Role of phosphatidylinositol-3-kinase-[gamma] (PI3K[gamma])-mediated pathway in 17[beta]-estradiol-induced killing of L. mexicana in macrophages from C57BL/6 mice

• Published in: Immunology and cell biology Vol. 86; no. 6; pp. 539 - 543
• Main Authors: Lezama-dávila, Claudio M, Isaac-márquez, Angelica P, Barbi, Joseph, Cummings, Hannah E, Lu, Bao, Satoskar, Abhay R
• Format: Journal Article
• Language: English
• Published: London Blackwell Science Ltd 01.08.2008
• Subjects: Leishmania mexicana
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2008.39

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 E2 -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 E 2 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.