Role of phosphatidylinositol-3-kinase-gamma (PI3Kgamma)-mediated pathway in 17beta-estradiol-induced killing of L. mexicana in macrophages from C57BL/6 mice

We recently demonstrated that 17beta-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-gamma (PI3Kgamma) 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-gammaRalpha, and also produced more interleukin (IL)-12, IL-6 and NO than both the sham controls and E2-treated male-derived macrophages. Sham-treated BMDMs from female PI3Kgamma-/- 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 PI3Kgamma-/- 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 PI3Kgamma-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 PI3Kgamma 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.