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

B. Mukherjee, R. Mukhopadhyay, B. Bannerjee, S. Chowdhury, S. Mukherjee, K. Naskar, U.S. Allam, D. Chakravortty, S. Sundar, J.C. Dujardin, S. Roy

Research output: Contribution to journalA1: Web of Science-article

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.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number7
Pages (from-to)E575-E582
Number of pages8
ISSN0027-8424
DOIs
Publication statusPublished - 2013

Keywords

  • Protozoal diseases
  • Kala azar
  • Visceral
  • Leishmaniasis
  • Leishmania donovani
  • Vectors
  • Sandflies
  • Phlebotomus argentipes
  • Drug resistance
  • Antimonials
  • Proteins
  • IL-10
  • Laboratory techniques and procedures

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