Interleukin‐12 Regulates the Response to Chemotherapy in Experimental Visceral Leishmaniasis

Bhaumik

et al. 2005

235

230

The emergence of an increasing number of Leishmania donovani strains resistant to pentavalent antimonials (SbV), the first line of treatment for visceral leishmaniasis worldwide, accounts for decreasing efficacy of chemotherapeutic interventions. A kinetoplastid membrane protein-11 (KMP-11)-encoding construct protected extremely susceptible golden hamsters from both pentavalent antimony responsive (AG83) and antimony resistant (GE1F8R) virulent L. donovani challenge. All the KMP-11 DNA vaccinated hamsters continued to survive beyond 8 mo postinfection, with the majority showing sterile protection. Vaccinated hamsters showed reversal of T cell anergy with functional IL-2 generation along with vigorous specific anti-KMP-11 CTL-like response. Cytokines known to influence Th1- and Th2-like immune responses hinted toward a complex immune modulation in the presence of a mixed Th1/Th2 response in conferring protection against visceral leishmaniasis. KMP-11 DNA vaccinated hamsters were protected by a surge in IFN-γ, TNF-α, and IL-12 levels along with extreme down-regulation of IL-10. Surprisingly the prototype candidature of IL-4, known as a disease exacerbating cytokine, was found to have a positive correlation to protection. Contrary to some previous reports, inducible NO synthase was actively synthesized by macrophages of the protected hamsters with concomitant high levels of NO production. This is the first report of a vaccine conferring protection to both antimony responsive and resistant Leishmania strains reflecting several aspects of clinical visceral leishmaniasis.

Section: Discussionsupporting

confidence: 38%

Kinetoplastid Membrane Protein-11 DNA Vaccination Induces Complete Protection against Both Pentavalent Antimonial-Sensitive and -Resistant Strains of Leishmania donovani That Correlates with Inducible Nitric Oxide Synthase Activity and IL-4 Generation: Evidence for Mixed Th1- and Th2-Like Responses in Visceral Leishmaniasis

Bhaumik

et al. 2005

235

230

“…Infection with Sb R LD was associated with depressed Ag-specific T cell responses, decreased IL-12, TNF-a, and IFN-g production, and upregulation of suppressive cytokines IL-10 and TGF-b in an animal model of VL (24,28). SSG with imipramine was found to be effective to mount anti-SLA-specific T cell expansion, coupled with generation of IL-12 and suppression of IL-10 ( Fig.…”

Section: Discussionmentioning

confidence: 92%

“…IL-12 is the key cytokine for the initiation and maintenance of Th1 responses and IFN-g production from Th1 cells (26,55). Endogenous IL-12 is also required for the expression of the leishmanicidal effect of conventional chemotherapy (28). Having established that imipramine is a potent inhibitor of MDR-1, we studied its efficacy in combination with SSG to clear Sb R LD from the organs of infected mice.…”

Section: Discussionmentioning

confidence: 99%

“…IL-10 promotes intracellular infection and persistence (24) and increases the risk of relapse (25); IL-12 is the key cytokine for IFN-g-producing Th1 cells (26,27). Endogenous IL-12 is also required for the enhancement of the leishmanicidal effect of conventional antileishmanial drugs (28). It acts as a potent histone modulator in the brains of maternally deprived adult rats (29).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Imipramine Exploits Histone Deacetylase 11 To Increase the IL-12/IL-10 Ratio in Macrophages Infected with Antimony-Resistant Leishmania donovani and Clears Organ Parasites in Experimental Infection

Mukherjee

Mukhopadhyay

et al. 2014

The efflux of antimony through multidrug resistance protein (MDR)-1 is the key factor in the failure of metalloid treatment in kala-azar patients infected with antimony-resistant Leishmania donovani (SbRLD). Previously we showed that MDR-1 upregulation in SbRLD infection is IL-10–dependent. Imipramine, a drug in use for the treatment of depression and nocturnal enuresis in children, inhibits IL-10 production from SbRLD-infected macrophages (SbRLD-Mϕs) and favors accumulation of surrogates of antimonials. It inhibits IL-10–driven nuclear translocation of c-Fos/c-Jun, critical for enhanced MDR-1 expression. The drug upregulates histone deacetylase 11, which inhibits acetylation of IL-10 promoter, leading to a decrease in IL-10 production from SbRLD-Mϕs. It abrogates SbRLD-mediated p50/c-Rel binding to IL-10 promoter and preferentially recruits p65/RelB to IL-12 p35 and p40 promoters, causing a decrease in IL-10 and overproduction of IL-12 in SbRLD-Mϕs. Histone deacetylase 11 per se does not influence IL-12 promoter activity. Instead, a imipramine-mediated decreased IL-10 level allows optimal IL-12 production in SbRLD-Mϕs. Furthermore, exogenous rIL-12 inhibits intracellular SbRLD replication, which can be mimicked by the presence of Ab to IL-10. This observation indicated that reciprocity exists between IL-10 and IL-12 and that imipramine tips the balance toward an increased IL-12/IL-10 ratio in SbRLD-Mϕs. Oral treatment of infected BALB/c mice with imipramine in combination with sodium stibogluconate cleared organ SbRLD parasites and caused an expansion of the antileishmanial T cell repertoire where sodium stibogluconate alone had no effect. Our study deciphers a detailed molecular mechanism of imipramine-mediated regulation of IL-10/IL-12 reciprocity and its impact on SbRLD clearance from infected hosts.

“…Previously, MG formation has been associated with clearance of Leishmania infection (36). An earlier report also suggested that the level of IL-12 might act as a critical factor in determining the nature of granuloma formation during experimental infection with VL (47). Because a parasite would not like to kill its host for the sake of its own survival, it is tempting to speculate that early activation of IL-12 and delayed activation of IL-10 in Sb R LD infection might be instrumental for survival of resistant parasites in the infected host.…”

Section: /2mentioning

confidence: 96%

Antimony-ResistantLeishmania donovaniExploits miR-466i To Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection

Mukherjee

Paul

Mukherjee

et al. 2015

Infection with antimony-resistant Leishmania donovani (SbRLD) induces aggressive pathology in the mammalian hosts as compared with ones with antimony-sensitive L. donovani (SbSLD) infection. SbRLD, but not SbSLD, interacts with TLR2/TLR6 to induce IL-10 by exploiting p50/c-Rel subunits of NF-κB in infected macrophages (Mϕs). Most of the TLRs exploit the universal adaptor protein MyD88 to activate NF-κB. We now show that infection of Mϕs from MyD88−/− mice with SbRLD gave rise to significantly higher intracellular parasite number coupled with elevated IL-10/IL-12 ratio in the culture supernatant as compared with infection in wild type (WT) Mϕs. Τhese attributes were not seen with SbSLD in similar experiments. Further, SbRLD infection upregulated miR-466i, which binds with 3′-untranslated region, leading to the downregulation of MyD88. Infection of MyD88−/− Mϕ or IL-12−/− Mϕ with SbRLD induced IL-10 surge at 4 h, whereas the same in WT Mϕ started from 12 h. Thus, absence of IL-12 in MyD88−/− mice favored early binding of NF-κB subunits to the IL-10 promoter, resulting in IL-10 surge. Infection of MyD88−/− mice with SbRLD showed significantly higher organ parasites coupled with ill-defined and immature hepatic granulomas, whereas in WT mice there were less organ parasites and the granulomas were well defined. From the survival kinetics it was observed that SbRLD-infected MyD88−/− mice died by 60 d postinfection, whereas the WT mice continued to survive. Our results demonstrate that SbRLD has evolved a unique strategy to evade host antileishmanial immune repertoire by manipulating host MyD88 to its advantage.