |
Publicador |
NATL ACAD SCIENCES |
Relação |
http://dx.doi.org/10.1073/pnas.1213839110 http://eprints.iisc.ernet.in/46248/ |
Palavras-Chave | #Microbiology & Cell Biology |
Tipo |
Journal Article NonPeerReviewed |