title: PreImplantation factor (PIF*) regulates systemic immunity and targets protective regulatory and cytoskeleton proteins.
abstract: Secreted by viable embryos, PIF is expressed by the placenta and found in maternal circulation. It promotes implantation and trophoblast invasion, achieving systemic immune homeostasis. Synthetic PIF successfully transposes endogenous PIF features to non-pregnant immune and transplant models. PIF affects innate and activated PBMC cytokines and genes expression. We report that PIF targets similar proteins in CD14+, CD4+ and CD8+ cells instigating integrated immune regulation. PIF-affinity chromatography followed by mass-spectrometry, pathway and heatmap analysis reveals that SET-apoptosis inhibitor, vimentin, myosin-9 and calmodulin are pivotal for immune regulation. PIF acts on macrophages down-stream of LPS (lipopolysaccharide-bacterial antigen) CD14/TLR4/MD2 complex, targeting myosin-9, thymosin-α1 and 14-3-3eta. PIF mainly targets platelet aggregation in CD4+, and skeletal proteins in CD8+ cells. Pathway analysis demonstrates that PIF targets and regulates SET, tubulin, actin-b, and S100 genes expression. PIF targets systemic immunity and has a short circulating half-life. Collectively, PIF targets identified; protective, immune regulatory and cytoskeleton proteins reveal mechanisms involved in the observed efficacy against immune disorders.
authors.affiliation: The Society for the Investigation of Early Pregnancy (SIEP), Cherry Hill, NJ, USA; BioIncept LLC, Cherry Hill, NJ, USA. Electronic address: barnea@earlypregnancy.org.
authors.forename: Eytan R
authors.initials: ER
authors.lastname: Barnea
authors.affiliation: Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Soren
authors.initials: S
authors.lastname: Hayrabedyan
authors.affiliation: Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Krassimira
authors.initials: K
authors.lastname: Todorova
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Almogi-Hazan
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Or
authors.affiliation: Chemical Biology and Proteomics, Banyan Biomarkers, Alachua, FL, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Guingab
authors.affiliation: School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK.
authors.forename: James
authors.initials: J
authors.lastname: McElhinney
authors.affiliation: School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, UK.
authors.forename: Nelson
authors.initials: N
authors.lastname: Fernandez
authors.affiliation: Research & Development, Eprogen, Inc., Downers Grove, IL, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Barder
mesh_terms: D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D019295:Computational Biology; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D006801:Humans; D056724:Immunity, Humoral; D056747:Immunomodulation; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D020409:Molecular Motor Proteins / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D002147:Calmodulin; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D011257:Pregnancy Proteins; D051197:Toll-Like Receptor 4; D014746:Vimentin; C000605122:preimplantation factor, human; D018995:Myosin Heavy Chains
keywords: Embryo tolerance; Immune regulation; Immune targets; Inflammation control; Oxidative stress; PreImplantation factor (PIF); Protein misfolding