Leishmania cysteine proteases are important virulence factors involved in host-parasite interaction. Previous studies revealed an important role for cysteine proteases in modulation of the T helper cell responses through interfering with macrophage functions or by targeting certain immune modulators for degradation. Therefore, we analyzed the inflammatory responses characterized by production of cytokines and chemokines upon Leishmania donovani (L. donovani) infection of macrophages and established whether Leishmania donovani cathepsin B influences these responses. To further our understanding of host inflammatory responses modulated by Leishmania, we have explored the inflammation-suppressive effects of Leishmania donovani in the context of macrophage infection during TLR4 agonist stimulation.Our data suggest that L. donovani uptake in the presence of LPS caused suppression of certain LPS-induced pro-inflammatory cytokines including IFN-?, IL-6, GM-CSF in addition to Th2 cytokines, IL-4 and IL-13, while augmented the release of other pro-inflammatory cytokines, such as IL-1?, TNF-?, IL-8 as well as the immunosuppressive cytokine IL-10. However, for MCP-1, its production does not significantly differ due to LPS stimulation. We found that cathepsin B significantly influences the production of MCP-1, IL-1 beta and GM-CSF by macrophages, however the elevated levels of IL-8, TNF-?, IL-10, and the suppressed levels of IFN-? and IL-6 or the Th2 cytokines IL4 and IL-13 do not seem to be regulated by cathepsin B. Additionally, L. donovani parasites deficient in cathepsin B appear to be significantly less able to confer same levels of infection and survival inside macrophages as the WT and CM counterparts, indicating that Cathepsin B could facilitate the parasite survival and infectivity of these parasites. We concluded that Leishmania donovani infection of macrophages challenge the induction of rapid immune responses characterized by the production of cytokines/chemokines and these responses are deferentially dependent on cathepsin B of the parasite.