Antileishmanial activity and immune modulatory effects of tannins and related compounds on Leishmania parasitised RAW 264.7 cells.

The antileishmanial and immunomodulatory potencies of a total of 67 tannins and structurally related compounds were evaluated in terms of extra- and intra-cellular leishmanicidal effects and macrophage activation for release of nitric oxide (NO), tumour necrosis factor (TNF) and interferon (IFN)-like activities. Their effects on macrophage functions were further assessed by expression analysis (iNOS, IFN-alpha, IFN-gamma, TNF-alpha, IL-1, IL-10, IL-12, IL-18). With few exceptions, e.g., caffeic acid derivatives, these polyphenols revealed little direct toxicity for extracellular promastigote Leishmania donovani or L. major strains. In contrast, many polyphenols appreciably reduced the survival of the intracellular, amastigote parasite form in vitro. Upon activation, e.g., by immune response mediators such as IFN-gamma, macrophages may transform from permissive host to leishmanicidal effector cells. Our data from functional bioassays suggested that the effects of polyphenols on intracellular Leishmania parasites were due to macrophage activation rather than direct antiparasitic activity. Gene expression analyses not only confirmed functional data, they also clearly showed differences in the response of infected macrophages when compared to that of noninfected cells. Conspicuously, infected macrophages showed augmented and prolonged activation of host defense mechanisms, indicating that parasitised macrophages were exquisitely predisposed or "primed" to react to activating molecules such as polyphenols. This promotive effect may be of special benefit, e.g., stimulation of the non-specific immune system selectively at the site of infection and when needed. Although these data provide the basis for an immunological concept of plant polyphenols for their beneficial effects in various infectious conditions, in vivo experiments are essential to prove the therapeutic benefits of polyphenolic immunomodulators.