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

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