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Background  Much 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.    Methods  We 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.    Results  Oleuropein 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 (m GCLC ) and the simultaneous downregulation of the corresponding enzyme of the parasite (Ld GCLC ). 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.    Conclusion  The 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.

The leishmanicidal activity of oleuropein is selectively regulated through inflammation- and oxidative stress-related genes