Leukemia inhibitory factor regulates the activation of inflammatory signals in macrophages and trophoblast cells

Mol Immunol. 2020 Apr:120:32-42. doi: 10.1016/j.molimm.2020.01.021. Epub 2020 Feb 8.

Abstract

The pleiotropic cytokine leukemia inhibitory factor (LIF) is a key gestational factor known to establish dynamic cellular and molecular cross talk at the feto-maternal interface. Previously, we described the regulatory role of the LIF-trophoblast-IL10 axis in the process of macrophage deactivation in response to pro-inflammatory cytokines. However, the direct regulatory effects of LIF in macrophage and trophoblast cell function remains elusive. In this study, we aimed to examine whether and how LIF regulates the behavior of macrophages and trophoblast cells in response to pro-inflammatory stress factors. We found that LIF modulated the activating effects of interferon-gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in macrophages and trophoblast cells by reducing the phosphorylation levels of signal transducer and activator of transcription-1 (Stat1) and -5 (Stat5). Cell activation with IFNγ inhibited cell invasion and migration but this immobilizing effect was abrogated when macrophages and trophoblast cells were deactivated with LIF; macrophage cell motility restitution could in part be explained by the positive effects of LIF in Stat3 activation and matrix metalloproteinase 9 (MMP-9) expression. Pharmacological inhibition of Stat1 and Stat3 indicated that IFNγ-induced Stat1 activation mediated macrophage motility inhibition, and that cell motility in IFNγ-activated macrophages is restored via LIF-induced Stat3 activation and Stat1 inhibition. Moreover, IFNγ-induced TNFα gene expression was also abrogated by LIF through Stat1 inhibition and Stat3 activation. Finally, we have found that cell invasion of trophoblast cells is inhibited when they were cocultured with GM-CSF-differentiated, IFNγ-stimulated macrophages. This effect, however, was inhibited when macrophages were exposed to LIF. Overall, this in vitro study reveals for the first time the anti-inflammatory and pro-gestational activities of LIF by acting directly on macrophages and trophoblast cells.

Keywords: Cell signaling; Cytokine; Gestational factors; Granulocyte-macrophage colony-stimulating factor; Interferon-gamma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Movement / immunology
  • Coculture Techniques
  • Female
  • Gene Expression
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Inflammation Mediators / immunology*
  • Interferon-gamma / immunology
  • Leukemia Inhibitory Factor / immunology*
  • Macrophage Activation
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Maternal-Fetal Exchange / immunology
  • Matrix Metalloproteinase 9 / metabolism
  • Pregnancy
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / immunology
  • Trophoblasts / cytology
  • Trophoblasts / immunology*
  • Trophoblasts / metabolism

Substances

  • CSF2 protein, human
  • Inflammation Mediators
  • LIF protein, human
  • Leukemia Inhibitory Factor
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • MMP9 protein, human
  • Matrix Metalloproteinase 9