Abstract
BackgroundMuch research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Oleuropein derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Our previous findings showed that oleuropein exhibits leishmanicidal effects against three Leishmania spp. in vitro, and minimizes the parasite burden in L. donovani-infected BALB/c mice. The aim of the present study is to investigate the possible mechanism(s) that mediate this leishmanicidal activity.MethodsWe determined the efficacy of oleuropein in elevating ROS and NO production in L. donovani-infected J774A.1 macrophages and in explanted splenocytes and hepatocytes obtained from L. donovani-infected BALB/c mice. We also assessed the expression of genes that are related to inflammation, T-cell polarization and antioxidant defense, in splenocytes. Finally, we determined the ratios of specific IgG2a/IgG1 antibodies and DTH reactions in L. donovani-infected BALB/c mice treated with oleuropein.ResultsOleuropein was able to elevate ROS production in both in vitro and in vivo models of visceral leishmaniasis and raised NO production in ex vivo cultures of splenocytes and hepatocytes. The extensive oxidative stress found in oleuropein-treated mice was obviated by the upregulation of the host’s antioxidant enzyme (mGCLC) and the simultaneous downregulation of the corresponding enzyme of the parasite (LdGCLC). Moreover, oleuropein was able to mount a significant Th1 polarization characterized by the expression of immune genes (IL-12β, IL-10, TGF-β1, IFN-γ) and transcription factors (Tbx21 and GATA3). Moreover, this immunomodulatory effect was also correlated with an inhibitory effect on IL-1β gene expression, rather than with the expression of IL-1α, IL-1rn and TNF-α. Furthermore, oleuropein-treated BALB/c mice mounted a delayed-type hypersensitivity (DTH) response and an elevated Leishmania-specific IgG2a/IgG1 ratio that clearly demonstrated an in vivo protective mechanism.ConclusionThe ability of Oleuropein to promote a Th1 type immune response in L. donovani-infected BALB/c mice points towards the candidacy of this bioactive compound as an immunomodulatory agent that may complement therapeutic approaches to leishmaniasis.
Highlights
Much research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis
Noninfected J774A.1 cells that were incubated with 138.8 μg/ml of Ole exhibited significantly higher levels of intracellular reactive oxygen species (ROS) compared to the corresponding levels generated by untreated J774A.1 cells
Ole was not able to strengthen the intracellular oxidative stress caused by LPS, which is a potent stimulator of macrophages
Summary
Much research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Much research effort has been directed towards the discovery of new therapeutic agents capable of killing the majority of Leishmania species and promoting the host immune response This activity of potent therapeutic agents must rely on the generation of a strong immune response orchestrated by both innate and adaptive immunity against Leishmania infection. The presence of TGF-β can halt the differentiation and the proliferation of immature T-cells into the above discrete subpopulations These differential immune responses are correlated with the existence of inflammatory messengers after the onset of disease or during parasite dissemination that will render a strengthened Th2-Th3 immune response allowing the gradual spread of the disease [9,10,11,12]
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