Leukaemia inhibitory factor in implantation and uterine biology

Kimber, Susan J.

doi:10.1530/rep.1.00304

Cited by 147 publications

(123 citation statements)

References 148 publications

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“…LIF plays an important role in the establishment of pregnancy by supporting decidual and placental differentiation and by influencing reproductive tract cells, such as leukocytes and luminal/glandular epithelial cells. 25 The best evidence that LIF may play a role in the regulation of Mws comes from data obtained from LIF KO mice, which present a more than half reduced percentage of uterine Mws by days 3-5 of pregnancy. 25 The LIF KO mouse model also revealed the central regulatory role of LIF in endotoxic shock and host defense.…”

Section: Introductionmentioning

confidence: 99%

“…25 The best evidence that LIF may play a role in the regulation of Mws comes from data obtained from LIF KO mice, which present a more than half reduced percentage of uterine Mws by days 3-5 of pregnancy. 25 The LIF KO mouse model also revealed the central regulatory role of LIF in endotoxic shock and host defense. Essentially, LIF expression following endotoxic shock enhances the expression of hepatic acute-phase proteins and IL-10, which downregulates TNF-a synthesis and release in the liver, conferring protection against endotoxemia.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…The factors required to promote differentiation and proliferation of EVT are unknown but may include interaction with extracellular matrix proteins and growth factors such as epidermal growth factor (EGF), leukemia inhibitory factor (LIF), bone morphogenetic factor-4 (BMP4), and fibroblast growth factor-4 (FGF4) (2)(3)(4)(5). EVT invade decidual tissue and interact with maternal decidual natural killer cells (dNK), decidual macrophages (dMϕ), and decidual T cells (dT) (1,6).…”

mentioning

confidence: 99%

Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes

Tilburgs

Crespo

Zwan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

183

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Invading human leukocyte antigen-G+ (HLA-G+) extravillous trophoblasts (EVT) are rare cells that are believed to play a key role in the prevention of a maternal immune attack on foreign fetal tissues. Here highly purified HLA-G+ EVT and HLA-G− villous trophoblasts (VT) were isolated. Culture on fibronectin that EVT encounter on invading the uterus increased HLA-G, EGF-Receptor-2, and LIFReceptor expression on EVT, presumably representing a further differentiation state. Microarray and functional gene set enrichment analysis revealed a striking immune-activating potential for EVT that was absent in VT. Cocultures of HLA-G+ EVT with sample matched decidual natural killer cells (dNK), macrophages, and CD4+ and CD8+ T cells were established. Interaction of EVT with CD4+ T cells resulted in increased numbers of CD4+CD25 HI FOXP3+CD45RA+ resting regulatory T cells (Treg) and increased the expression level of the Treg-specific transcription factor FOXP3 in these cells. However, EVT did not enhance cytokine secretion in dNK, whereas stimulation of dNK with mitogens or classical natural killer targets confirmed the distinct cytokine secretion profiles of dNK and peripheral blood NK cells (pNK). EVT are specialized cells involved in maternal-fetal tolerance, the properties of which are not imitated by HLA-G-expressing surrogate cell lines.Treg | FOXP3 | NK cell | human | pregnancy

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“…The same observations were made when celecoxib and aspirin (selective inhibitors of COX-2 and COX-1, respectively) were used in wildtype mice (29). Based on these results, one of the mechanisms implicated in decidualization could be the action of PGE 2 and prostacyclin (PGI 2 ) through production of cytokines and growth factors (30).…”

Section: The Peri-implantatory Endometrial Changesmentioning

confidence: 53%

Blastocyst-endometrium interaction: intertwining a cytokine network

Castro-Rendón¹,

Castro-Álvarez²,

Guzmán-Martinez³

et al. 2006

Braz J Med Biol Res

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The successful implantation of the blastocyst depends on adequate interactions between the embryo and the uterus. The development of the embryo begins with the fertilized ovum, a single totipotent cell which undergoes mitosis and gives rise to a multicellular structure named blastocyst. At the same time, increasing concentrations of ovarian steroid hormones initiate a complex signaling cascade that stimulates the differentiation of endometrial stromal cells to decidual cells, preparing the uterus to lodge the embryo. Studies in humans and in other mammals have shown that cytokines and growth factors are produced by the pre-implantation embryo and cells of the reproductive tract; however, the interactions between these factors that converge for successful implantation are not well understood. This review focuses on the actions of interleukin-1, leukemia inhibitory factor, epidermal growth factor, heparin-binding epidermal growth factor, and vascular endothelial growth factor, and on the network of their interactions leading to early embryo development, peri-implantatory endometrial changes, embryo implantation and trophoblast differentiation. We also propose therapeutical approaches based on current knowledge on cytokine interactions.

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Leukaemia inhibitory factor in implantation and uterine biology

Cited by 147 publications

References 148 publications

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

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

Human HLA-G+ extravillous trophoblasts: Immune-activating cells that interact with decidual leukocytes

Blastocyst-endometrium interaction: intertwining a cytokine network

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