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

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Show simple item record Mukherjee, B. Mukhopadhyay, R. Bannerjee, B. Chowdhury, S. Mukherjee, S. Naskar, K. Allam, U. S. Chakravortty, D. Sundar, S. Dujardin, J. C. Roy, S. 2013-05-24T08:58:28Z 2013-05-24T08:58:28Z 2013
dc.identifier.issn 0027-8424
dc.identifier.other ITG-B10A
dc.identifier.other DBM
dc.identifier.other U-MOLPAR
dc.identifier.other JIF
dc.identifier.other DOI
dc.identifier.other Abstract
dc.identifier.other UPD55
dc.description.abstract The molecular mechanism of antimony-resistant Leishmania donovani (Sb(R)LD)-driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (Ms) has been investigated. This study showed that both promastigote and amastigote forms of Sb(R)LD, 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 Sb(R)LD (KD Sb(R)LD), compromises the ability to induce the above effects. Infection of Ms with KD Sb(R)LD enhanced the sensitivity toward antimonials compared with infection with Sb(R)LD, and infection of BALB/c mice with KD Sb(R)LD caused significantly less organ parasite burden compared with infection induced by Sb(R)LD. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by Sb(R)LD to activate ERK and nuclear translocation of NF-kappaB 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 Sb(R)LD up-regulate MDR1 in M with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but Ms derived from IL-10(-/-) mice are unable to show MDR1 up-regulation on infection with Sb(R)LD. 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-kappaB, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs. en
dc.language English en
dc.subject Protozoal diseases en
dc.subject Kala azar en
dc.subject Visceral en
dc.subject Leishmaniasis en
dc.subject Leishmania donovani en
dc.subject Vectors en
dc.subject Sandflies en
dc.subject Phlebotomus argentipes en
dc.subject Drug resistance en
dc.subject Antimonials en
dc.subject Proteins en
dc.subject IL-10 en
dc.subject Laboratory techniques and procedures en
dc.title Antimony-resistant but not antimony-sensitive Leishmania donovani up-regulates host IL-10 to overexpress multidrug-resistant protein 1 en
dc.type Article en
dc.citation.issue 7 en
dc.citation.jtitle Proceedings of the National Academy of Sciences of the United States of America en
dc.citation.volume 110 en
dc.citation.pages E575-E582 en
dc.citation.jabbreviation Proc Natl Acad Sci U S A en

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