title: 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.
abstract: BACKGROUND
  Macrophage migration inhibitory factor (MIF) participates in the immune response to Toxoplasma gondii, triggers ERK1/2 and prostaglandin E2 (PGE2) 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 PGE2 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 PGE2 production by Western blotting and ELISA, respectively. Cells were also treated with increasing concentrations of rMIF, rPGE2, or ERK1/2 inhibitor and tested for T. gondii proliferation. The supernatants of cells treated with rPGE2 were assayed for cytokine production by ELISA or CBA.
  
  
  RESULTS
  ERK1/2 phosphorylation and PGE2 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 PGE2 release. BeWo cells demonstrated increased T. gondii proliferation and reduced production of pro-inflammatory cytokines when treated with PGE2, while PD98059 diminished the parasite proliferation.
  
  
  CONCLUSIONS
  The intracellular mechanisms triggered by MIF are dose-dependent in BeWo cells, and PGE2 is an important factor for the persistence of T. gondii at the maternal fetal interface.
  
  
  CONCLUSIONS
  MIF was unable to control T. gondii infection in BeWo cells at low concentrations since ERK1/2 and PGE2 expression were activated, demonstrating a critical effect of these mediators favoring parasite proliferation.
authors.affiliation: Laboratory of Histology and Embryology, Institute of Biomedical Sciences, Federal University of Uberlândia, Av. Pará, 1720, 38405-320 Uberlândia, MG, Brazil. Electronic address: bellisafb@icbim.ufu.br.
authors.forename: B F
authors.initials: BF
authors.lastname: Barbosa
authors.affiliation: Department of Life Science, University of Siena, Aldo Moro Road 2, Siena, Italy. Electronic address: luana.riccipaulesu@unisi.it.
authors.forename: L
authors.initials: L
authors.lastname: Paulesu
authors.affiliation: Department of Life Science, University of Siena, Aldo Moro Road 2, Siena, Italy. Electronic address: ietta@unisi.it.
authors.forename: F
authors.initials: F
authors.lastname: Ietta
authors.affiliation: Department of Life Science, University of Siena, Aldo Moro Road 2, Siena, Italy. Electronic address: nikoniko29@libero.it.
authors.forename: N
authors.initials: N
authors.lastname: Bechi
authors.affiliation: Department of Life Science, University of Siena, Aldo Moro Road 2, Siena, Italy. Electronic address: romagnolir@unisi.it.
authors.forename: R
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: Laboratory of Histology and Embryology, Institute of Biomedical Sciences, Federal University of Uberlândia, Av. Pará, 1720, 38405-320 Uberlândia, MG, Brazil. Electronic address: angellicagomes@yahoo.com.br.
authors.forename: A O
authors.initials: AO
authors.lastname: Gomes
authors.affiliation: Department of Biology, Cuesta College, Highway Road 1, San Luis Obispo, CA, United States. Electronic address: favoretojr@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Favoreto-Junior
authors.affiliation: Laboratory of Immunoparasitology, Institute of Biomedical Sciences, Federal University of Uberlândia, Av. Pará, 1720, 38405-320 Uberlândia, MG, Brazil. Electronic address: daosilva@yahoo.com.br.
authors.forename: D A O
authors.initials: DA
authors.lastname: Silva
authors.affiliation: Laboratory of Immunoparasitology, Institute of Biomedical Sciences, Federal University of Uberlândia, Av. Pará, 1720, 38405-320 Uberlândia, MG, Brazil. Electronic address: jrmineo@ufu.br.
authors.forename: J R
authors.initials: JR
authors.lastname: Mineo
authors.affiliation: Laboratory of Immunoparasitology, Institute of Biomedical Sciences, Federal University of Uberlândia, Av. Pará, 1720, 38405-320 Uberlândia, MG, Brazil. Electronic address: tiagomineo@gmail.com.
authors.forename: T W P
authors.initials: TW
authors.lastname: Mineo
authors.affiliation: Laboratory of Histology and Embryology, Institute of Biomedical Sciences, Federal University of Uberlândia, Av. Pará, 1720, 38405-320 Uberlândia, MG, Brazil. Electronic address: eloisa@umuarama.ufu.br.
authors.forename: E A V
authors.initials: EA
authors.lastname: Ferro
mesh_terms: D000953:Antigens, Protozoan / Q000494:pharmacology; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000008:administration & dosage*; D010766:Phosphorylation; D014122:Toxoplasma / Q000254:growth & development / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology; D014327:Trophoblasts / Q000378:metabolism* / Q000469:parasitology
chemical_list: D000953:Antigens, Protozoan; D005419:Flavonoids; D008263:Macrophage Migration-Inhibitory Factors; C094052:soluble tachyzoite antigen, Toxoplasma gondii; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: ERK1/2; MIF; PGE(2); Toxoplasma gondii; Trophoblast cells