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Leukaemia inhibitory factor in implantation and uterine biology

Faculty of Life Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK

Correspondence should be addressed to S J Kimber; Email: sue.kimber{at}manchester.ac.uk

	Abstract

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Leukaemia inhibitory factor (LIF) is one of the most important cytokines in the reproductive tract. Without expression of LIF in the uterus, implantation of a blastocyst cannot begin. Yet, 13 years after publication of the phenotype of the LIF knockout mouse we are only just beginning to understand how LIF functions in the uterus. This review addresses our knowledge of the role of LIF in regulating implantation through its influence on the luminal epithelium and stromal decidualization, but also its influence on reproductive tract cells such as leukocytes and glandular epithelium, during the pre-implantation phase of pregnancy.

	Introduction

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Blastocyst implantation is a unique feature of mammalian reproduction and a tightly regulated process. Changes in ovarian steroids during the pre-implantation period instigate the required maturation of the endometrial epithelium and stroma. Following priming with preovulatory oestrogen, increasing ovarian progesterone produces a sensitized uterus. In rodents, the ability of the uterus to support and facilitate the implantation of the blastocyst is regulated by the downstream effects of a subsequent small transient increase in oestrogen (Finn & Martin 1970). Oestrogen induces changes which allow the uterus to support implantation of the blastocyst over a short period of the reproductive cycle, the receptive period. This spans about 18–24 h in rodents and probably several days in the human (Navot et al. 1991) although experimentally the amount of oestrogen can influence the duration of the receptive phase (Ma et al. 2003). The endometrial response involves differentiation of the endometrial epithelium and stroma to a phenotype favouring interaction with the trophectoderm. Changes in the luminal epithelium (LE), with which the trophectoderm of the activated blastocyst first interacts, are essential for the initiation of implantation (Kimber & Spanswick 2000, Aplin & Kimber 2004). The steroid-prepared stroma must also undergo a process of further differentiation, known as decidualization, triggered by an embryonic signal (or artificial mimic). Decidualization is induced in stroma around the implantation site from late on day 4 of pregnancy in mice. In women, decidual changes occur in the absence of an embryo. Decidualization involves changes in the expression of a large number of genes (Farrar & Carson 1992, Paria et al. 2001) and is marked by a rapid increase in vascular permeability with resulting oedema in the stroma around the implantation site (Abrahamsohn & Zorn 1993). In spite of the well-established requirement for oestrogen priming before blastocyst signals can establish a decidual response, in mice decidualization has been shown to occur in the absence of a functional oestrogen receptor- (Curtis et al. 1999, Paria et al. 1999, Curtis-Hewitt et al. 2002). Following the receptive period, the uterus becomes refractory, no longer allowing implantation of any remaining blastocysts. Thus tightly regulated synchrony between embryonic development and uterine maturation is essential for successful pregnancy.

It is clear that implantation of the mammalian embryo requires co-ordinated interaction between the embryo and the uterus. Although it has long been known that ovarian steroids regulate this process, it is only in the last couple of decades that some of the local factors have been identified. Steroidal regulation of uterine function is mediated to a large extent through the action of growth factors and cytokines on their receptors (for review see Sharkey 1998, Saito 2001).

	Leukaemia inhibitory factor (LIF)

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
One cytokine which is essential for successful implantation is Leukaemia Inhibitory Factor (LIF), a member of the interleukin (IL)-6 family. LIF is a highly glycosylated 40–50 kDa glycoprotein with a range of biological functions (Haines et al. 2000). It is expressed in various embryonic and adult tissues (Hilton & Gough 1991, Schafer-Somi 2003) with particularly high levels in the uterus. At the cell surface, LIF receptor-ß (LIF-Rß) binds the glycoprotein gp-130 (the common signalling receptor for IL-6 family cytokines) to form a high affinity receptor through which LIF signalling is triggered (Heinrich et al. 2003). Transduction of the signal can occur by activation of several pathways, the main ones being the JAK/STAT pathway, the Src homology 2-domain-containing tyrosine phoshatase (SHP-2)/Ras/extracellular signal-regulated kinase (ERK) pathway or the phosphatidylinositol-3-kinase (PI3K)/Akt pathways, the relative importance of which varies with tissue. Signalling can be inhibited by suppressors of cytokine signalling or protein inhibitor of activated STAT (PIAS) proteins (Chung et al. 1997, Bousquet et al. 1999, Duval et al. 2000).

	LIF and implantation

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
In inbred female C57Bl mice, null for the LIF gene, embryos develop to the blastocyst stage but do not implant (Stewart et al. 1992, Cheng et al. 2002) and the uteri show little evidence of decidualization (Chen et al. 2000). We observed a similar phenotype on an outbred, MF1, background (Sherwin et al. 2004, Fouladi-Nashta et al. 2005). In spite of the presence of anti-mesometrially located blastocysts in the uterine lumen, no decidual reaction is evident, nor is there penetration of LE by trophoblast, even by day 7 of pregnancy (Fig. 1). LIF –/– embryos can implant in the uteri of wild-type female mice and delivery of LIF, either by a micro-osmotic pump or injection on day 4, restores implantation capacity to homozygous mutant females (Stewart et al. 1992, Chen et al. 2000, Sherwin et al. 2004). Since LIF-null embryos develop to term in heterozygous dams and can implant after transfer to wild-type females of appropriate endocrine status it is clear that the major implantation defect is on the maternal side. This is supported by the absence of an implantation defect in embryos lacking components of the LIF signalling cascade. For instance, gp-130-null embryos die only during the second half of gestation with multiple abnormalities including in heart and haematopoietic progenitors (Yoshida et al. 1996) while LIF-Rß knockout animals implant normally but have, for instance, placental defects and motor neuron degeneration and die at birth (Ware et al. 1995). Deletion of the signal transducer and activator of transcription 3 (Stat-3) is embryo lethal but only after implantation has occurred (Takeda et al. 1997). The lack of implantation in females carrying the LIF-null mutation suggests that the action of LIF in the uterus is essential for even early events in this process. However, the precise role of maternal LIF at the molecular level is still unclear in any species.

View larger version (144K): [in this window] [in a new window]   Figure 1 Histological features of the uterus in LIF-null and wild-type mice. Semi-thin resin sections from days 5 and 6 of pregnancy were stained with toluidine blue. The insets show high magnification of differentiated polygonal stromal cells in the wild-type and undifferentiated fibroblast-like stroma cells in the LIF-null mice on day 6 of pregnancy. E = embryo, scale bars = 50 µm (Reprinted from Developmental Biology, vol 281, Fouladi-Nashta et al. Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice, pp 1–21, 2005, with permission from Elsevier).

	LIF in the human uterus

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

	Regulation of LIF expression in mice

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
In mice, the highest levels of LIF mRNA are found prior to implantation in glandular epithelium following the nidatory surge of oestrogen on the morning of day 4 of pregnancy (Bhatt et al. 1991, Chen et al. 2000). Highest levels of LIF protein have also been reported on day 4, mainly in the epithelium but some in stroma (Yang et al. 1995, Fouladi-Nashta et al. 2004). In ovariectomized mice, uterine LIF mRNA increases markedly within 1 h of oestrogen injection and is not affected by progesterone, strongly suggesting oestrogenic control (Bhatt et al. 1991, Stewart & Cullinan 1997, Chen et al. 2000). LIF mRNA declines to a low level by days 6–7 of pregnancy and the transient nature of the LIF signal may be important in its role in implantation. Mice null for the homeobox gene Hmx3 are infertile, lack normal decidualization and do not upregulate LIF in the glandular epithelium at the appropriate time in pregnancy (Wang et al. 1998). Another homeobox gene Hoxa-11 is also required for normal decidualization and completion of implantation. Again, in its absence, LIF does not show an upsurge at day 4 of pregnancy (Gendron et al. 1997). This suggests that these two genes may be involved in regulating the increase in LIF at implantation. LIF activity may also be regulated by soluble receptor expression.

	Regulation of LIF expression in the human

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Observations on cultured human endometrial cells emphasize that LIF is linked to inflammatory pathways, e.g. through IL-1 and tumour necrosis factor- (TNF-), which poses the question as to whether LIF is involved in inflammation or implantation (or both) in humans. IL-1ß stimulates LIF secretion by endometrial epithelial cells in vitro (Perrier d’Hauterive et al. 2004). Recent evidence suggests that in these cells LIF and LIF-R, and IL-1ß, its receptor and receptor antagonist are all regulated by leptin via the leptin receptor OB-R (Gonzalez et al. 2003, 2004), a cytokine better known for its role in regulating satiety. Moreover, IL-1ß as well as leptin upregulate LIF-R and both effects are blocked by inhibition of IL-1R type-1. Thus it appears that leptin may be a primary regulator of the LIF response at several levels at least in human endometrium and feedback loops exist between IL-1 and LIF in endometrial epithelial cells. It remains to be demonstrated whether IL-1 regulates LIF and its receptor in the mouse. In cultured endometrial epithelial cells, TNF- stimulates LIF, along with IL-6, secretion in a nerve factor-B-dependent manner that also requires a functional proteosome compartment (Laird et al. 2000). IL-1ß, transforming growth factor-ß (TGF-ß) and TNF- have also been shown to stimulate LIF production by first trimester human decidual cell-enriched cultures (Sawai et al. 1997). However, these observations may not necessarily indicate the signalling pathways involved during early stages in implantation.

A role for the human blastocyst in endometrial LIF regulation has been suggested (Perrier d’Hauterive et al. 2004). In vivo (Licht et al. 2001) and in vitro (Perrier d’Hauterive et al. 2004), human chorionic gonadotrophin (hCG) has been shown to stimulate LIF secretion by endometrial epithelial cells. Paradoxically, the effect in vitro was dramatic using follicular phase endometrial epithelium but less impressive with secretory epithelium which appears to express a higher level of hCG/luteinizing hormone receptor transcripts. Perhaps this indicates differences in the amount of receptor protein which are not reflected in transcript levels, or already near-saturated receptor stimulation in biopsied secretory phase tissue. Since it is known that LIF can stimulate hCG production by the trophoblast (Sawai et al. 1995, Nachtigall et al. 1996) these findings suggest a potential positive feedback loop. Insulin-like growth factor (IGF)-I and II and TGF-ß were also found to induce a dose-dependent stimulation of LIF secretion by human endometrial epithelial cells whilst the IGFs (like hCG) also inhibited IL-6 secretion (Perrier d’Hauterive et al. 2004). In women, progesterone given in vivo was reported to inhibit subsequent in vitro LIF secretion by human endometrium (Hambartsoumian et al. 1998b). Interestingly, progesterone and IL-4 have both been shown to upregulate LIF in Th-2 cells (Piccinni et al. 1998).

	Cellular targets and LIF signalling in the murine uterus

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
A key cellular target for LIF in the murine uterus appears to be the LE in which LIF-Rß mRNA increases between days 3 and 4 of pregnancy, as the time of implantation approaches. However, both LIF-Rß and gp-130 protein can be detected in LE on days 3–5 of pregnancy (Cheng et al. 2001). gp-130 expression in LE is stimulated by oestrogen together with progesterone (Cheng et al. 2001, Ni et al. 2002). LIF signalling in the uterus occurs mainly through the JAK/STAT pathway and not the alternative SHP-2/RAS/ERK pathway (Cheng et al. 2001). Stat-3 is present in LE throughout early pregnancy but is only susceptible to activation (via tyrosine phosphorylation) and nuclear translocation on day 4 at the onset of the receptive phase. Oil infusion into the murine uterus induces decidualization following progesterone and oestrogen priming but it is notable that oil can induce Stat-3 phosphorylation as well as transient cyclo-oxygenase (Cox-2) expression independent of hormones (Curtis-Hewitt et al. 2002). So the temporal response to LIF in LE may be partly regulated at the level of sensitivity of Stat-3 to phosphorylation. Indeed mice homozygous for deletion of the STAT activation site in gp-130 show an apparently identical infertility defect to LIF-null females (Ernst et al. 2001). The lack of Stat-3 phosphorylation in pseudopregnant mice (Teng et al. 2004), together with the effect of oil, points to the role of an embryonic signal in facilitating activation of Stat-3 in LE. At the same time, Stat-3 can also transduce the response to other IL-6 family cytokines such as IL-11, which is also implicated in reproductive tract function. IL-11 transcripts are expressed at the murine implantation site and although implantation occurs in IL-11 receptor- knockout animals, secondary decidualization is grossly defective and trophoblast giant cells appear in excess. After 7.5 days post coitum the majority of embryos was found to be necrotic (Robb et al. 1998).

Suppressor of cytokine signalling protein-3 (SOCS-3) is induced by LIF and acts as a feedback inhibitor, preventing phosphorylation of gp-130 and Stats. It has been implicated in regulating uterine LIF signalling and might curtail Stat-3 signalling. Embryos in which SOCS-3 has been deleted die in utero (Roberts et al. 2001) so are not informative for uterine implantation.

It is therefore likely that LIF acts co-operatively with blastocyst signals to induce decidualization on days 4–5 of pregnancy by activation of Stat-3 signalling and subsequent promotion of new gene expression and secondary signalling from LE. In addition, LIF-Rß transcripts and activated Stat-3 are detected in stroma particularly after decidualization in both mice and humans (Yang et al. 1995, Ni et al. 2002, Fouladi-Nashta et al. 2004, Perrier d’Hauterive et al. 2004, Teng et al. 2004). Thus stromal cells are also capable of responding directly to LIF.

	Ultrastructural changes in LE during the peri-implantation period in LIF-null mice

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
In wild-type animals, luminal epithelial cell polarity becomes less marked in the peri-implantation period when latero-basal markers become detectable in the apical membrane (Thie et al. 1996, Kimber 2000, Kimber & Spanswick 2000). Prior to implantation, LE cells normally become more cuboidal and microvilli are replaced by bulbous protrusions called pinopods (Nilsson 1966, Lopata et al. 2002, Murphy 2000a) which increase in number up to day 5 postcoitus (Bansode et al. 1998). In rodents, these apical modifications of the uterine LE appear to mediate uptake of fluid (Enders & Nelson 1973) and macromolecules (Parr & Parr 1974). In contrast, in LIF-null animals on days 4–5 of pregnancy LE cells remain more columnar, similar to wild-type LE on days 2–3 of pregnancy but with a rather domed apical surface. Pinopods do not develop over the apical cell membranes which remain microvillous (Fig. 2) up to day 7 of pregnancy (Fouladi-Nashta et al. 2005). In the human, uterodomes, which develop at an equivalent stage in the menstrual cycle to rodent pinopods, have been associated with receptivity (Nikas et al. 1995). It has been suggested that they carry potential embryo-adhesion molecules (Bentin-Ley et al. 1999, Creus et al. 2002) although they are not pinocytotic (Adams et al. 2002). Our results have indicated that failure of apical maturation and pinopod formation by LE cells is a major reason for the inability of embryos to interact firmly and irreversibly with the uterus in LIF-null mice. By day 5 of pregnancy, wild-type LE cells make intimate association with the trophoectoderm (TE) cell surface via the pinopod membranes while in LIF-null animals more superficial contact is observed at the LE microvillar tips (Fouladi-Nashta et al. 2005). However, it should be noted that pinopods develop in rats in experimental delay of implantation so pinopod formation is insufficient for implantation in the absence of embryonic activation (Isychoyos & Mandon 1971). Hoxa-10 has also been shown to be required for pinopod formation: after Hoxa-10-antisense treatment uterodomes do not appear on the LE at the start of the period of receptivity (Bagot et al. 2001). Thus both Hoxa-10 and LIF play a role in apical LE differentiation.

View larger version (177K): [in this window] [in a new window]   Figure 2 Ultrastructure of LE in LIF-null and wild-type mice on days 4 and 5 of pregnancy. On day 4, both the wild-type and null mice have LE bearing microvilli, but the microvilli of the wild-type mouse have less glycocalyx than those of the null animal which has a prominent filamentous covering over many microvillous processes (arrows). Scale bars = 0.5µm. On the morning of day 5 of pregnancy in the wild-type mice, pinopods (P) of the LE make close contact, sometimes indenting the surface of the blastocyst trophoectoderm (TE) (arrows) whereas, in the null mouse, the blastocyst is only contacted by the tips of untransformed microvilli (arrow heads) and no intimate contact is made. Scale bars = (left) 1 µm and (right) 0.5µm (Reprinted from Developmental Biology, vol 281, Fouladi-Nashta et al. Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice, pp 1–21, 2005, with permission from Elsevier).

	Molecular changes in the LE of LIF-null animals

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

Changes in LE glycosylation are well established in the pre- and peri-implantation period (Aplin 1991, Kimber 1994, Kimber et al. 2001) and these occur in parallel with a reduction in the LE glycocalyx (Chavez & Anderson 1985). Failure to develop pinopods in LIF-null mice is associated with aberrant retention of thick glycocalyx and glycosyl residues on the surface of the LE. This includes the continued presence on day 5 (especially adjacent to the embryo) and day 6 of pregnancy of H-type-1 antigen (Fig. 3) and fucosylated molecules bound by Ulexeuropaens agglutinin 1 (UEA-1) and Tetragonolobus purpureus agglutinin (LTA) lectins (Fouladi-Nashta et al. 2005). Thus LIF, either directly or indirectly in conjunction with embryonic signalling, downregulates fucosylated oligosaccharides as the uterus becomes refractory. However, embryos null for the fucosyl transferase responsible for H-type-1 epitope formation do not have an implantation phenotype, so this saccharide epitope is not indispensable for implantation (Domino et al. 2001). Interestingly, it appears that a similar mis-regulation occurs for transcripts of the homeodomain protein Msx-1 (Daikoku et al. 2004). In wild-type mice, transcripts are absent on day 1 then strongly expressed in LE and glands on the morning of day 4 of pregnancy. They are dramatically downregulated by the evening of day 4 in both pregnancy and pseudopregnancy. However, in LIF-null mice, Msx-1 downregulation does not occur. Whether this is related in any way to the aberrations in the apical LE cell surface observed in these mice is not yet clear.

View larger version (25K): [in this window] [in a new window]   Figure 3 Immunofluorescence staining for H-type-1 antigen in LIF –/– and wild-type mouse uterus. Frozen sections from days 3, 5 and 6 after mating were stained, using mouse monoclonal 667/9E9, for H-type-1 antigen which is expressed in the LE. Note the retention of H-type-1 staining on days 5 and 6 of pregnancy. GE = glandular epithelium and S = stroma. Scale bars = 50µm (Reprinted from Developmental Biology, vol 281, Fouladi-Nashta et al. Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice, pp 1–21, 2005, with permission from Elsevier).

	Use of microarray and subtractive hybridization to identify LIF targets

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Several potential LIF-regulated molecules have been discovered by subtractive hybridization or microarray approaches. Cochlin, an extracellular matrix protein containing von Willebrand factor A-binding domains, has recently been identified as restricted to LE on day 4 of pregnancy and lacking in LIF-null mice (Rodriguez et al. 2004). Once again, gene deletion of this molecule does not give an implantation phenotype, suggesting that loss of cochlin alone cannot explain the lack of implantation in the absence of LIF. IGF-binding protein-3 (IGFBP-3) expression was recently identified to be increased by LIF (Sherwin et al. 2004). IGFBP-3 is expressed mainly in the LE before implantation and then at the implantation site, but in situ hybridization revealed no difference in distribution or intensity of signal between LIF-null and heterozygote or wild-type animals. Thus upregulation by LIF must occur above a detectable basal level, presumably that induced by progesterone. The spread of IGFBP-3 to the stroma around the embryo in pregnant wild-type animals on day 5 was not seen in LIF-null animals. Two other progesterone-responsive genes, immune response gene 1 (IRG1) and amphiregulin were also induced in uteri by LIF injection although this was not found for several other progesterone-regulated molecules. Knockout data have suggested that amphiregulin and IGFBP-3 are not indispensable for implantation (Luetteke et al. 1999, Pintar 2001). IRG1 is stimulated by progesterone but upregulated to a greater extent by both progesterone and oestrogen (Chen et al. 2003, Cheon et al. 2003, Sherwin et al. 2004). It has been found to be an essential factor for implantation (Cheon et al. 2003). So deficiency in IRG1 expression may, at least partly, explain the implantation defect in LIF-null mice. Paradoxically, in another study, IRG1 did not appear to be affected by the absence of LIF (Chen et al. 2003) so future work is needed to clarify the relationships between these molecules.

	LIF and decidualization

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Although decidualization in normal mice requires signals from the blastocyst, in humans it occurs without the involvement of the embryo, so regulatory routes may differ. Stromal cells at the implantation site show marked signs of differentiation by day 5 of murine pregnancy (Abrahamsohn & Zorn 1993). They enlarge, take on a more epithelial appearance with deposition of glycogen in the cytoplasm and some become binucleate. By days 5–6 loss of extracellular matrix and close cell–cell apposition is apparent in the cells of the primary decidual zone. In LIFnull mice, however, even by days 6–7 of pregnancy stromal cells adjacent to the blastocyst appear fibroblastic with none of the ultrastructural changes indicative of decidualization (Chen et al. 2000, Fouladi-Nashta et al. 2005).

In culture we have shown that LIF induces IL-1 secretion by semi-polarized LE cells, an effect blocked by a competitive inhibitor of LIF (A A Fouladi-Nashta, L Mohamet, N Nijjar, J K Heath & S J Kimber, manuscript in preparation). Cox-2 is aberrantly expressed in the absence of LIF at both protein (Fouladi-Nashta et al. 2005) and mRNA (Song et al. 2000) levels. Protein is expressed in the LE adjacent to the embryo but there is extremely limited expression in adjacent stroma (Fig. 4). IL-1 has previously been shown to induce stromal expression of Cox-2, as well as inducing prostaglandin E₂ (PGE-₂) synthesis in stromal cells in vitro (Jacobs & Carson 1993, Jacobs et al. 1994, Bany & Kennedy 1995). Prostacyclin, acting via the nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a key mediator of decidualization in vivo (Lim et al. 1999, Lim & Dey 2000). PGE₂ is also a trigger for the vascular oedema, angiogenenesis and stromal cell differentiation during the decidual response to embryonic signals in rodents (Sananes et al. 1976, Kennedy 1977, Kennedy & Ross 1993). Therefore it is possible that transduction by LE of the LIF signal combined with a blastocyst signal(s) stimulates production of IL-1 sufficient to trigger local decidual changes. This, together with the loss of most Cox-2 expression at the implantation site in LIF-null females, supports a signalling cascade involving IL-1 induction of prostaglandins in the decidualization response. All the same, although implantation was reported to be blocked by repeated intraperitoneal injection of the receptor antagonist IL-1ra (Simon et al. 1994) it occurred normally in mice lacking the IL-1 type-1 receptor (Abbondanzo et al. 1996). Thus even if IL- 1 is downstream of LIF, signalling through this receptor may not be essential for implantation.

View larger version (82K): [in this window] [in a new window]   Figure 4 Immunofluorescence staining for Cox-2 and oncostatin M (OsM) in LIF-null and wild-type mouse uterus on days 5 and 6 of pregnancy. Cox-2 protein is strongly expressed in the LE and underlying stromal cells (arrows) at the implantation site on day 5 and expression extended deeper into the stroma by day 6. In LIF-null mice, expression was limited to the LE cells and only a few stromal cells expressed Cox-2 in the day-6 uterus. The pattern of expression for OsM protein in wild-type mice was similar to Cox-2. In LIF-null animals, OsM was completely absent around the embryo on days 5 and 6 of pregnancy. E = embryo, scale bar = 100µm (Reprinted from Developmental Biology, vol 281, Fouladi-Nashta et al. Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice, pp 1–21, 2005, with permission from Elsevier).

	Stromal phenotype in the presence or absence of LIF

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

Stromal cells maintain LIF-Rß expression in primary culture and we have shown that LIF has a moderate dose-dependent inhibitory effect on stromal decidualization in vitro (Fouladi-Nashta et al. 2004). The repression of cellular differentiation was not simply a result of inhibition of PGE-2 secretion by stromal cells which was unaffected by LIF. One possibility is that a direct effect of LIF on stroma may limit decidualization to the implantation site and prevent it spreading to uterine segments lacking an implanting embryo. This inhibition may only be over-ridden in the presence of a distinct LE signal at the implantation site. Reduction or loss of bone marrow-derived cell populations in stromal culture (e.g. loss of natural killer (NK) cells) might also affect the response of stromal fibroblasts to LIF. The expression of high levels of LIF in human decidua suggests a role in decidualization, but receptor localization and functional studies have suggested that a major target in humans is the trophoblast and placenta (Kojima et al. 1994, 1995, Sawai et al. 1995, Nachtigall et al. 1996, Ren et al. 1997, Sharkey et al. 1999, Kayisli et al. 2002, Chen et al. 2004).

One of the most distinct aspects of the LIF-null phenotype is the complete absence at the implantation site of expression of oncostatin M (OsM), another member of the IL-6 family (Fouladi-Nashta et al. 2005) (Fig. 4). OsM is a 28 kDa protein which binds to a heterodimeric receptor consisting of the OsM receptor-ß (OsM-Rß) and gp-130, although human OsM (but not murine) can also signal through the LIF-R (Ichihara et al. 1997, Wang et al. 2000). Signalling leads to activation of both Stats (3 and/or 5) and the ERK pathway. Although showing overlapping functions, LIF and OsM also have distinct independent functions (Hara et al. 1998). OsM protein shows exquisitely defined temporal and spatial regulation in the murine uterus, which is quite distinct from the glandular expression seen for LIF. We have been unable to detect any LIF protein adjacent to the implanting embryo on late day 4 or day 5 of pregnancy (Fouladi-Nashta et al. 2005) in contrast to the report of transient transcript expression (Song et al. 2000). OsM is expressed only adjacent to the implanting mouse embryo, first in the LE and then in adjacent stroma at the implantation site (Fouladi-Nashta et al. 2005) (Fig. 4). The role of OsM has not been previously investigated in the mouse uterus, but the in human it is reported to reduce proliferation and induce differentiation in uterine stroma in the secretory phase (Ogata et al. 2000, Ohata et al. 2001) and has been implicated in tissue remodelling in other systems. It has been shown to upregulate both matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in diverse cell types (Richards et al. 1993, Korzus et al. 1997, Sanchez et al. 2004) as well as tissue plasminogen activator and plasminogen activator inhibitor (Macfelda et al. 2002, Spence et al. 2002), while in human vascular smooth muscle cells it induces alkaline phosphatase (Shioi et al. 2002) and in astocytes Cox-2 (Repovic et al. 2003). All of these are present in decidualizing stroma, a tissue undergoing intense remodelling at the time of implantation. There is evidence that TIMP-1 regulates trophoblast protease activity (Behrendtsen et al. 1992). However, the OsM-Rß knockout mouse apparently does not have an implantation or fertility-related phenotype (Tanaka et al. 2003), indicating that OsM signalling may not be indispensable for implantation.

	LIF and the pre-implantation uterus

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Although the major research emphasis has been on the role of LIF at the time of implantation, it may also affect uterine cells in the pre-implantation period since it is transiently expressed after ovulation on day 1 of pregnancy, mainly by the LE (Bhatt et al. 1991). Seminal fluid has been shown to induce increased LIF in the human uterus (Gutsche et al. 2003). As well as epithelial cells and stromal fibroblasts, other cell populations such as leukocytes may be adversely affected in the absence of LIF. We have identified differences between the LIF-null and wild-type uterus in several uterine cell populations, including overall stromal cell dynamics, the proportions and distribution of various leukocyte subsets and the density of uterine glands with a peak effect on day 3 of pregnancy (Schofield & Kimber 2005).

Since LIF appears to be a downstream mediator of oestrogen action in the murine peri-implantation uterus, one possible role might be regulation of cell proliferation. During the reproductive cycle, preovulatory oestrogen stimulates luminal and glandular proliferation, which is curtailed by the rise in progesterone on days 2–3 of pregnancy. A transient rise in oestrogen early on day 4 of pregnancy then stimulates stromal proliferation. It has been reported that absence of LIF has no effect on proliferation in either LE or stroma during early pregnancy in inbred C57Bl6 mice (Chen et al. 2000). However, detailed comparison of different regions of the uterus between LIF-null and wild-type outbred animals after labelling with the nucleotide precursor bromodeoxyuridine revealed alterations in cell proliferation in the absence of LIF on days 4 and 5 of pregnancy. The overall percentage of proliferative cells in stroma was found to be reduced in the LIF-null uterus compared with wild-type and regional differences were also evident (G Schofield & S J Kimber, manuscript in preparation).

	LIF and uterine glands

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
In the absence of LIF, we also found greater numbers of uterine glandular profiles from day 3 of pregnancy, suggesting that it may have a cytostatic effect on glandular proliferation or branching morphogenesis. Interestingly the Hoxa-11 knockout mouse does not express LIF in the uterus but shows a deficit of uterine glands, suggesting the complexity of their regulation. Oestrogen exposure at the correct time is well established to be critical for regular glandular morphogenesis. Diethylstilboesterol given in utero perturbs proper reproductive tract morphogenesis including inhibiting uterine gland development, an effect mimicked by loss of Wnt7a (Miller et al. 1998, Carta & Sassoon 2004). Wnt7a –/– mice are sterile and in adults uterine cell death is enhanced in response to diethylstilboestrol, while proliferation is unaffected; the adult uterus also shows a range of molecular mis-regulations. Any interaction between the LIF and wnt pathways in this context is as yet unknown nor have we yet determined if differences in apoptosis between LIF-null and wild-type glands are evident.

	Leukocyte populations in the LIF-null uterus

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Macrophages, NK cells and eosinophils are present in the pregnant uterus and are thought to be beneficial. Alterations in the proportions of NK cells and macrophages can adversely affect pregnancy (Pollard et al. 1991, Guimond et al. 1997, Ashkar & Croy 1999). Strikingly, the percentage of macrophages is reduced by more than a half in LIF-null mice on day 3 of pregnancy and their distribution is also altered (Schofield & Kimber 2005), suggesting that LIF is a chemokine for these cells. However, by day 4, macrophage density appeared similar to that in the wild-type. NK cells were detected as early as day 3 of pregnancy in wild-type and LIF-null mice but the LIF knockout uteri had double the wild-type percentage of NK cells at day 3, with particularly high levels at the anti-mesometrial side of the uterus. So it is possible that LIF restricts migration of NK cells into the uterus. The increase in eosinophils on days 3 and 4 in specific regions of the LIF-null stroma suggests similar control for these cells. Thus the absence of LIF leads to different relative proportions of cells on day 3 of pregnancy compared with wild-type uterus. Alterations in the uterine leukocyte subpopulations in LIF knockout mice may give rise to a less robust pregnancy and contribute to failure of implantation at least on an MF1 background. Since several injections of LIF early on day 4 of pregnancy are enough to correct the implantation defect in the null mice, a supply of LIF on day 4 may be sufficient to redress the effects of leukocyte and glandular aberrations present on day 3 and allow normal uterine function. Alternatively, these abnormalities may not be sufficient to interfere with implantation and, once threshold levels of particular bone marrow-derived cells are acquired, their contribution to uterine function may be sufficient for implantation and establishment of the placenta. All the same, the role of the high levels of LIF seen on day 1 of pregnancy still requires further investigation.

	Role of LIF in peri-implantation and later development of the embryo

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
Mammalian blastocysts express LIF-R (Charnock-Jones et al. 1994, Nichols et al. 1996, Chen et al. 1999) with reciprocal expression of LIF by trophoblast and its receptor by inner cell mass (ICM) in mouse blastocysts (Nichols et al. 1996). LIF enhances blastocyst development and differentiation in vitro (Lavranos et al. 1995, Dunglison et al. 1996). Furthermore, it has been reported that the proportion of morulae and/or blastocysts is reduced after microinjection of LIF antisense at the two-cell stage (Cheng et al. 2004). As noted above, LIF-null, gp-130-null and LIF-R-null embryos are all able to progress through the pre-implantation period and implant, suggesting that LIF has no function in the embryo during this time. However, gp-130 is required for reactivation of the blastocyst to implant after the diapause-like condition caused by experimental delay of implantation (Nichols et al. 2001).

Trophoblast and placenta are also important targets for LIF in both the mouse and human (Harvey et al. 1995, Sharkey et al. 1999). Murine blastocyst trophoblast out-growths upregulate MMP-9 and urokinase-type plasminogen activator in response to LIF (Harvey et al. 1995) and MMP-9 plays a role in trophoblast invasion into the uterus (Salamonsen 1999). LIF stimulates hCG and oncofetal fibronectin production by human trophoblast and its induction of human trophoblast differentiation is hCG dependent (Nachtigall et al. 1996, Yang et al. 2003, see above).

In our analysis of the progeny of matings involving animals with a deletion of the gene encoding LIF we found that the number of nulls was 58–68% that expected for a Mendelian ratio, for both males and females. The lower proportion of LIF-null offspring indicates some embryo loss in the MF1 strain of mouse. It has been reported that on an inbred C57BL6/J background there is no loss of null offspring in utero and Mendelian frequencies are obtained (Stewart et al. 1992). LIF has a variety of effects on different cell types in vitro, inhibiting the differentiation of embryonic stem cells and promoting the survival and/or proliferation of neurons, primitive haematopoietic precursors and primordial germ cells (Hilton 1992). The breadth of influence is reflected in the defects reported in LIF-Rnull fetuses (Ware et al. 1995). As well as placental defects, LIF-deficient mice have dramatically decreased numbers of stem cells in spleen and bone marrow, while heterozygous animals are intermediate in phenotype, implying that LIF has a dosage effect. Deficiency in the stem cell population can be prevented by exogenous LIF (Escary et al. 1993).

	Summary

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
It is indisputable that LIF is essential for implantation in mice and important in other animals including humans. However, LIF has complex regulatory roles.Working out the LIF-generated sequence of molecular interactions which are critical for implantation, rather than merely secondary repercussions of the loss of primary LIF targets (see Fig. 5), will require further research. Recent evidence has focused on the co-operative action of LIF and progesterone in gene regulation. The molecular cascades controlling implantation of the embryo require strict temporal and spatial regulation. In normal development, a remarkable degree of synchrony is needed between differentiation of the epithelial and stromal compartments of the uterus and the developing embryo if implantation is to be successful. This is perhaps most evident in species like the mouse where the period during which implantation can occur is so short. Even a brief delay in maturation of the uterus can result in asynchrony with the blastocyst. Asynchronous embryo transfer studies indicate that the embryo can normally wait while the uterus differentiates to the receptive state and that, experimentally, the embryo may have some influence over the time of implantation (see Aplin & Kimber 2004). One may speculate that in the absence of LIF, lack of uterine maturation may be equivalent to an asynchrony between embryo and uterus which is never resolved by the development of the appropriate trophoblast-interactive epithelium. Cellular and molecular analysis shows this is not just equivalent to experimental delay of implantation (Fouladi-Nashta et al. 2005). The blastocyst remains apparently quiescent in the lumen, is never activated and the pregnancy fails. Therefore, timeliness of expression of LIF and its targets in the uterus is likely to be particularly important.

View larger version (53K): [in this window] [in a new window]   Figure 5 Diagram showing some of the interactions of LIF in the uterus around the time of implantation. Sequential changes over Days 3–5 detailed. Black dashed arrow indicates influence of unknown blastocyst signal on stromal phenotype at implantation site. The blastocyst sends signals which are transduced by the LE in conjunction with LIF from the glandular epithelium (GE) and LIF induced molecules (shown by blue boxed X and pink arrow) contribute to the various stromal cell expression and phenotype changes detailed. Green arrows indicate positive effects. Blue dashed line indicates possible regulation of LIF by Hoxa-11 and Hmx3. LIF is not required for expression of Cox-2 protein or transcripts in LE but is required for significant stromal expression at the implantation site. LIF is needed for both LE and stromal OsM protein expression. Blastocyst signals are also needed for expression of Cox-2 in LE and underlying stroma. In LE, LIF expresses H-type-1 antigen, promoting its downregulation on the evening of day 4. LIF stimulates expression of a number of LE proteins, some already associated with the implantation process and others with unknown function. Morphological pinopods do not develop in LE in the absence of LIF. The regulation of trophoblast-derived LIF is not shown. The likely route of indirect induction of decidualization is illustrated and direct repression of decidualization by LIF is also indicated.

	Acknowledgements

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 
I am extremely grateful to Ali Fouladi-Nashta, Gemma Schofield, Lisa Mohamet, Nahida Nijjar and Carolyn Jones for all their excellent research, which has contributed to the work from my own laboratory. The latter was funded by a grant from the BBSRC, UK to the author a BBSRC studentship and an MRC studentship. I would also like to express my sincere thanks to Professor J D Aplin for his extremely pertinent comments on the manuscript.

The author declares that there is no conflict of interest that would prejudice the impartiality of this scientific work.

	Footnotes

 
Received 27 January 2005
First decision 14 April 2005
Revised manuscript received 12 May 2005
Accepted 19 May 2005

	References

Top Abstract Introduction Leukaemia inhibitory factor... LIF and implantation LIF in the human... Regulation of LIF expression... Regulation of LIF expression... Cellular targets and LIF... Ultrastructural changes in LE... Molecular changes in the... Use of microarray and... LIF and decidualization Stromal phenotype in the... LIF and the pre-implantation... LIF and uterine glands Leukocyte populations in the... Role of LIF in... Summary Acknowledgements References

 

Abbondanzo SJ, Cullinan EB, McIntyre K, Labow MA & Stewart CL 1996 Reproduction in mice lacking a functional type 1 IL-1 receptor. Endocrinology 137 3598–3601.[Abstract]

Abrahamsohn PA & Zorn TM 1993 Implantation and decidualization in rodents. Journal of Experimental Zoology 266 603–628.

Adams SM, Gayer N, Hosie MJ & Murphy CR 2002 Human uterodomes (pinopods) do not display pinocytotic function. Human Reproduction 17 1980–1986.[Abstract/Free Full Text]

Aghajanova L, Stavreus-Evers A, Nikas Y, Hovatta O & Landgren BM 2003 Coexpression of pinopodes and leukemia inhibitory factor, as well as its receptor, in human endometrium. Fertility and Sterility 79 (Suppl 1) 808–814.

Aplin JD 1991 Glycans as biochemical markers of human endometrial secretory differentiation. Journal of Reproduction and Fertility 92 525–541.[Abstract/Free Full Text]

Aplin JD & Kimber SJ 2004 Trophoblast-uterine interactions at implantation. Reproductive Biology and Endocrinology 2 1–12.

Arici A, Engin O, Attar E & Olive DL 1995a Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in human endometrium. Journal of Clinical Endocrinology and Metabolism 80 1908–1915.[Abstract]

Ashkar AA & Croy BA 1999 Interferon-gamma contributes to the normalcy of murine pregnancy. Biology of Reproduction 61 493–502.[Abstract/Free Full Text]

Bagot CN, Kliman HJ & Taylor HS 2001 Maternal Hoxa10 is required for pinopod formation in the development of mouse uterine receptivity to embryo implantation. Developmental Dynamics 222 538–544.[CrossRef][Web of Science][Medline]

Bansode FW, Chauhan SC, Makker A & Singh MM 1998 Uterine luminal epithelial alkaline phosphatase activity and pinopod development in relation to endometrial sensitivity in the rat. Contraception 58 61–68.[CrossRef][Web of Science][Medline]

Bany BM & Kennedy TG 1995 Interleukin-1 alpha regulates prostaglandin production and cyclooxygenase activity in sensitized rat endometrial stromal cells in vitro. Biology of Reproduction 53 126–132.[Abstract]

Behrendtsen O, Alexander CM & Werb Z 1992 Metalloproteinases mediate extracellular matrix degradation by cells from mouse blastocyst outgrowths. Development 114 447–456.[Abstract]

Bentin-Ley U, Sjogren A, Nilsson L, Hamberger L, Larsen JF & Horn T 1999 Presence of uterine pinopodes at the embryo–endometrial interface during human implantation in vitro. Human Reproduction 14 515–520.[Abstract/Free Full Text]

Bhatt H, Brunet LJ & Stewart CL 1991 Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. PNAS 88 11408–11412.[Abstract/Free Full Text]

Bousquet C, Susini C & Melmed S 1999 Inhibitory roles for SHP-1 and SOCS-3 following pituitary proopiomelanocortin induction by leukemia inhibitory factor. Journal of Clinical Investigation 104 1277–1285.[Web of Science][Medline]

Braga VM & Gendler SJ 1993 Modulation of Muc-1 mucin expression in the mouse uterus during the estrus cycle, early pregnancy and placentation. Journal of Cell Science 105 397–405.[Abstract]

Carta L & Sassoon D 2004 Wnt7a is a suppressor of cell death in the female reproductive tract and is required for postnatal and estrogen-mediated growth. Biology of Reproduction 71 444–454.[Abstract/Free Full Text]

Charnock-Jones DS, Sharkey AM, Fenwick P & Smith SK 1994 Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time. Journal of Reproduction and Fertility 101 421–426.[Abstract/Free Full Text]

Chavez DJ & Anderson TL 1985 The glycocalyx of the mouse uterine luminal epithelium during estrus, early pregnancy, the peri-implantation period, and delayed implantation. I. Acquisition of Ricinus communis I binding sites during pregnancy. Biology of Reproduction 32 1135–1142.[Abstract]

Chen B, Zhang D & Pollard JW 2003 Progesterone regulation of the mammalian ortholog of methylcitrate dehydratase (immune response gene 1) in the uterine epithelium during implantation through the protein kinase C pathway. Molecular Endocrinology 17 2340–2354.[Abstract/Free Full Text]

Chen DB, Hilsenrath R, Yang ZM, Le SP, Kim SR, Chuong CJ, Poindexter AN 3rd & Harper MJ 1995 Leukaemia inhibitory factor in human endometrium during the menstrual cycle: cellular origin and action on production of glandular epithelial cell prostaglandin in vitro. Human Reproduction 10 911–918.[Abstract/Free Full Text]

Chen HF, Shew JY, Ho HN, Hsu WL & Yang YS 1999 Expression of leukemia inhibitory factor and its receptor in preimplantation embryos. Fertility and Sterility 72 713–719.[CrossRef][Web of Science][Medline]

Chen HF, Chao KH, Shew JY, Yang YS & Ho HN 2004 Expression of leukemia inhibitory factor and its receptor is not altered in the decidua and chorionic villi of human anembryonic pregnancy. Human Reproduction 19 1647–1654.[Abstract/Free Full Text]

Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L & Stewart CL 2000 Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology 141 4365–4372.[Abstract/Free Full Text]

Cheng JG, Chen JR, Hernandez L, Alvord WG & Stewart CL 2001 Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation. PNAS 98 8680–8685.[Abstract/Free Full Text]

Cheng JG, Rodriguez CI & Stewart CL 2002 Control of uterine receptivity and embryo implantation by steroid hormone regulation of LIF production and LIF receptor activity: towards a molecular understanding of ‘the window of implantation’. Reviews in Endocrine and Metabolic Disorders 3 119–126.

Cheng TC, Huang CC, Chen CI, Liu CH, Hsieh YS, Huang CY, Lee MS & Liu JY 2004 Leukemia inhibitory factor antisense oligonucleotide inhibits the development of murine embryos at preimplantation stages. Biology of Reproduction 70 1270–1276.[Abstract/Free Full Text]

Cheon YP, Xu X, Bagchi MK & Bagchi IC 2003 Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. Endocrinology 144 5623–5630.[Abstract/Free Full Text]

Chobotova K, Spyropoulou I, Carver J, Manek S, Heath JK, Gullick WJ, Barlow DH, Sargent IL & Mardon HJ 2002 Heparin-binding epidermal growth factor and its receptor ErbB4 mediate implantation of the human blastocyst. Mechanisms of Development 119 137–144.[CrossRef][Web of Science][Medline]

Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P & Shuai K 1997 Specific inhibition of Stat3 signal transduction by PIAS3. Science 278 1803–1805.[Abstract/Free Full Text]

Classen-Linke I, Muller-Newen G, Heinrich PC, Beier HM & von Rango U 2004 The cytokine receptor gp130 and its soluble form are under hormonal control in human endometrium and decidua. Molecular and Human Reproduction 10 495–504.[Abstract/Free Full Text]

Creus M, Ordi J, Fabregues F, Casamitjana R, Ferrer B, Coll E, Vanrell JA & Balasch J 2002 Alphavbeta3 integrin expression and pinopod formation in normal and out-of-phase endometria of fertile and infertile women. Human Reproduction 17 2279–2286.[Abstract/Free Full Text]

Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA & Stewart CL 1996 Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/ paracrine function in regulating embryo implantation. PNAS 93 3115–3120.[Abstract/Free Full Text]

Curtis SW, Clark J, Myers P & Korach KS 1999 Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor alpha knockout mouse uterus. PNAS 96 3646–3651.[Abstract/Free Full Text]

Curtis-Hewitt S, Goulding EH, Eddy EM & Korach KS 2002 Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent. Biology of Reproduction 67 1268–1277.[Abstract/Free Full Text]

Daikoku T, Song H, Guo Y, Riesewijk A, Mosselman S, Das SK & Dey SK 2004 Uterine Msx-1 and Wnt4 signaling becomes aberrant in mice with the loss of leukemia inhibitory factor or Hoxa-10: evidence for a novel cytokine-homeobox-Wnt signaling in implantation. Molecular Endocrinology 18 1238–1250.[Abstract/Free Full Text]

Domino SE, Zhang L, Gillespie PJ, Saunders TL & Lowe JB 2001 Deficiency of reproductive tract alpha(1,2)fucosylated glycans and normal fertility in mice with targeted deletions of the FUT1 or FUT2 alpha(1,2)fucosyltransferase locus. Molecular and Cellular Biology 21 8336–8345.[Abstract/Free Full Text]

Dunglison GF, Barlow DH & Sargent IL 1996 Leukaemia inhibitory factor significantly enhances the blastocyst formation rates of human embryos cultured in serum-free medium. Human Reproduction 11 191–196.[Abstract/Free Full Text]

Duval D, Reinhardt B, Kedinger C & Boeuf H 2000 Role of suppressors of cytokine signaling (Socs) in leukemia inhibitory factor (LIF)-dependent embryonic stem cell survival. FASEB Journal 14 1577–1584.[Abstract/Free Full Text]

Enders AC & Nelson DM 1973 Pinocytotic activity of the uterus of the rat. American Journal of Anatomy 138 277–299.

Ernst M, Inglese M, Waring P, Campbell IK, Bao S, Clay FJ, Alexander WS, Wicks IP, Tarlinton DM & Novak U et al. 2001 Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. Journal of Experimental Medicine 194 189–203.[Abstract/Free Full Text]

Escary JL, Perreau J, Dumenil D, Ezine S & Brulet P 1993 Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation. Nature 363 361–364.[CrossRef][Medline]

Farrar JD & Carson DD 1992 Differential temporal and spatial expression of mRNA encoding extracellular matrix components in decidua during the peri-implantation period. Biology of Reproduction 46 1095–1108.[Abstract]

Finn CA & Martin L 1970 The role of the oestrogen secreted before oestrus in the preparation of the uterus for implantation in the mouse. Journal of Endocrinology 47 431–438.

Fouladi-Nashta AA, Andreu CV, Nijjar N, Heath JK & Kimber SJ 2004 Role of leukemia inhibitor factor (LIF) in decidualisation of murine uterine stromal cells in vitro. Journal of Endocrinology 181 477–492.[Abstract]

Fouladi-Nashta AA, Jones CJ, Nijjar N, Mohamet L, Smith A, Chambers I & Kimber SJ 2005 Characterization of the uterine phenotype during the peri-implantation period for LIF-null, MF1 strain mice. Developmental Biology 281 1–21.[CrossRef][Web of Science][Medline]

Gendron RL, Paradis H, Hsieh-Li HM, Lee DW, Potter SS & Markoff E 1997 Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biology of Reproduction 56 1097–1105.[Abstract]

Giess R, Tanasescu I, Steck T & Sendtner M 1999 Leukaemia inhibitory factor gene mutations in infertile women. Molecular Human Reproduction 5 581–586.[Abstract/Free Full Text]

Glasser SR, Lampelo S, Munir MI & Julian J 1987 Expression of desmin, laminin and fibronectin during in situ differentiation (decidualization) of rat uterine stromal cells. Differentiation 35 132–142.[CrossRef][Web of Science][Medline]

Gonzalez RR, Leary K, Petrozza JC & Leavis PC 2003 Leptin regulation of the interleukin-1 system in human endometrial cells. Molecular Human Reproduction 9 151–158.[Abstract/Free Full Text]

Gonzalez RR, Rueda BR, Ramos MP, Littell RD, Glasser S & Leavis PC 2004 Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling. Endocrinology 145 3850–3857.[Abstract/Free Full Text]

Guimond MJ, Luross JA, Wang B, Terhorst C, Danial S & Croy BA 1997 Absence of natural killer cells during murine pregnancy is associated with reproductive compromise in TgE26 mice. Biology of Reproduction 56 169–179.[Abstract]

Gutsche S, von Wolff M, Strowitzki T & Thaler CJ 2003 Seminal plasma induces mRNA expression of IL-1beta, IL-6 and LIF in endometrial epithelial cells in vitro. Molecular Human Reproduction 9 785–791.[Abstract/Free Full Text]

Haines BP, Voyle RB & Rathjen PD 2000 Intracellular and extracellular leukemia inhibitory factor proteins have different cellular activities that are mediated by distinct protein motifs. Molecular Biology of the Cell 11 1369–1383.[Abstract/Free Full Text]

Hambartsoumian E 1998a Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. American Journal of Reproductive Immunology 39 137–143.

Hambartsoumian E, Taupin JL, Moreau JF, Frydman R & Chaouat G 1998b In vivo administration of progesterone inhibits the secretion of endometrial leukaemia inhibitory factor in vitro. Molecular Human Reproduction 4 1039–1044.[Abstract/Free Full Text]

Hara T, Tamura K, de Miguel MP, Mukouyama Y, Kim H, Kogo H, Donovan PJ & Miyajima A 1998 Distinct roles of oncostatin M and leukemia inhibitory factor in the development of primordial germ cells and Sertoli cells in mice. Developmental Biology 201 144–153.[CrossRef][Web of Science][Medline]

Harvey MB, Leco KJ, Arcellana-Panlilio MY, Zhang X, Edwards DR & Schultz GA 1995 Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor. Development 121 1005–1014.[Abstract]

Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G & Schaper F 2003 Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical Journal 374 1–20.[CrossRef][Web of Science][Medline]

Hilton DJ 1992 LIF: lots of interesting functions. Trends in Biochemical Science 17 72–76.

Hilton DJ & Gough NM 1991 Leukemia inhibitory factor: a biological perspective. Journal of Cellular Biochemistry 46 21–26.[CrossRef][Web of Science][Medline]

Ichihara M, Hara T, Kim H, Murate T & Miyajima A 1997 Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice. Blood 90 165–173.[Abstract/Free Full Text]

Illingworth IM, Kiszka I, Bagley S, Ireland GW, Garrod DR & Kimber SJ 2000 Desmosomes are reduced in the mouse uterine luminal epithelium during the preimplantation period of pregnancy: a mechanism for facilitation of implantation. Biology of Reproduction 63 1764–1773.[Abstract/Free Full Text]

Inagaki N, Stern C, McBain J, Lopata A, Kornman L & Wilkinson D 2003 Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Human Reproduction 18 608–615.[Abstract/Free Full Text]

Jacobs AL & Carson DD 1993 Uterine epithelial cell secretion of interleukin-1 alpha induces prostaglandin E2 (PGE2) and PGF2 alpha secretion by uterine stromal cells in vitro. Endocrinology 132 300–308.[Abstract/Free Full Text]

Jacobs AL, Hwang D, Julian J & Carson DD 1994 Regulated expression of prostaglandin endoperoxide synthase-2 by uterine stroma. Endocrinology 135 1807–1815.[Abstract]

Julian J, Chiquet-Ehrismann R, Erickson HP & Carson DD 1994 Tenascin is induced at implantation sites in the mouse uterus and interferes with epithelial cell adhesion. Development 120 661–671.[Abstract]

Kayisli UA, Selam B, Demir R & Arici A 2002 Expression of vasodilator-stimulated phosphoprotein in human placenta: possible implications in trophoblast invasion. Molecular Human Reproduction 8 88–94.[Abstract/Free Full Text]

Kennedy TG 1977 Evidence for a role for prosaglandins in the initiation of blastocyst implantation in the rat. Biology of Reproduction 16 286–291.[Abstract]

Kennedy TG & Ross HE 1993 Effect of prostaglandin E2 on rate of decidualization in rats. Prostaglandins 46 243–250.[CrossRef][Web of Science][Medline]

Kimber SJ 1994 Carbohydrates and implantation of the mammalian embryo. In Endocrinology of Embryo–Endometrium Interactions, pp 279–296. Eds MJ Glasser & A Psychoyos. New York: Plenum.

Kimber SJ 2000 Molecular interactions at the maternal–embryonic interface during the early phase of implantation. Seminars in Reproductive Medicine 18 237–253.[CrossRef][Web of Science][Medline]

Kimber SJ & Spanswick C 2000 Blastocyst implantation: the adhesion cascade. Seminars in Cell and Developmental Biology 11 77–92.

Kimber SJ, Lindenberg S & Lundblad A 1988 Distribution of some Gal beta 1-3(4)GlcNAc related carbohydrate antigens on the mouse uterine epithelium in relation to the peri-implantational period. Journal of Reproductive Immunology 12 297–313.[CrossRef][Web of Science][Medline]

Kimber SJ, Stones RE & Sidhu SS 2001 Glycosylation changes during differentiation of the murine uterine epithelium. Biochemical Society Transactions 29 156–162.[CrossRef][Web of Science][Medline]

Kojima K, Kanzaki H, Iwai M, Hatayama H, Fujimoto M, Inoue T, Horie K, Nakayama H, Fujita J & Mori T 1994 Expression of leukemia inhibitory factor in human endometrium and placenta. Biology of Reproduction 50 882–887.[Abstract]

Kojima K, Kanzaki H, Iwai M, Hatayama H, Fujimoto M, Narukawa S, Higuchi T, Kaneko Y, Mori T & Fujita J 1995 Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts. Human Reproduction 10 1907–1911.[Abstract/Free Full Text]

Korzus E, Nagase H, Rydell R & Travis J 1997 The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase 1 gene expression. Journal of Biological Chemistry 272 1188–1196.[Abstract/Free Full Text]

Laird SM, Tuckerman EM, Dalton CF, Dunphy BC, Li TC & Zhang X 1997 The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Human Reproduction 12 569–574.

Laird SM, Tuckerman EM, Cork BA & Li TC 2000 Expression of nuclear factor kappa B in human endometrium; role in the control of interleukin 6 and leukaemia inhibitory factor production. Molecular Human Reproduction 6 34–40.[Abstract/Free Full Text]

Lass A, Weiser W, Munafo A & Loumaye E 2001 Leukemia inhibitory factor in human reproduction. Fertility and Sterility 76 1091–1096.[CrossRef][Web of Science][Medline]

Lavranos TC, Rathjen PD & Seamark RF 1995 Trophic effects of myeloid leukaemia inhibitory factor (LIF) on mouse embryos. Journal of Reproduction and Fertility 105 331–338.[Abstract/Free Full Text]

Ledee-Bataille N, Lapree-Delage G, Taupin JL, Dubanchet S, Frydman R & Chaouat G 2002 Concentration of leukaemia inhibitory factor (LIF) in uterine flushing fluid is highly predictive of embryo implantation. Human Reproduction 17 213–218.[Abstract/Free Full Text]

Licht P, Russu V, Lehmeyer S & Wildt L 2001 Molecular aspects of direct LH/hCG effects on human endometrium–lessons from intrauterine microdialysis in the human female in vivo. Reproductive Biology 1 10–19.[Medline]

Lim H & Dey SK 2000 PPAR delta functions as a prostacyclin receptor in blastocyst implantation. Trends in Endocrinology and Metabolism 11 137–142.[CrossRef][Web of Science][Medline]

Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM & Dey SK 1997 Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 91 197–208.[CrossRef][Web of Science][Medline]

Lim H, Gupta RA, Ma WG, Paria BC, Moller DE, Morrow JD, DuBois RN, Trzaskos JM & Dey SK 1999 Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes and Development 13 1561–1574.[Abstract/Free Full Text]

Lindenberg S, Sundberg K, Kimber SJ & Lundblad A 1988 The milk oligosaccharide, lacto-N-fucopentaose I, inhibits attachment of mouse blastocysts on endometrial monolayers. Journal of Reproduction and Fertility 83 149–158.[Abstract/Free Full Text]

Lindenberg S, Kimber SJ & Kallin E 1990 Carbohydrate binding properties of mouse embryos. Journal of Reproduction and Fertility 89 431–439.[Abstract/Free Full Text]

Lopata A, Bentin-Ley U & Enders A 2002 ‘Pinopodes’ and implantation. Reviews in Endocrine and Metabolic Disorders 3 77–86.

Luetteke NC, Qiu TH, Fenton SE, Troyer KL, Riedel RF, Chang A & Lee DC 1999 Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for the EGF receptor ligands in mouse mammary gland development. Development 126 2739–2750.[Abstract]

Ma WG, Song H, Das SK, Paria BC & Dey SK 2003 Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. PNAS 100 2963–2968.[Abstract/Free Full Text]

Macfelda K, Weiss TW, Kaun C, Breuss JM, Zorn G, Oberndorfer U, Voegele-Kadletz M, Huber-Beckmann R, Ullrich R & Binder BR et al. 2002 Plasminogen activator inhibitor 1 expression is regulated by the inflammatory mediators interleukin-1alpha, tumor necrosis factor-alpha, transforming growth factor-beta and oncostatin M in human cardiac myocytes. Journal of Molecular & Cellular Cardiology 34 1681–1691.

Miller C, Degenhardt K & Sassoon DA 1998 Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis. Nature Genetics 20 228–230.[CrossRef][Web of Science][Medline]

Modric T, Kowalski AA, Green ML, Simmen RC & Simmen FA 2000 Pregnancy-dependent expression of leukaemia inhibitory factor (LIF), LIF receptor-beta and interleukin-6 (IL-6) messenger ribonucleic acids in the porcine female reproductive tract. Placenta 21 345–353.[CrossRef][Web of Science][Medline]

Murphy CR 2000a Understanding the apical surface markers of uterine receptivity: pinopods-or uterodomes? Human Reproduction 15 2451–2454.[Abstract/Free Full Text]

Murphy CR 2000b Junctional barrier complexes undergo major alterations during the plasma membrane transformation of uterine epithelial cells. Human Reproduction 15 (Suppl 3) 182–188.

Nachtigall MJ, Kliman HJ, Feinberg RF, Olive DL, Engin O & Arici A 1996 The effect of leukemia inhibitory factor (LIF) on trophoblast differentiation: a potential role in human implantation. Journal of Clinical Endocrinology and Metabolism 81 801–806.[Abstract]

Navot D, Bergh PA, Williams M, Garrisi GJ, Guzman I, Sandler B, Fox J, Schreiner-Engel P, Hofmann GE & Grunfeld L 1991 An insight into early reproductive processes through the in vivo model of ovum donation. Journal of Clinical Endocrinology and Metabolism 72 408–414.[Abstract/Free Full Text]

Ni H, Ding NZ, Harper MJ & Yang ZM 2002 Expression of leukemia inhibitory factor receptor and gp130 in mouse uterus during early pregnancy. Molecular Reproduction and Development 63 143–150.[CrossRef][Web of Science][Medline]

Nichols J, Davidson D, Taga T, Yoshida K, Chambers I & Smith A 1996 Complementary tissue-specific expression of LIF and LIFreceptor mRNAs in early mouse embryogenesis. Mechanisms of Development 57 123–131.[CrossRef][Web of Science][Medline]

Nichols J, Chambers I, Taga T & Smith A 2001 Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development 128 2333–2339.

Nikas G, Drakakis P, Loutradis D, Mara-Skoufari C, Koumantakis E, Michalas S & Psychoyos A 1995 Uterine pinopodes as markers of the ‘nidation window’ in cycling women receiving exogenous oestradiol and progesterone. Human Reproduction 10 1208–1213.[Abstract/Free Full Text]

Nilsson O 1966 Structural differentiation of luminal membrane in rat uterus during normal and experimental implantations. Zeitschrift fuer Anatomische Entwicklungsgesch 125 152–159.

Noda N, Minoura H, Nishiura R, Toyoda N, Imanaka-Yoshida K, Sakakura T & Yoshida T 2000 Expression of tenascin-C in stromal cells of the murine uterus during early pregnancy: induction by interleukin-1 alpha, prostaglandin E(2), and prostaglandin F(2 alpha). Biology of Reproduction 63 1713–1720.[Abstract/Free Full Text]

Ogata I, Shimoya K, Moriyama A, Shiki Y, Matsumura Y, Yamanaka K, Nobunaga T, Tokugawa Y, Kimura T & Koyama M et al. 2000 Oncostatin M is produced during pregnancy by decidual cells and stimulates the release of HCG. Molecular Human Reproduction 6 750–757.[Abstract/Free Full Text]

Ohata Y, Harada T, Fujii A, Yoshida S, Iwabe T & Terakawa N 2001 Menstrual cycle-specific inhibition of endometrial stromal cell proliferation by oncostatin M. Molecular Human Reproduction 7 665–670.[Abstract/Free Full Text]

Orchard MD & Murphy CR 2002 Alterations in tight junction molecules of uterine epithelial cells during early pregnancy in the rat. Acta Histochemica 104 149–155.[CrossRef][Web of Science][Medline]

Oshima K, Watanabe H, Yoshihara K, Kojima T, Dochi O, Takenouchi N, Fukushima M & Komatsu M 2003 Gene expression of leukemia inhibitory factor (LIF) and macrophage colony stimulating factor (M-CSF) in bovine endometrium during early pregnancy. Theriogenology 60 1217–1226.[CrossRef][Web of Science][Medline]

Paria BC, Tan J, Lubahn DB, Dey SK & Das SK 1999 Uterine decidual response occurs in estrogen receptor-alpha-deficient mice. Endocrinology 140 2704–2710.[Abstract/Free Full Text]

Paria BC, Ma W, Tan J, Raja S, Das SK, Dey SK & Hogan BL 2001 Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. PNAS 98 1047–1052.[Abstract/Free Full Text]

Parr MB & Parr EL 1974 Uterine luminal epithelium: protrusions mediate endocytosis, not apocrine secretion, in the rat. Biology of Reproduction 11 220–233.[Abstract]

Perrier d’Hauterive S, Charlet-Renard C, Berndt S, Dubois M, Munaut C, Goffin F, Hagelstein MT, Noel A, Hazout A & Foidart JM et al. 2004 Human chorionic gonadotropin and growth factors at the embryonic-endometrial interface control leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) secretion by human endometrial epithelium. Human Reproduction 19 2633–2643.[Abstract/Free Full Text]

Piccinni MP, Beloni L, Livi C, Maggi E, Scarselli G & Romagnani S 1998 Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nature Medicine 4 1020–1024.[CrossRef][Web of Science][Medline]

Pintar JE 2001 Single and multiple knockouts of the IGFBPs. Programme of the 83rd Annual meeting of the Endocrine Society, Denver, CO p 44 (Abstract S33-1).

Pollard JW, Hunt JS, Wiktor-Jedrzejczak W & Stanley ER 1991 A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female fertility. Developmental Biology 148 273–283.[CrossRef][Web of Science][Medline]

Psychoyos A & Mandon P 1971 Scanning electron microscopy of the surface of the rat utherine epithelium during delayed implantation. Journal of Reproduction and Fertility 26 137–138.[Abstract/Free Full Text]

Raab G, Kover K, Paria BC, Dey SK, Ezzell RM & Klagsbrun M 1996 Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development 122 637–645.[Abstract]

Ren SG, Melmed S & Braunstein GD 1997 Decidual leukemia inhibitory factor production and action on human chorionic gonadotropin secretion at different stages of gestation in vitro. Early Pregnancy 3 102–108.

Repovic P, Mi K & Benveniste EN 2003 Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factoralpha, and bacterial lipopolysaccharide. Glia 42 433–446.[CrossRef][Web of Science][Medline]

Richards CD, Shoyab M, Brown TJ & Gauldie J 1993 Selective regulation of metalloproteinase inhibitor (TIMP-1) by oncostatin M in fibroblasts in culture. Journal of Immunology 150 5596–5603.[Abstract]

Robb L, Li R, Hartley L, Nandurkar HH, Koentgen F & Begley CG 1998 Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nature Medicine 4 303–308.[CrossRef][Web of Science][Medline]

Roberts AW, Robb L, Rakar S, Hartley L, Cluse L, Nicola NA, Metcalf D, Hilton DJ & Alexander WS 2001 Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. PNAS 98 9324–9329.[Abstract/Free Full Text]

Rodriguez CI, Cheng JG, Liu L & Stewart CL 2004 Cochlin, a secreted von Willebrand factor type a domain-containing factor, is regulated by leukemia inhibitory factor in the uterus at the time of embryo implantation. Endocrinology 145 1410–1418.[Abstract/Free Full Text]

Saito S 2001 Cytokine cross-talk between mother and the embryo/ placenta. Journal of Reproductive Immunology 52 15–33.[CrossRef][Web of Science][Medline]

Salamonsen LA 1999 Role of proteases in implantation. Reviews in Reproduction 4 11–22.

Sananes N, Baulieu EE & Le Goascogne C 1976 Prostaglandin(s) as inductive factor of decidualization in the rat uterus. Molecular and Cellular Endocrinology 6 153–158.[Web of Science][Medline]

Sanchez C, Deberg MA, Burton S, Devel P, Reginster JY & Henrotin YE 2004 Differential regulation of chondrocyte metabolism by oncostatin M and interleukin-6. Osteoarthritis Cartilage 12 801–810.[CrossRef][Web of Science][Medline]

Sawai K, Azuma C, Koyama M, Ito S, Hashimoto K, Kimura T, Samejima Y, Nobunaga T & Saji F 1995 Leukemia inhibitory factor (LIF) enhances trophoblast differentiation mediated by human chorionic gonadotropin (hCG). Biochemical and Biophysical Research Communications 211 137–143.[CrossRef][Web of Science][Medline]

Sawai K, Matsuzaki N, Okada T, Shimoya K, Koyama M, Azuma C, Saji F & Murata Y 1997 Human decidual cell biosynthesis of leukemia inhibitory factor: regulation by decidual cytokines and steroid hormones. Biology of Reproduction 56 1274–1280.[Abstract]

Schafer-Somi S 2003 Cytokines during early pregnancy of mammals: a review. Animal Reproductive Science 75 73–94.

Schofield G & Kimber SJ 2005 Leukocyte subpopulations in the uteri of leukemia inhibitory factor knockout mice during early pregnancy. Biology of Reproduction 72 872–878.[Abstract/Free Full Text]

Sharkey A 1998 Cytokines and implantation. Reviews in Reproduction 3 52–61.

Sharkey AM, King A, Clark DE, Burrows TD, Jokhi PP, Charnock-Jones DS, Loke YW & Smith SK 1999 Localization of leukemia inhibitory factor and its receptor in human placenta throughout pregnancy. Biology of Reproduction 60 355–364.[Abstract/Free Full Text]

Sherwin JR, Smith SK, Wilson A & Sharkey AM 2002 Soluble gp130 is up-regulated in the implantation window and shows altered secretion in patients with primary unexplained infertility. Journal of Clinical Endocrinology and Metabolism 87 3953–3960.[Abstract/Free Full Text]

Sherwin J, Freeman T, Stephens R, Kimber S, Smith A, Chambers I, Smith S & Sharkey A 2004 Identification of genes regulated by leukaemia inhibitory factor in the mouse uterus at the time of implantation. Molecular Endocrinology 18 2185–2195.[Abstract/Free Full Text]

Shioi A, Katagi M, Okuno Y, Mori K, Jono S, Koyama H & Nishizawa Y 2002 Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages. Circulation Research 91 9–16.[Abstract/Free Full Text]

Simon C, Frances A, Piquette GN, el Danasouri I, Zurawski G, Dang W & Polan ML 1994 Embryonic implantation in mice is blocked by interleukin-1 receptor antagonist. Endocrinology 134 521–528.[Abstract/Free Full Text]

Song H, Lim H, Das SK, Paria BC & Dey SK 2000 Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Molecular Endocrinology 14 1147–1161.[Abstract/Free Full Text]

Spence MJ, Streiff R, Day D & Ma Y 2002 Oncostatin M induces tissue-type plasminogen activator and plasminogen activator inhibitor-1 in Calu-1 lung carcinoma cells. Cytokine 18 26–34.[CrossRef][Web of Science][Medline]

Steck T, Giess R, Suetterlin MW, Bolland M, Wiest S, Poehls UG & Dietl J 2004 Leukaemia inhibitory factor (LIF) gene mutations in women with unexplained infertility and recurrent failure of implantation after IVF and embryo transfer. European Journal of Obstetrics, Gynecology and Reproductive Biology 112 69–73.[CrossRef][Web of Science][Medline]

Stewart CL & Cullinan EB 1997 Preimplantation development of the mammalian embryo and its regulation by growth factors. Developmental Genetics 21 91–101.[CrossRef][Web of Science][Medline]

Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F & Abbondanzo SJ 1992 Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature 359 76–79.[CrossRef][Medline]

Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T & Akira S 1997 Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. PNAS 94 3801–3804.[Abstract/Free Full Text]

Tanaka M, Hirabayashi Y, Sekiguchi T, Inoue T, Katsuki M & Miyajima A 2003 Targeted disruption of oncostatin M receptor results in altered hematopoiesis. Blood 102 3154–3162.[Abstract/Free Full Text]

Teng CB, Diao HL, Ma XH, Xu LB & Yang ZM 2004 Differential expression and activation of Stat3 during mouse embryo implantation and decidualization. Molecular Reproduction and Development 69 1–10.[CrossRef][Web of Science][Medline]

Thie M, Fuchs P & Denker HW 1996 Epithelial cell polarity and embryo implantation in mammals. International Journal of Developmental Biology 40 389–393.[Web of Science][Medline]

Vogiagis D, Marsh MM, Fry RC & Salamonsen LA 1996 Leukaemia inhibitory factor in human endometrium throughout the menstrual cycle. Journal of Endocrinology 148 95–102.[Abstract/Free Full Text]

Vogiagis D, Fry RC, Sandeman RM & Salamonsen LA 1997 Leukaemia inhibitory factor in endometrium during the oestrous cycle, early pregnancy and in ovariectomized steroid-treated ewes. Journal of Reproduction and Fertility 109 279–288.[Abstract/Free Full Text]

Wang W, Van De Water T & Lufkin T 1998 Inner ear and maternal reproductive defects in mice lacking the Hmx3 homeobox gene. Development 125 621–634.[Abstract]

Wang Y, Robledo O, Kinzie E, Blanchard F, Richards C, Miyajima A & Baumann H 2000 Receptor subunit-specific action of oncostatin M in hepatic cells and its modulation by leukemia inhibitory factor. Journal of Biological Chemistry 275 25273–25285.[Abstract/Free Full Text]

Ware CB, Horowitz MC, Renshaw BR, Hunt JS, Liggitt D, Koblar SA, Gliniak BC, McKenna HJ, Papayannopoulou T & Thoma B et al. 1995 Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 121 1283–1299.[Abstract]

Yang M, Lei ZM & Rao Ch V 2003 The central role of human chorionic gonadotropin in the formation of human placental syncytium. Endocrinology 144 1108–1120.[Abstract/Free Full Text]

Yang ZM, Le SP, Chen DB, Cota J, Siero V, Yasukawa K & Harper MJ 1995 Leukemia inhibitory factor, LIF receptor, and gp130 in the mouse uterus during early pregnancy. Molecular Reproduction and Development 42 407–414.[CrossRef][Web of Science][Medline]

Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T & Nakahata T et al. 1996 Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. PNAS 93 407–411.[Abstract/Free Full Text]

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