Leukemia inhibitory factor regulates the activation of inflammatory signals in macrophages and trophoblast cells
Leukemia inhibitory factor regulates the activation of inflammatory signals in macrophages and trophoblast cells
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DOI：
10.1016/j.molimm.2020.01.021
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发表时间：
2020-04-01
影响因子：
3.6
通讯作者：
Reyes-Moreno, Carlos
中科院分区：
文献类型：
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作者：
Hamelin-Morrissette, Jovane;Dallagi, Angham;Reyes-Moreno, Carlos
多效细胞因子白血病抑制因子（LIF）是已知的在胎儿-母亲界面建立动态细胞和分子串扰的关键妊娠因子。之前，我们描述了lif -滋养细胞- il10轴在巨噬细胞对促炎细胞因子的失活过程中的调节作用。然而，LIF对巨噬细胞和滋养细胞功能的直接调节作用尚不明确。在这项研究中，我们旨在研究LIF是否以及如何调节巨噬细胞和滋养细胞对促炎应激因子的反应。我们发现，LIF通过降低信号换能器和转录激活因子-1 （Stat1）和-5 （Stat5）的磷酸化水平，调节巨噬细胞和滋养细胞中干扰素- γ (IFN γ)和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的激活作用。IFN γ激活细胞抑制细胞侵袭和迁移，但当LIF使巨噬细胞和滋养细胞失活时，这种固定作用被取消；巨噬细胞运动恢复可以部分解释为LIF对Stat3激活和基质金属蛋白酶9 （MMP-9）表达的积极作用。药理抑制Stat1和Stat3表明，IFN γ诱导的Stat1激活介导巨噬细胞运动抑制，IFN γ激活的巨噬细胞通过IFN γ诱导的Stat3激活和Stat1抑制恢复细胞运动。此外，IFN γ诱导的TNF α基因表达也被LIF通过Stat1抑制和Stat3激活而消除。最后，我们发现滋养层细胞与gm - csf分化的IFN γ刺激巨噬细胞共培养时，细胞侵袭受到抑制。然而，当巨噬细胞暴露于LIF中时，这种作用被抑制。总之，这项体外研究首次揭示了LIF直接作用于巨噬细胞和滋养细胞的抗炎和促孕活性。
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 (IFN gamma) 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 IFN gamma 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 IFN gamma-induced Stat1 activation mediated macrophage motility inhibition, and that cell motility in IFN gamma-activated macrophages is restored via LIF-induced Stat3 activation and Stat1 inhibition. Moreover, IFN gamma-induced TNF alpha 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, IFN gamma-stimulated macrophages. This effect, however, was inhibited when macrophages were exposed to LIF. Overall, this in vitro study reveals for the first time the the anti-inflammatory and pro-gestational activities of LIF by acting directly on macrophages and trophoblast cells.