Role of phosphatidylinositol-3-kinase-γ (PI3Kγ)-mediated pathway in 17Β-estradiol-induced killing of L. mexicana in macrophages from C57BL/6 mice

We recently demonstrated that 17Β-estradiol (E₂) enhances killing of Leishmania mexicana in macrophages from both male and female DBA/2 mouse by increasing nitric oxide (NO) production. Here, we analyzed the effect of E₂ on leishmanicidal activity and cytokine production by bone marrow-derived macrophages (BMDMs) from male and female C57BL/6 mice in vitro, specifically examining the role of phosphatidylinositol-3-kinase-γ (PI3Kγ) in E₂-induced parasite killing. Unlike its effect on macrophages from both male and female DBA/2 mice, E₂ only increased leishmanicidal activity in macrophages from female C57BL/6 mice, which was evident by a significant reduction in both infection rates and infection levels compared to sham controls. E₂-treated BMDMs from female C57BL/6 mice expressed higher levels of interferon-γRα, and also produced more interleukin (IL)-12, IL-6 and NO than both the sham controls and E ₂-treated male-derived macrophages. Sham-treated BMDMs from female PI3Kγ^-/- C57BL/6 mice displayed lower infection rates and infection levels compared to sham-treated wild-type (WT) macrophages. However E₂, unlike its effect on macrophages from female WT C57BL/6 mice, failed to reduce infection rates and infection levels in BMDMs from female PI3Kγ^-/- mice. Interestingly, E₂-treated BMDMs from female C57BL/6 mice produced significant amounts of inflammatory cytokines and NO in levels comparable to those observed in sham-treated PI3Kγ-deficient macrophages as well as E2-treated macrophages from WT mice. These findings show that E₂ exerts a distinct effect on leishmanicidal activity of macrophages from male versus female C57BL/6 mice. In addition, they suggest that PI3Kγ is not required for E₂-induced cytokine and NO production in L. mexicana-infected macrophages from female C57BL/6 mice but it may be involved in parasite clearance from these cells.