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-c) and leukemia inhibitory factor (LIF) are key gestational factors that may differentially affect leukocyte function during gestation. Because IFN-c 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-c on macrophage activation. IFN-c reduces macrophage motility, but enhances Stat1 activation, pro-inflammatory gene expression and cytotoxic functions. Soluble factors from villous cytotrophoblasts (vCT1LIF cells) and BeWo cells (BW/ST1LIF cells) that were differentiated in the presence of LIF inhibit macrophage Stat1 activation but inversely sustain Stat3 activation in response to IFN-c. 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/ST1LIF cells reduce cell proliferation but enhance the migratory responses of monocytes. In addition, these factors reverse the inhibitory effect of IFN-c on monocyte/macrophage motility. BW/ST1LIF cells also generate IFN-c-activated macrophages with enhanced IL-10 expression, but reduced tumor-necrosis factor alpha (TNF-a), 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-c-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.

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“…We also observed the regulation of a wide variety of genes encoding cell surface proteins by WTD treatment, including CD93 -a receptor critical for monocyte phagocytosis and CD44 and CD9 -markers involved in cell surface adhesion (Sup. Figure 5b); and an inhibition of type I IFN gene signature, in agreement with previous studies (Dallagi et al, 2015;Ito et al, 1999) (Sup. Figure 5b).…”

The Interactions Between Cancer Stem Cells and the Innate Interferon Signaling Pathway

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“…They also form a major line of defence against invading pathogens in the decidua and thus protect the foetus from infection . In vitro studies have shown that dMϕ differentiation and polarization are regulated by factors produced by trophoblasts such as IL‐10, suppressing IFNγ‐induced Stat1 activation . During early gestation, dMϕ are also major producers of IL‐10 and are able to suppress and regulate the decidua immune response .…”