Susceptibility to Toxoplasma gondii proliferation in BeWo human trophoblast cells is dose-dependent of macrophage migration inhibitory factor (MIF), via ERK1/2 phosphorylation and prostaglandin E2 production

Introduction: Macrophage migration inhibitory factor (MIF) participates in the immune response to Toxoplasma gondii, triggers ERK1/2 and prostaglandin E-2 (PGE(2)) activation, but there is limited information on these mechanisms in human trophoblast. The present study aimed to verify the role of MIF in the ERK1/2 phosphorylation and PGE(2) production, as well as its effect on the susceptibility to T. gondii in BeWo cells. Methods: BeWo cells were treated with increasing concentrations of recombinant MIF (rMIF) and/or T gondii-soluble tachyzoite antigen (STAg) and analyzed for ERK1/2 phosphorylation and PGE(2) production by Western blotting and ELISA, respectively. Cells were also treated with increasing concentrations of rMIF, rPGE(2), or ERK1/2 inhibitor and tested for 7'. gondii proliferation. The supernatants of cells treated with rPGE(2) were assayed for cytokine production by ELISA or CBA. Results: ERK1/2 phosphorylation and PGE(2) production increased when the cells were treated with low MIF concentrations while the parasitism control occurred only at high MIF concentrations. STAg was unable to change ERK1/2 phosphorylation or PGE(2) release. BeWo cells demonstrated increased T gondii proliferation and reduced production of pro-inflammatory cytokines when treated with PGE(2), while PD98059 diminished the parasite proliferation. Discussion: The intracellular mechanisms triggered by MIF are dose-dependent in BeWo cells, and PGE(2) is an important factor for the persistence of T. gondii at the maternal fetal interface. Conclusion: MIF was unable to control 7'. gondii infection in BeWo cells at low concentrations since ERK1/2 and PGE(2) expression were activated, demonstrating a critical effect of these mediators favoring parasite proliferation. (C) 2014 Elsevier Ltd. All rights reserved.