Pentalinonsterol exhibits the immunomodulatory action in macrophages through activation of Phospholipase A2

Abstract

Leishmaniasis, a protozoan parasitic disease, is caused by the infection with the parasite, Leishmania spp. Pentalinonsterol (cholest‐4,20,24‐trien‐3‐one) (PEN) is a natural product recently isolated from the roots of Pentalinon andrieuxii. Previous in vitro and in vivo studies have demonstrated that P. andrieuxii root extracts possess potent immunomodulatory properties, which markedly increase the activity of macrophages and dendritic cells. Given the beneficial characteristics of this root extract, the objective of this study was to elucidate the mechanism of action of the immunomodulatory action(s) of PEN in macrophages on membrane phospholipid metabolism towards the anti‐leishmanial action of PEN. Phospholipase A2 (PLA2), plays an important role in membrane phospholipid homeostasis, cell signaling and generation of the eicosanoid inflammatory bioactive lipids. Therefore, in this study, we investigated PEN‐mediated modulation of PLA2 activity in RAW 264.7 macrophages and the bone marrow‐derived primary macrophages (BMDMs) from mice in vitro and how the upstream PLA2 activation would modulate the downstream cytokine release in the macrophages. Our results demonstrated that, (1) PEN induced PLA2 activation (arachidonic acid release), in a dose‐ and time‐dependent manner that was regulated upstream by mitogen‐activated protein kinases (MAPKs): (2) the PEN induced activation of PLA2 was attenuated by the cPLA2‐specific pharmacological inhibitors; and (3) cPLA2‐specific pharmacological inhibitors attenuated the release of the inflammatory cytokines from macrophages. We also observed that PEN enhances the Leishmania‐induced cPLA2 activation in the RAW macrophages. Our study demonstrated that PEN exerted immunomodulatory actions through cPLA2 activation in macrophages, which is advantageous for vaccine development against Leishmaniasis.Support or Funding InformationSupported by the U.S. Army/Department of Defense and Center for Clinical and Translational Science, Ohio State University.