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The activating effect of IFN-gamma on monocytes/macrophages is regulated by the LIF-trophoblast-IL-10 axis via Stat1 inhibition and Stat3 activation


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Dallagi, Angham; Girouard, Julie; Hamelin-Morrissette, Jovane; Dadzie, Rachel; Laurent, Laetitia; Vaillancourt, Cathy; Lafond, Julie; Carrier, Christian; Reyes-Moreno, Carlos (2015). The activating effect of IFN-gamma on monocytes/macrophages is regulated by the LIF-trophoblast-IL-10 axis via Stat1 inhibition and Stat3 activation Cellular and Molecular Immunology , vol. 12 , nº 3. p. 326-341. DOI: 10.1038/cmi.2014.50.

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Interferon gamma (IFN-gamma) and leukemia inhibitory factor (LIF) are key gestational factors that may differentially affect leukocyte function during gestation. Because IFN-gamma 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-gamma on macrophage activation. IFN-gamma 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-gamma. vCT1LIF 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-gamma on monocyte/macrophage motility. BW/ST+LIF cells also generate IFN-gamma-activated macrophages with enhanced IL-10 expression, but reduced tumor-necrosis factor alpha (TNF-alpha), 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-gamma-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.

Type de document: Article
Mots-clés libres: cell migration/motility; embryonic cell; gestational factors; inflammatory cell; macrophage deactivation; human decidual macrophages; necrosis-factor-alpha; cell-line bewo; interferon-gamma; alternative activation; human trophoblast; gene-expression; human placenta; thp-1 cells; nk cells
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 30 mai 2017 20:21
Dernière modification: 30 mai 2017 20:21
URI: http://espace.inrs.ca/id/eprint/3174

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