The pentavalent antimonial therapy against experimental Leishmania amazonensis infection is more effective under the inhibition of the NF-κB pathway

Abstract

During Leishmania infection, host immune response is important to prevent the growth/survival of intracellular amastigotes. In this study, we evaluated in vitro and in vivo whether or not during Leishmania amazonensis infection, pentavalent antimonial treatment/therapy could be more effective under TNF-α inhibition. Both L. amazonensis-infected macrophages (in vitro model) and mice (in vivo model) were treated with a nuclear factor-κB (NF-κB) inhibitor and with Glucantime®, alone and in combined administrations. The in vitro amastigote counts, cytokines and nitrites' production were assessed after 48h incubation with the drugs. Paw lesion sizes and amastigote counts were also evaluated in vivo. Quantification of IL-1β from the infected tissue was performed. In vitro results show that when infected macrophages were incubated with QNZ+Glucantime®, a greater clearance was observed for the amastigotes' growth and this was related to greater nitrite production compared to the group that was only infected. In vivo results show that mice that received the combined treatment had their paw lesion sizes and amastigote nests inside the macrophages greatly diminished, correlating with increased IL-1β levels.

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis

“…While IFN-γ has been shown to have a protective role in CL, TNF-α secretion may promote pathology in the skin ( 33 , 40 , 41 ). Previous studies have shown that the control of inflammatory potential by blocking TNF-α in vitro or during antimonial therapy for CL in vivo are able to promote faster healing of lesions and higher cure rates than patients with anti- Leishmania treatment alone ( 42 , 43 ). From our results we predict that this skewing of cytokine production may induce protective and non-pathogenic immunity since PD-1 blockade of CD8 + T cells does not exacerbate TNF-α secretion but instead induces protective IFN-γ based immune responses.…”

Effects of trans-stilbene and terphenyl compounds on different strains of Leishmania and on cytokines production from infected macrophages

“…Moreover, macrophages and mice that were deficient in IL-1R were just as susceptible to infection as those deficient in Caspase 1, adaptor protein ASC or NLRP3 inflammasome, which suggests that IL-1 signaling is important for the inflammasome-dependent restriction of Leishmania replication (Lima-Junior et al, 2013). Finally, the high IL-1b levels produced by macrophages and other antigen-presenting cell in infected BALB/c mice during QNZ (N4-[2-(4-phenoxyphenyl) ethyl]) þ glucantime administration were able to maintain a better cellular activation profile with increased NO production, avoiding TNF-a overproduction, decreasing Leishmania replication and enhancing healing in the infected mice (Macedo et al, 2015).…”

Glucantime reduces mechanical hyperalgesia in cutaneous leishmaniasis and complete Freund's adjuvant models of chronic inflammatory pain

“…Evidence shows that leishmanicidal activity of Glucantime depends on immunomodulation as observed in in vitro data that antimonial drug promotes TNF‐α production, which contributes to enhance macrophages activity against parasites . However, other studies have demonstrated that proinflammatory cytokines may be decreased during antimonial therapy in leishmaniasis .…”