title: The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF-trophoblast-IL-10 axis via Stat1 inhibition and Stat3 activation.
abstract: Interferon gamma (IFN-γ) and leukemia inhibitory factor (LIF) are key gestational factors that may differentially affect leukocyte function during gestation. Because IFN-γ induces a pro-inflammatory phenotype in macrophages and because trophoblast cells are principal targets of LIF in the placenta, we investigated whether and how soluble factors from trophoblast cells regulate the effects of IFN-γ on macrophage activation. IFN-γ reduces macrophage motility, but enhances Stat1 activation, pro-inflammatory gene expression and cytotoxic functions. Soluble factors from villous cytotrophoblasts (vCT+LIF cells) and BeWo cells (BW/ST+LIF cells) that were differentiated in the presence of LIF inhibit macrophage Stat1 activation but inversely sustain Stat3 activation in response to IFN-γ. vCT+LIF cells produce soluble factors that induce Stat3 activation; this effect is partially abrogated in the presence of neutralizing anti-interleukin 10 (IL-10) antibodies. Moreover, soluble factors from BW/ST+LIF cells reduce cell proliferation but enhance the migratory responses of monocytes. In addition, these factors reverse the inhibitory effect of IFN-γ on monocyte/macrophage motility. BW/ST+LIF cells also generate IFN-γ-activated macrophages with enhanced IL-10 expression, but reduced tumor-necrosis factor alpha (TNF-α), CD14 and CD40 expression as well as impaired cytotoxic function. Additional assays performed in the presence of neutralizing anti-IL-10 antibodies and exogenous IL-10 demonstrate that reduced macrophage cytotoxicity and proliferation, but increased cell motility result from the ability of trophoblast IL-10 to sustain Stat3 activation and suppress IFN-γ-induced Stat1 activation. These in vitro studies are the first to describe the regulatory role of the LIF-trophoblast-IL-10 axis in the process of macrophage activation in response to pro-inflammatory cytokines.
authors.affiliation: 1] Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Université du Québec à Trois-Rivières, département de biologie médicale, Trois-Rivières, PQ, G9A 5H7, Canada [2] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada.
authors.forename: Angham
authors.initials: A
authors.lastname: Dallagi
authors.affiliation: 1] Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Université du Québec à Trois-Rivières, département de biologie médicale, Trois-Rivières, PQ, G9A 5H7, Canada [2] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Girouard
authors.affiliation: 1] Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Université du Québec à Trois-Rivières, département de biologie médicale, Trois-Rivières, PQ, G9A 5H7, Canada [2] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada.
authors.forename: Jovane
authors.initials: J
authors.lastname: Hamelin-Morrissette
authors.affiliation: 1] Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Université du Québec à Trois-Rivières, département de biologie médicale, Trois-Rivières, PQ, G9A 5H7, Canada [2] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dadzie
authors.affiliation: 1] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada [2] INRS-Institut Armand-Frappier, Université du Québec, Laval, PQ, H7V 1B7, Canada.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Laurent
authors.affiliation: 1] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada [2] INRS-Institut Armand-Frappier, Université du Québec, Laval, PQ, H7V 1B7, Canada.
authors.forename: Cathy
authors.initials: C
authors.lastname: Vaillancourt
authors.affiliation: 1] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada [2] Université du Québec à Montréal, département des sciences biologiques, Montréal, QC, H3C 3P8, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Lafond
authors.affiliation: Centre Hospitalier Régional de Trois-Rivières, Trois-Rivières, PQ, G9A 1Y1, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Carrier
authors.affiliation: 1] Groupe de Recherche en Oncologie et Endocrinologie Moléculaires, Université du Québec à Trois-Rivières, département de biologie médicale, Trois-Rivières, PQ, G9A 5H7, Canada [2] Centre de recherche BioMed UQAM-UQTR-INRS, Montréal, PQ, H3C 3P8, Canada.
authors.forename: Carlos
authors.initials: C
authors.lastname: Reyes-Moreno
mesh_terms: D045744:Cell Line, Tumor; D002824:Chorionic Villi / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D011247:Pregnancy / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000276:immunology*
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D016753:Interleukin-10; D007371:Interferon-gamma