Leishmania major parasites induced macrophage tolerance: implication of MAPK and NF-kappaB pathways.

During infection pathogens elicit early inflammatory events and modulate mediators of the host inflammatory response. We show in the present study that the two stages of the Leishmania parasite differentially modulate the production of inflammatory cytokines with amastigotes inducing cytokine production but not promastigotes. However once they infect macrophages both stages were able to induce a state of tolerance characterized by the inhibition of TNFalpha production in response to a subsequent contact with the parasite. This effect was not due to the action of soluble deactivating cytokines released in the supernatant, but likely reflect direct cell-parasite interactions. Moreover, we show that parasite viability is required for macrophage tolerisation. Cross-stimulation experiments using two stimuli namely Leishmania and LPS, demonstrated a hierarchy of signalling with LPS mediating abrogation of Leishmania tolerance but not vice versa. Indeed, while LPS was able to overcome Leishmania induced tolerance LPS induced cell tolerance was refractory to subsequent Leishmania stimulation. This state of tolerance correlates with the hypo responsiveness of MAPK transduction pathways and defective activation of NF-kappaB transcription factor.