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Objectives Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD) is a life-threatening disease, the aetiology of which remains unclear. To detect potential diagnostic markers, a transcriptome analysis of the lung sample from a patient with anti-MDA5 antibody-positive RP-ILD was performed. Methods RNA sequencing analyses of an autopsy lung sample from a 74-year-old woman with anti-MDA5 antibody-positive RP-ILD was performed and compared with an age- and sex-matched normal lung sample. Genes with changes of gene expression ≥5-fold were considered differentially expressed genes and analysed by Metascape. The levels of leukaemia inhibitory factor (LIF) were measured in the serum samples from 12 cases of anti-MDA5 antibody-positive ILD, 12 cases of anti-aminoacyl tRNA synthetase (ARS) antibody-positive ILD, 10 cases of anti-transcription intermediary factor 1γ/anti-Mi-2 antibody DM and 12 healthy volunteers. Results Gene ontology enrichment analysis on the RNA sequencing data showed a strong association with antigen binding. Upregulated expressions of IL-1β, IL-6 and LIF were also detected. Serum LIF levels were significantly elevated in anti-MDA5 antibody-positive ILD patients {median 32.4 pg/ml [interquartile range (IQR) 13.2–125.7]} when compared with anti-ARS antibody-positive ILD patients [4.9 pg/ml (IQR 3.1–19.7), P  < 0.05] and DM patients [5.3 pg/ml (IQR 3.9–9.7), P  < 0.05]. Conclusion Our present study suggested that upregulation of LIF might be a new potential disease marker specific for anti-MDA5 antibody-positive ILD. [ABSTRACT FROM AUTHOR]

Background: Kisspeptin plays a role in the oestradiol negative-feedback regulation of GnRH as well as gonadotropin. In addition, kisspeptin has been postulated to induce the production of an important cytokine called leukaemia inhibitory factor (LIF). Aims: This study aims to investigate the correlation between varying oestradiol levels measured on trigger day of the ovarian stimulation and the mRNA expression level of endometrial kisspeptin and LIF. Study Setting and Design: Prospective cross-sectional study took place in Morula IVF Jakarta clinic. Materials and Methods: A total of 43 infertile couples underwent an in-vitro fertilization (IVF) program. Subjects were grouped based on oestradiol levels as follows: group A ([≧ 3000 pg/mL, n = 15], group B [2000–2999 pg/mL, n = 14], group C [

Leukaemia Inhibitory Factor (LIF) is a stem cell growth factor critical to health. LIF belongs to the IL-6 family of cytokines but LIF-signalling is unique and qualified by its cell surface receptor, LIF-R. As a strategy to treat pancreatic cancer, Hunter et al. [1] report an engineered therapeutic LIF-Trap (soluble LIF-R) to deplete human LIF. Whilst applauding the engineering success of the LIF-Trap, I argue a case of mistaken identity. Is it LIF, or IL-6, promoting tumour progression? The rationale is based on the earlier work of the same group reported by Shi et al. [2] who have already generated a specific anti-LIF antibody for the same therapeutic purpose as the LIF-Trap: this antibody has since been acquired by a leading pharmaceutical company. CRITIQUE: There are two major issues with the Hunter and Shi publications. First Safety – Hunter claims safety of their LIF-Trap despite extensive data arguing to the contrary: thus removal of LIF signalling risks pathogenic effects in multiple systems. Second Scientific – the group fail to take into account LIF biology, where mode of action places IL-6, rather than LIF, as candidate for driver of tumour progression. Importantly, clinical data suggests LIF-signalling functions as a tumour suppressor in pancreatic cancer [3], raising the question – would removal of LIF-signalling be counter-indicated in cancer?

Background: Kisspeptin plays a role in the oestradiol negative-feedback regulation of GnRH as well as gonadotropin. In addition, kisspeptin has been postulated to induce the production of an important cytokine called leukaemia inhibitory factor (LIF). Aims: This study aims to investigate the correlation between varying oestradiol levels measured on trigger day of the ovarian stimulation and the mRNA expression level of endometrial kisspeptin and LIF. Study Setting and Design: Prospective cross-sectional study took place in Morula IVF Jakarta clinic. Materials and Methods: A total of 43 infertile couples underwent an in-vitro fertilization (IVF) program. Subjects were grouped based on oestradiol levels as follows: group A ([≥ 3000 pg/mL, n = 15], group B [2000-2999 pg/mL, n = 14], group C [<2000 pg/mL, n = 14]). Statistical Analysis Used: ANOVA test was utilised to compare the expression of kisspeptin and LIF among study groups while Pearson correlation was used to identify the correlation between variables. Results: A significantly higher mRNA expression of both Kisspeptin and LIF was found in group A than in groups B and C (P < 0.001). The mRNA expression of kisspeptin and LIF correlated positively with the oestradiol level (r = 0.638, P < 0.001 and r = 0.634, P < 0.001, respectively). Moreover, a strong association between Kisspeptin and LIF expression was also detected (r = 0.700, P < 0.001). Conclusions: mRNA expression of kisspeptin and LIF was significantly different according to the oestradiol levels in the study groups. Increased oestradiol level was shown to elevate the expression of endometrial kisspeptin and LIF in women undergoing the IVF programme. [ABSTRACT FROM AUTHOR]

Abstract Background Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukaemia inhibitory factor (LIF), which induces cachexia. We characterized how LIF promotes cachexia‐associated weight loss and anorexia in mice through Janus kinase (JAK)‐dependent changes in adipose and hypothalamic tissues. Methods Cachexia was induced in vivo with the heterotopic allotransplanted administration of C26c20 colon adenocarcinoma cells or the intraperitoneal administration of recombinant LIF in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cytokine/adipokine enzyme‐linked immunosorbent assays, immunoblot analysis, and quantitative reverse transcription polymerase chain reaction (RT‐PCR). Cachexia‐associated lipolysis was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or interleukin (IL)‐6 in the absence or presence of lipase or JAK inhibitors. These adipocytes were processed for glycerol release into the media, immunoblot analysis, and RT‐PCR. Results Tumour‐secreted LIF induced changes in adipose tissue expression and serum levels of IL‐6 and leptin in a JAK‐dependent manner influencing cachexia‐associated adipose wasting and anorexia. We identified two JAK inhibitors that block IL‐6 family‐mediated adipocyte lipolysis and IL‐6 induction using an in vitro cachexia lipolysis assay. JAK inhibitors administered to the in vivo C26c20 cancer cachexia mouse models led to (i) a decrease in signal transducer and activator of transcription 3 phosphorylation in hypothalamic and adipose tissues, (ii) a reverse in the cachexia serum cytokine/adipokine signature, (iii) a delay in cancer cachexia‐associated anorexia and adipose loss, and (iv) an improvement in overall survival. Conclusions JAK inhibitors suppress LIF‐associated adipose loss and anorexia in both in vitro and in vivo models of cancer cachexia.

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Objectives: To testify that endothelial cells (ECs) induce astrocyte maturation by leukaemia inhibitory factor (LIF) secretion. Materials and Methods: In vivo experiments, mice bearing floxed alleles of YAP were crossed with mice expressing a Cre recombinase driven by the endothelial Tek promoter (Tek‐Cre) to finally obtain the following three genotypes: YAPf/f, Tek‐Cre; YAPf/w, Tek‐Cre; and YAPf/f. Retinal vascularization and astrocyte network were evaluated by whole‐mount fluorescence and Western blotting. In vitro, experiments were performed in an astrocyte and human microvascular endothelial cell (HMEC‐1) coculture model to analyse the mechanisms underlying the effect of endothelial YAP on astrocytes. Results: In vivo, YAPf/f;Tek‐Cre mice showed delayed angiogenesis, sparse vessels and decreased glial fibrillary acidic protein (GFAP)+ astrocytes but aberrant growth of endothelial networks and immature astrocytes (platelet‐derived growth factor A, PDGFRA+ astrocytes) overgrowth. In vitro, Yap deletion attenuated the LIF release that delayed the maturation of retinal astrocyte which was consistent with the results of HMEC‐1—astrocyte coculture. The effect of YAP overexpression on LIF‐LIFR axis in HMEC‐1 interferes the GFAP expression of astrocyte. In contrast, LIF protein rescues the astrocytic GFAP expression when EC YAP was inhibited by siRNAs. Conclusions: We show that EC yes‐associated protein (YAP) is not only a critical coactivator of Hippo signalling in retinal vessel development but also plays an essential role in retinal astrocyte maturation by regulating LIF production. [ABSTRACT FROM AUTHOR]

The cytokine leukaemia Inhibitory factor (LIF) promotes self-renewal of mouse embryonic stem cells (ESC) through activation of the transcription factor Stat3. However, the contribution of other ancillary pathways stimulated by LIF in ESCs, such as the MAPK and PI3K pathways, is less well understood. We show here that naïve-type mouse ESCs express high levels of a novel effector of the MAPK and PI3K pathways. This effector is an isoform of the Gab1 (Grb2-associated binder protein 1) adaptor protein that lacks the N-terminal Pleckstrin Homology (PH) membrane-binding domain. Although not essential for rapid unrestricted growth of ESCs under optimal conditions, the novel Gab1 variant (Gab1β) is required for LIF-mediated cell survival under conditions of limited nutrient availability. This enhanced survival is absolutely dependent upon a latent palmitoylation site that targets Gab1β directly to ESC membranes. These results show that constitutive association of Gab1 with membranes through a novel mechanism promotes LIF-dependent survival of murine ESCs in nutrient poor conditions. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, ovarian dysfunction and polycystic ovarian morphology. Leukaemia inhibitory factor (LIF) affects many reproductive activities, including follicular development, embryo implantation and growth. The aim of this study was to evaluate LIF concentrations in serum and follicular fluid of women with PCOS and controls who underwent IVF with embryo transfer (IVF–ET). Serum and follicular fluid LIF concentrations were lower in women with PCOS compared with controls. Oestradiol concentrations in follicular fluid were higher in PCOS subjects compared with controls. LIF concentrations in serum ( r = 0.6263, P < 0.05) and follicular fluid ( r = 0.7093, P < 0.05) were negatively correlated with oestradiol concentration in the PCOS group. LIF concentrations in follicular fluid showed no difference between women who conceived and women who did not in both PCOS and control groups. However, LIF concentrations in embryo culture medium were higher in women who conceived following IVF compared with women who did not, in combined PCOS and control groups. The findings indicate that low LIF concentrations in serum and follicular fluid may contribute to disordered folliculogenesis in PCOS. LIF concentrations in embryo culture medium may predict the outcome of IVF treatment. [ABSTRACT FROM AUTHOR]

This was a prospective case–control study that measured the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Mycoplasma genitalium (MG) by an IVD CE multiplex PCR kit in fresh Fallopian tubes (FT) obtained from 96 ectopic pregnancies (EP) and 61 controls in the midluteal phase of the cycle. We later measured the expression profile of IL-6, leukaemia inhibitory factor (LIF) and their signalling molecules, in respect to the type and number of infections, by immunohistochemistry, ELISA and quantitative RT-PCR. The frequencies of CT, and MG mono- and co-infections were significantly higher in EP. IL-6, LIF, their receptors and intracellular mediators were significantly up-regulated at the gene and protein levels in positive compared with negative FTs within each group (P < 0.05). EP tubal samples with co-infections showed the highest significant expression of the candidate cytokines by all techniques (P < 0.05). CT and MG are frequent in EP and up-regulate the tubal expression of IL-6, LIF and their signalling molecules. Both cytokines could be involved in the tubal immune response against bacterial infections, as well as the pathogenesis of EP. Further studies are needed to explore the roles of IL-6 family in infection-induced tubal inflammation and EP. [ABSTRACT FROM AUTHOR]

Objective: To assess leukaemia inhibitory factor (LIF) and vascular endothelial growth factor (VEGF) expression as markers of intrauterine device (IUD) efficacy in a rat model. Methods: Twenty nulliparous female Wistar rats were divided into two groups with 10 animals per group: group I (IUD) and group II (control group, no IUD). In group I, a 2-cm 3-0 silk suture was placed into one horn of the rat bicornuate uterus. On day 20 (after IUD insertion) rats were sacrificed and their uteri removed. The number of vessels and the distribution of LIF and VEGF were compared among the uterine horns. Results: There were no significant differences in LIF and VEGF expression in the groups and all horns (p > 0.05). The number of vessels was higher in the IUD+ horn than in the IUD- horn of group I and in the horn of group II (p < 0.05). There was no significant difference in the number of vessels between the IUD- horns of groups I and II (p > 0.05). Conclusion: LIF and VEGF expression did not correlate with IUD efficacy in a rat model. An IUD may increase the number of vessels in the uterine horn independent of VEGF expression. [ABSTRACT FROM AUTHOR]

Embryo implantation is mediated by the combined actions of the ovarian hormones E2 and P4 on the uterus. In addition, the pro-inflammatory cytokine, leukaemia inhibitory factor ( LIF), plays a pivotal role in regulating uterine receptivity. LIF is expressed in the endometrial glands and has a robust action on the uterine luminal epithelium ( LE). In mice, LIF is induced by nidatory E2 and functions to convert the LE from a non-receptive to an embryo-responsive state. LIF mediates its actions by activating the JAK- STAT pathway specifically in the LE. Activation of JAK- STAT pathway results in the induction of many additional pathways, including some 40 + transcription factors, many of which initiate a cascade of changes affecting epithelial polarity, epithelial-mesenchymal interactions, angiogenesis, stromal cell decidualization, and inhibiting cell proliferation. This review discusses the role of LIF and the recent analysis of its action on the uterine LE in regulating endometrial receptivity and implantation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether eutopic endometrial expression of leukaemia inhibitory factor (LIF), LIF receptor (LIFR) and glycoprotein 130 (gp130) in subfertile women with endometriosis and in healthy controls is related to the probability of spontaneous pregnancy. In addition, we aimed to study peritoneal fluid (PF) levels of interleukin (IL)-1α and IL-6 in the same subsets of women. Methods: Eutopic endometrial biopsy and PF samples were taken from patients with rASRM stage I-II endometriosis and healthy controls undergoing laparoscopy. Endometrial LIF, LIFR and gp130 immunostaining and PF levels of IL-1α and IL-6 were assessed. Endometrial biopsy samples were obtained again after postoperative goserelin acetate treatment and on-going pregnancies were registered during a 6-month follow-up period. Results: Reduced endometrial staining of LIF, LIFR and gp130, unaffected by surgery and goserelin, was seen in endometriosis patients without a recorded pregnancy during the study. Elevated PF levels of IL-6 and, in particular, IL-1α were detected in these patients. Conclusions: Reduced eutopic endometrial LIF, LIFR and gp130 protein expression may be associated with subfertility in women with minimal-mild endometriosis. Combined surgical and goserelin acetate treatment does not seem to restore the expression of these members of the IL-6 cytokine superfamily. Elevated peritoneal fluid levels of IL-1α and IL-6 may further contribute to the difficulties of achieving pregnancy in these patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro , NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo , using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo : this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS. [ABSTRACT FROM AUTHOR]

We investigated the serum concentrations of interleukin-6 (IL-6) and two IL-6 family of cytokines (leukaemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) as well as IL-6 soluble receptor (sIL-6R) using an enzyme-linked immunosorbent assay (ELISA) in 66 patients with rheumatoid arthritis (RA) and 24 healthy controls. We examined a possible association between the serum levels of these peptides and RA activity according to the Mallya and Mace scoring system and Ritchie's index. We also evaluated the correlation between the serum levels of IL-6, LIF, CNTF and sIL-6R and duration of the disease and calculated sIL-6R/IL-6 ratio in RA patients and in the control group. IL-6 and sIL-6R were detectable in all 66 patients with RA and 24 normal individuals. LIF was also found in the serum of all patients with RA and in 16 (66.7%) normal individuals. In contrast CNTF was measurable only in 15 (22.7%) patients with RA and 24 (33.3%) normal individuals. The highest IL-6 and sIL-6R levels were found in the patients with Stages 3 and 4 of RA activity and the lowest in the control group. In contrast there were no statistically significant diferences between the LIF and CNTF levels in RA patients and normal individuals. We found positive correlation between IL-6 and sIL-6R concentrations and Ritchie's index and a lack of such correlation with LIF and CNTF. IL-6 serum level correlated positively with the disease duration, but sIL-6R, LIF and CNTF did not. Serum sIL-6R/IL-6 ratio was significantly lower in RA patients than in healthy controls. In conclusion, an increase in the serum levels of IL-6 and sIL-6R, but not LIF and CNTF concentrations, may be useful markers for RA activity.

Problem The aim of this study was to investigate the relative importance of STAT3 and ERK1/2 activation in leukaemia inhibitory factor ( LIF)-mediated invasion of JEG-3 cells. Method of Study Matrigel matrix-based invasion assay; Western blot; c DNA microarray; quantitative RT- PCR; gene silencing by si RNA. Results Leukaemia inhibitory factor treatment led to the activation of STAT3 and ERK1/2 signaling pathways which was followed by changes in the expression of several invasion-associated molecules such as mucin1 ( MUC1), Fos, Jun, etc. Abrogation of either STAT3 or ERK1/2 signaling reduced ( P < 0.05) the LIF-mediated invasion of JEG-3 cells. It was associated with a significant reduction in the expression of both MUC1 and Fos, suggesting a common denominator in LIF- STAT3- ERK1/2 signaling. To this effect, we observed a decrease in LIF-mediated p-STAT3 (Ser727) upon blocking STAT3 or ERK1/2 signaling. Conclusions ERK1/2 as well as JAK- STAT-mediated STAT3 (Ser727) phosphorylation play an important role in LIF-mediated JEG-3 trophoblastic cell invasion and gene expression. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effect of supplementation of recombinant leukaemia inhibitory factor (LIF) in culture media on blastocyst development, total cell number and blastocyst hatching rates and the reverse transcription-polymerase chain reaction analysis of preimplantation buffalo embryos to determine whether they contain the LIF-encoding mRNA and its beta receptor (LIFRβ) genes in different stages of preimplantation buffalo embryos. Cumulus–oocyte complexes retrieved from slaughterhouse buffalo ovaries were matured in vitro and fertilized using frozen buffalo semen. After 18 h of co-incubation with sperm, the presumptive zygotes were cultured in modified synthetic oviductal fluid without (control) or with rhLIF (100 ng/ml). There was no significant difference in the overall cleavage rate up to morula stage however the development of blastocysts, hatching rate and total cell numbers were significantly higher in the LIF-treated group than control. Transcripts for LIFRβ were detected from immature, in vitro-matured oocytes and in the embryos up to blastocyst stage, while transcripts for the LIF were detected from 8–16-cell stage up to blastocyst, which indicated that embryo-derived LIF can act in an autocrine manner on differentiation process and blastocyst formation. This study indicated that the addition of LIF to the embryo culture medium improved development of blastocysts, functional (hatching) and morphological (number of cells) quality of the blastocysts produced in vitro. The stage-specific expression pattern of LIF and LIFRβ mRNA transcripts in buffalo embryos indicated that LIF might play an important role in the preimplantation development and subsequent implantation of buffalo embryos. [ABSTRACT FROM AUTHOR]

This study is investigating the role of leukaemia inhibitory factor (LIF) in the development of inflammation and joint damage in the mouse K/B×N serum transfer arthritis model. LIF knock-out (LIF−/−) mice were generated by mating heterozygote females (LIF+/−) with heterozygote males. Arthritis was induced in 8-20-week-old LIF knock-out mice (LIF−/−) by intraperitoneal injection of pooled K/B×N sera (50 µl) on days 0 and 2. Clinical disease was scored daily for 6 days. Safranin-O and haematoxylin-stained sections were scored for synovitis, joint space exudate, cartilage degradation and bone damage. RNA was extracted from ankle joints and used to investigate gene expression levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1, LIF, LIF receptor, oncostatin M (OSM), OSM receptor, IL-6 and their common receptor subunit gp130 by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The results show that wild-type mice developed severe clinically overt polyarthritis. In contrast, LIF−/− mice showed a more than 50% reduction in clinical arthritis severity. Significantly lower histological scores were observed in LIF−/− mice compared to wild-type disease controls. LIF−/− mice had histopathological scores that were similar to normal healthy mice. IL-6 subfamily cytokine and receptor subunit expression remained unchanged. The expression levels for IL-6 were reduced significantly in all the diseased mice, whether wild-type or LIF−/− mice ( P < 0·001), compared to healthy wild-type mice. We conclude that LIF contributes to the development of disease in the K/B×N serum transfer model of arthritis. These results provide further evidence for the role of LIF in inflammation and cartilage bone resorption and provide impetus to test the effects of LIF blockade as a therapeutic strategy in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

BACKGROUND Several studies have suggested that endometrial interleukin 15 (IL-15) and the leukaemia inhibitory factor (LIF) may be important in embryo implantation. IL-15 is postulated to play a role in the control of uterine natural killer (uNK) cell proliferation and function, and uNK cells are also known to play a role in implantation. The aims of this study was to (1) compare endometrial levels of IL-15 and the LIF in women with recurrent implantation failure (RIF) after IVF with those in fertile women (controls) and (2) examine the relation of IL-15 and LIF levels to the uNK cell number. METHODS We investigated IL-15 and LIF in precisely timed endometrial biopsies (days LH + 7-LH + 9, where the day of the LH surge is LH + 0) obtained from control women (n = 15) and women with RIF (n = 45) by immunohistochemistry. A semi-quantitative analysis was performed by the H-score analysis of staining intensity in the stroma, glandular epithelium and luminal epithelium, separately. We also correlated expression of LIF and IL15 with uNK cell numbers (obtained in an earlier study of the same samples). RESULTS The quantity of the LIF protein in endometrial glandular epithelium in women with RIF [median and range; 179 (70–365)] was lower (P = 0.01) than in control women [median and range; 247 (120–287)]. In contrast, the level of the IL-15 protein in the stroma in women with RIF [median and range; 90 (0–175)] was higher (P = 0.009) than in control women [median and range; 60 (15–150)]. There was a significant correlation between the uNK cell number and stromal expression of IL-15 (r = 0.427, P = 0.001). No correlation between the LIF expression in any compartment and the uNK cell number was seen. CONCLUSIONS The results show an altered expression of LIF and IL-15 in the endometrium of women with RIF. Despite the limitation of not identifying uNK cells by phenotypic markers, the correlation between the uNK cell number and the stromal cell IL-15 suggests that IL-15 may play a role in the control of endometrial uNK cell function or proliferation. [ABSTRACT FROM AUTHOR]

BACKGROUND Marijuana, the most used recreational drug, has been shown to have adverse effects on human reproduction. Endogenous cannabinoids (also called endocannabinoids) bind to the same receptors as those of Δ9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa. The most extensively studied endocannabinoids are anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol. The endocannabinoids, their congeners and the cannabinoid receptors, together with the metabolic enzymes and putative transporters form the endocannabinoid system (ECS). In this review, we summarize current knowledge about the relationships of ECS, sex steroid hormones and cytokines in female fertility, and underline the importance of this endocannabinoid–hormone–cytokine network. METHODS Pubmed and the Web of Science databases were searched for studies published since 1985, looking into the ECS, sex hormones, type-1/2 T-helper (Th1/Th2) cytokines, leukaemia inhibitory factor, leptin and reproduction. RESULTS The ECS plays a pivotal role in human reproduction. The enzymes involved in the synthesis and degradation of endocannabinoids normalize levels of AEA for successful implantation. The AEA degrading enzyme (fatty acid amide hydrolase) activity as well as AEA content in blood may potentially be used for the monitoring of early pregnancies. Progesterone and oestrogen are involved in the maintenance of endocannabinoid levels. The ECS plays an important role in the immune regulation of human fertility. CONCLUSIONS The available studies suggest that tight control of the endocannabinoid–hormone–cytokine network is required for successful implantation and early pregnancy maintenance. This hormone–cytokine network is a key element at the maternal–foetal interface, and any defect in such a network may result in foetal loss. [ABSTRACT FROM AUTHOR]

Mouse ES (embryonic stem) cells are maintained in an undifferentiated state in the presence of LIF (leukaemia-inhibitory factor). In general, LIF engages a heterodimeric receptor complex composed of a low-affinity LIF receptor (LIFRb) and gp130, and activates STAT3 (signal transducers and activators of transcription 3) and ERKs (extracellular signal-regulated kinases). However, in undifferentiated ES cells in the presence of LIF, STAT3 is phosphorylated but ERKs are not. The removal of LIF-induced dephosphorylation of phospho-STAT3 and phosphorylation of ERKs resulted in the differentiation of ES cells. Here, we show that the dephosphorylation of phospho-STAT3 corresponds to the activation of ERKs pathway from the time-courses of the phosphorylation levels in detail. We found that the treatment of membrane-permeable STAT3IP (STAT3 inhibitory peptide), which inhibits homodimeric formation of STAT3, induced the phosphorylation of ERKs in ES cells in the presence of LIF. In addition, the removal of LIF decreased the expression level of SOCS3 (suppressor of cytokine signalling 3), a negative regulator of LIF signalling, and the phosphorylation of ERKs was efficiently induced in the ES cells where SOCS3 was down-regulated. These results suggested that LIF-induced SOCS3 suppressed the ERKs activation pathway in undifferentiated ES cells, and the down-regulation of SOCS3 by the removal of LIF triggered the phosphorylation of ERKs. [ABSTRACT FROM AUTHOR]

Objective To compare the assessment of endometrial maturation parameters in endometrial secretion samples obtained by a novel minimally invasive technique with those assessed in tissue biopsies. Design Prospective study. Setting University Hospital. Population Healthy female volunteers attending a gynaecological outpatient clinic. Methods Endometrial secretion fluid and tissue sampling 5 days after a spontaneous ovulation assessed with ultrasound. Main outcome measures Progesterone (P) receptor, Ki-67 expression and the Noyes criteria were used to date endometrial biopsies. In the endometrial fluid samples, glycodelin A (GdA), leukaemia inhibitory factor (LIF) and P levels were analysed, and protein content and electrophoresis patterns were determined. Results All data were correlated to estradiol (E2) and P serum concentrations. The dating according to histology and immunohistochemical staining patterns correlated significantly with GdA levels ( r = 0.376, P =0.048) in endometrial fluid samples as well with serum levels of E2 ( r = 0.568, P =0.001) and P ( r = 0.408, P =0.023). No correlation was observed between tissue dating and LIF levels and protein content in endometrial fluid samples. Conclusions The measurement of GdA in endometrial secretion samples may provide a less invasive method for assessing endometrial maturation in potential conception cycles without disrupting implantation. [ABSTRACT FROM AUTHOR]

Abstract: Thrombopoietin (TPO), a hematopoietic growth factor regulating platelet production, and its receptor (TPOR) were recently shown to be expressed in the brain where they exert proapoptotic activity. Here we used PC12 cells, an established model of neuronal differentiation, to investigate the effects of TPO on neuronal survival and differentiation. These cells expressed TPOR mRNA. TPO increased cell death in neuronally differentiated PC12 cells but had no effect in undifferentiated cells. Surprisingly, TPO inhibited nerve growth factor (NGF)-induced differentiation of PC12 cells in a dose- and time-dependent manner. This inhibition was dependent on the activity of Janus kinase-2 (JAK2). Using phospho-kinase arrays and Western blot we found downregulation of the NGF-stimulated phosphorylation of the extracellular signal-regulated kinase p42ERK by TPO with no effect on phosphorylation of Akt or stress kinases. NGF-induced phosphorylation of ERK-activating kinases, MEK1/2 and C-RAF was also reduced by TPO while NGF-induced RAS activation was not attenuated by TPO treatment. In contrast to its inhibitory effects on NGF signalling, TPO had no effect on epidermal growth factor (EGF)-stimulated ERK phosphorylation or proliferation of PC12 cells. Our data indicate that TPO via activation of its receptor-bound JAK2 delays the NGF-dependent acquisition of neuronal phenotype and decreases neuronal survival by suppressing NGF-induced ERK activity. [Copyright &y& Elsevier]

Leukaemia inhibitory factor (LIF) is a glycoprotein of the interleukin-6 family, which has potent pro-inflammatory properties and is involved in regulation of neuronal differentiation. We have previously identified its upregulation in gene microarrays following acute ischaemic stroke in man. LIF expression and localization was measured in human ischaemic stroke autopsy specimens, in a rat model of middle cerebral artery occlusion (MCAO) and in human foetal neural cell cultures following oxygen-glucose deprivation (OGD) by Western blotting and immunohistochemistry. Circulating LIF was determined in the plasma of patients in the hyper-acute stroke phase using a multiplex enzyme-linked-immunosorbent serologic assay system. Patients demonstrated an increase in LIF expression in peri-infarcted regions with localization in neurons and endothelial cells of microvessels surrounding the infarcted core. The rat MCAO model showed similar upregulation in neurons with a peak increase at 90 min. Circulating serum LIF expression was significantly decreased in the hyper-acute phase of stroke. Brain-derived neurons and glia cultured in vitro demonstrated an increase in gene/protein and protein expression respectively following exposure to OGD. Increased LIF expression in peri-infarcted regions and sequestration from the peripheral circulation in acute stroke patients characteristic of the pathobiological response to ischaemia and tissue damage. [ABSTRACT FROM AUTHOR]

Abstract: Cytokines are an integral part of the adaptive and innate immune responses. The signalling pathways triggered by receptor engagement translate exposure to cytokine into a coordinated biological response. To contain these responses, the initiation, duration and magnitude of the signal is controlled at multiple levels. Suppressor of cytokine signalling (SOCS) proteins act in a negative feedback loop to inhibit signal transduction. Mice with a deletion of SOCS3 die at midgestion due to placental insufficiency. SOCS3-null placentae have increased numbers of mature trophoblast giant cells, disruption of the labyrinthine layer and a decrease in the spongiotrophoblast layer. Genetic crosses have revealed that the phenotype is due to dysregulation of signalling downstream of the leukaemia inhibitory factor (LIF) receptor alpha (LIFRα) and that the ligand responsible for this, LIF, is produced by embryonic tissues and acts in a paracrine fashion. These observations highlight the role of LIF as an extrinsic factor regulating trophoblast differentiation in vivo. The creation of mice with conditional deletion of SOCS3 in different tissues has also uncovered critical roles for SOCS3 in the regulation of IL-6, G-CSF and leptin signalling. [Copyright &y& Elsevier]