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Leukemia Inhibitory Factor (leukemia + inhibitory_factor)
Selected AbstractsLeukemia Inhibitory Factor: An Important Regulator of Endometrial FunctionAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2004Zdzis, awa Kondera-Anasz Problem:, Leukemia inhibitory factor (LIF) is multifunctional cytokine that displays biological activities in different cells, including endometrial cells. The aim of this study is to describe implications of LIF on a physiological function of endometrium. Method of study:, The role of LIF in the endometrial function is reviewed and summarized from the available literature. Results:, LIF plays an important role in a physiological function of endometrium. In human endometrial LIF expression depends on cellular localizations, steroid hormones, menstrual stages and a local cytokine network. Stronger LIF expression exists in an endometrial epithelium during a luteal phase of the menstrual cycle, which coincides with the time of an implantation. The impairments of the endometrial LIF expression may play a significant role in the pathological processes involving implantation and the infertility. Conclusions:, There is a substantial evidence that LIF is a potential regulator of the endometrial function and might be one of the factors that play a key role in human reproduction. [source] Extrinsic factors derived from mouse embryonal carcinoma cell lines maintain pluripotency of mouse embryonic stem cells through a novel signal pathwayDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 2 2009Shinjirou Kawazoe Embryonic carcinoma (EC) cells, which are malignant stem cells of teratocarcinoma, have numerous morphological and biochemical properties in common with pluripotent stem cells such as embryonic stem (ES) cells. However, three EC cell lines (F9, P19 and PCC3) show different developmental potential and self-renewal capacity from those of ES cells. All three EC cell lines maintain self-renewal capacity in serum containing medium without Leukemia Inhibitory factor (LIF) or feeder layer, and show limited differentiation capacity into restricted lineage and cell types. To reveal the underlying mechanism of these characteristics, we took the approach of characterizing extrinsic factors derived from EC cells on the self-renewal capacity and pluripotency of mouse ES cells. Here we demonstrate that EC cell lines F9 and P19 produce factor(s) maintaining the undifferentiated state of mouse ES cells via an unidentified signal pathway, while P19 and PCC3 cells produce self-renewal factors of ES cells other than LIF that were able to activate the STAT3 signal; however, inhibition of STAT3 activation with Janus kinase inhibitor shows only partial impairment on the maintenance of the undifferentiated state of ES cells. Thus, these factors present in EC cells-derived conditioned medium may be responsible for the self-renewal capacity of EC and ES cells independently of LIF signaling. [source] Differential stimulation-induced receptor localization in lipid rafts for interleukin-6 family cytokines signaling through the gp130/leukemia inhibitory factor receptor complexJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Martha D. Port Abstract Leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) are cytokines which signal through receptor complexes that include the receptor subunits glycoprotein 130 (gp130) and the LIF receptor (LIFR), but CNTF also requires the non-signal transducing CNTF receptor (CNTFR) for binding. We show here that in IMR-32 neuronal cells endogenously expressing the receptor subunits for LIF and CNTF, CNTFR, but not gp130 or LIFR, is found in detergent-resistant lipid rafts. In addition, stimulation of these cells with CNTF resulted in a rapid translocation of a portion of gp130 and LIFR into detergent-resistant lipid rafts while an equivalent stimulation with LIF did not. Disruption of lipid rafts by cholesterol depletion of cell membranes blocked the CNTF-induced translocation of LIFR and gp130. Interestingly, while cholesterol-depletion did not inhibit signal transducer and activator of transcription 3 phosphorylation by either CNTF or LIF stimulation, it strongly inhibited both CNTF- and LIF-mediated phosphorylation of extracellular signal-regulated kinases 1 and 2 and Akt. LIF and CNTF generally appear to have redundant effects in cells responsive to both cytokines. Intriguingly, the data presented here suggest a possible mechanism whereby CNTF or other cytokines that signal through CNTFR could generate signals distinct from those elicited by cytokines such as LIF which utilize a LIFR/gp130 heterodimer, via association with or exclusion from lipid rafts. [source] Leukemia inhibitory factor inhibits neuronal development and disrupts synaptic organization in the mouse retinaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2005David M. Sherry Abstract Leukemia inhibitory factor (LIF) belongs to the interleukin-6 cytokine family, all members of which signal through the common gp130 receptor. Neurotrophic members of this cytokine family are known to arrest photoreceptor maturation and are likely to regulate maturation of other retinal neurons as well. We have used transgenic mice that constitutively express LIF beginning in embryonic development to determine its effects on synaptic organization and molecular maturation of all classes of retinal neurons. LIF reduced the numbers of cells showing markers characteristic of mature cells of all neuronal classes and caused synaptic ectopia. The net effect was disrupted morphological development and disturbed synaptic organization. Our study suggests that cytokines signaling through gp130 are capable of regulating many aspects of neuronal differentiation in the retina, including synaptic targeting. © 2005 Wiley-Liss, Inc. [source] Leukemia Inhibitory Factor: An Important Regulator of Endometrial FunctionAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2004Zdzis, awa Kondera-Anasz Problem:, Leukemia inhibitory factor (LIF) is multifunctional cytokine that displays biological activities in different cells, including endometrial cells. The aim of this study is to describe implications of LIF on a physiological function of endometrium. Method of study:, The role of LIF in the endometrial function is reviewed and summarized from the available literature. Results:, LIF plays an important role in a physiological function of endometrium. In human endometrial LIF expression depends on cellular localizations, steroid hormones, menstrual stages and a local cytokine network. Stronger LIF expression exists in an endometrial epithelium during a luteal phase of the menstrual cycle, which coincides with the time of an implantation. The impairments of the endometrial LIF expression may play a significant role in the pathological processes involving implantation and the infertility. Conclusions:, There is a substantial evidence that LIF is a potential regulator of the endometrial function and might be one of the factors that play a key role in human reproduction. [source] TGF-, signaling potentiates differentiation of embryonic stem cells to Pdx-1 expressing endodermal cellsGENES TO CELLS, Issue 6 2005Nobuaki Shiraki Embryonic stem (ES) cells have the capacity to differentiate to every cell type that constitutes fetal or adult tissues. To trace and quantitatively assess the differentiation of ES cells into gut endodermal cells, we used an ES cell line with the lacZ gene inserted into the pdx-1 locus. Targeted mutations of pdx-1 in mice demonstrate that pdx-1 is required for pancreatic and rostral duodenal development; therefore, pdx-1 serves as an excellent early gut regional specific marker. When these ES cells were differentiated by removal of leukemia inhibitory factor (LIF), only fractional cells turned into lacZ positive, which indicates pancreatic-duodenal differentiation. Co-cultivation of ES cells with pancreatic rudiments induced a significant increase in the proportion of lacZ positive cell numbers and this increase was further enhanced by forced expression of a chick putative endoderm inducer gene, cmix. Transforming growth factor (TGF)-,2 mimicked the effects of pancreatic rudiments and this effect was enhanced by cmix expression. Expression analysis showed over-expression of cmix induced endodermal marker genes. These data indicate that one can make use of this knowledge on molecular events of embryonic development to drive ES cells to differentiate into pdx-1 expressing endodermal cells in vitro. [source] Stable generation of serum- and feeder-free embryonic stem cell-derived mice with full germline-competency by using a GSK3 specific inhibitorGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 6 2009Hiromu Sato Abstract C57BL/6 (B6)-derived embryonic stem (ES) cells are not widely used to generate knockout mice despite the advantage of a well-defined genetic background because of poor developmental potential. We newly established serum- and feeder-free B6 ES cells with full developmental potential by using leukemia inhibitory factor (LIF) and 6-bromoindirubin-3,-oxime (BIO), a glycogen synthase kinase-3 (GSK3) inhibitor. BIO treatment significantly increased the expression levels of 364 genes including pluripotency markers such as Nanog and Klf family. Unexpectedly, by aggregating or microinjecting those ES cells to each eight-cell-stage diploid embryo, we stably generated germline-competent ES-derived mice. Furthermore, founder mice completely derived from female XO, heterozygous, or homozygous mutant B6 ES cells were directly available for intercross breeding and phenotypic analysis. We hereby propose that serum- and feeder-free B6 ES cells stimulated with LIF plus GSK3 inhibitor are valuable for generating mouse models on B6 background. genesis 47:414,422, 2009. © 2009 Wiley-Liss, Inc. [source] Involvement of gp130-associated cytokine signaling in Müller cell activation following optic nerve lesionGLIA, Issue 7 2010Matthias Kirsch Abstract Ciliary neurotrophic factor (CNTF) and the related cytokine leukemia inhibitory factor (LIF) have been implicated in regulating astrogliosis following CNS lesions. Application of the factors activates astrocytes in vivo and in vitro, and their expression as well as their receptors is upregulated after brain injury. Here, we investigated their function by studying Müller cell activation induced by optic nerve crush in CNTF- and LIF-deficient mice, and in animals with deficiencies in cytokine signaling pathways. In the retina of CNTF,/, mice, basal GFAP expression was reduced, but unexpectedly, injury-induced upregulation in activated Müller cells was increased during the first 3 days after lesion as compared to wild-type animals and this corresponded with higher phosphorylation level of STAT3, an indicator of cytokine signaling. The observation that LIF expression was strongly upregulated in CNTF,/, mice but not in wild-type animals following optic nerve lesion provided a possible explanation. In fact, additional ablation of the LIF gene in CNTF/LIF double knockout mice almost completely abolished early lesion-induced GFAP upregulation in Müller cells and STAT3 phosphorylation. Early Müller cell activation was also eliminated in LIF,/, mice, despite normal CNTF levels, as well as in mutants deficient in gp130/JAK/STAT signaling and in conditional STAT3 knockout mice. Our results demonstrate that LIF signaling via the gp130/JAK/STAT3 pathway is required for the initiation of the astrogliosis-like reaction of retinal Müller cells after optic nerve injury. A potential role of CNTF was possibly masked by a compensatory increase in LIF signaling in the absence of CNTF. © 2010 Wiley-Liss, Inc. [source] Selected Stro-1-enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferationINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 1 2009A. NASEF Summary Mesenchymal stem cells (MSCs) have an immunosuppressive effect and can inhibit the proliferation of alloreactive T cells in vitro and in vivo. Cotransplantation of MSCs and hematopoietic stem cells (HSCs) from HLA-identical siblings has been shown to reduce the incidence of acute graft- vs.-host disease. MSCs are heterogeneous and data on the inhibitory effects of different MSC subsets are lacking. The antigen Stro1 is a marker for a pure primitive MSC subset. We investigated whether Stro-1-enriched induce a more significant suppressive effect on lymphocytes in a mixed lymphocyte reaction (MLR), and whether this action is related to a specific gene expression profile in Stro-1-enriched compared to other MSCs. We demonstrated that the Stro-1-enriched population elicits a significantly more profound dose-dependent inhibition of lymphocyte proliferation in a MLR than MSCs. One thousand expanded Stro-1-enriched induced an inhibitory effect comparable to that of 10 times as many MSCs. Inhibition by Stro-1-enriched was more significant in contact-dependent cultures than in noncontact-dependant cultures at higher ratio. The Stro-1-enriched inhibitory effect in both culture types was linked to increased gene expression for soluble inhibitory factors such as interleukin-8 (IL-8), leukemia inhibitory factor (LIF), indoleamine oxidase (IDO), human leukocyte antigen-G (HLA-G), and vascular cell adhesion molecule (VCAM1). However, tumor growth factor-,1 (TGF-,) and IL-10 were only up-regulated in contact-dependant cultures. These results may support using a purified Stro-1-enriched population to augment the suppressive effect in allogeneic transplantation. [source] Characterization of an immortalized oviduct cell line from the cynomolgus monkey (Macaca fascicularis)JOURNAL OF MEDICAL PRIMATOLOGY, Issue 2 2005H. Okada Abstract:, To establish reproductive biological techniques in mammals, it is important to understand the growth environment of the embryo. Oviduct epithelial cells are in close proximity to the embryo during pre-implantation development. We, therefore, established an immortalized oviduct epithelial cell line from the cynomolgus monkey, evaluated the usefulness of these cells as feeder cells for embryo culture, and investigated the gene expression of several growth factors and cytokines in the cells. The immortalized cells were positive for the anti-cytokeratin antibody, as determined by immunocytochemistry, indicating that they are epithelial. They also expressed oviductin, which is specific to oviduct epithelial cells, glyceraldehyde-3-phosphate dehydrogenase (control), leukemia inhibitory factor, vascular endothelial growth factor, epidermal growth factor, insulin-like growth factor 1, transforming growth factor beta-2, and interleukin 4. Mouse embryo development was improved when the immortalized cells were used as feeder cells. This cell line is also useful for studying the factors secreted by oviduct epithelial cells. [source] STAT3 activation in photoreceptors by leukemia inhibitory factor is associated with protection from light damageJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Yumi Ueki Abstract Members of the interleukin-6 cytokine family, including leukemia inhibitory factor (LIF), signal through gp130. The neuroprotective role of gp130 activation has been widely demonstrated in both CNS and PNS, but the mechanism by which this is accomplished is not well established. We investigated temporal and cell-specific activation of signaling pathways induced by LIF in the mature mouse retina. Intravitreal injection of LIF preserved photoreceptor function and prevented photoreceptor cell death from light-induced oxidative damage in a dose-dependent manner (2 days post-injection). A therapeutic dose of LIF induced rapid and sustained activation of signal transducer and activator of transcription (STAT) 3. Activated STAT3 was localized to all the retinal neurons and glial cells, including photoreceptors. Activation of extracellular signal-regulated kinase 1 and 2 was robust but transient in Müller glial cells, and undetectable at the time of light exposure. Akt was not activated by LIF. We also show that at the time of neuroprotection, STAT3 but not extracellular signal-regulated kinase 1 and 2 or the Akt pathways was active in LIF-treated retinas, and activated STAT3 was clearly localized in transcriptionally active areas of photoreceptor nuclei. Our data suggest that photoreceptor protection in response to LIF can be directly mediated by activation of STAT3 in photoreceptors. [source] JAK-STAT signaling pathway mediates astrogliosis in brains of scrapie-infected miceJOURNAL OF NEUROCHEMISTRY, Issue 2 2007Yeo-Jung Na Abstract Scrapie is characterized histologically, in part, by astrogliosis in brain and spinal cord. However, the mechanisms of astrogliosis in brain injury occurring during prion infection are not well understood. In this study, we investigated the expression levels and cellular localization of Janus kinase (JAK) -signal transducers and activators of transcription (STAT) signaling molecules and growth factors such as leukemia inhibitory factor (LIF) and ciliary neurotropic factor (CNTF) by western blot analysis and immunohistochemistry. We found that expression levels of LIF and CNTF were increased in scrapie-infected brains and phosphorylated (p)-JAK2, p-STAT1 (Ser727 and Tyr701), p-STAT3 (Tyr705), and glial fibrillary acidic protein were expressed strongly in scrapie-infected brains. Moreover, we found that p-STAT1 and p-STAT3 were found mainly in the nucleus in scrapie-infected brains. Immunohistochemically, p-STAT1 was colocalized with LIF and CNTF and p-JAK2 in many reactive astrocytes in scrapie-infected brains. In contrast, immunostaining for p-STAT3 was found in comparatively few astrocytes in limited regions; p-STAT3 staining merged with p-JAK2 in hippocampus sections of scrapie-infected brains. Taken together, our results suggest that activation of JAK2-STAT1 signaling pathway occurred in reactive astrocytes in hippocampus of scrapie-infected brains. [source] Multiple promoter elements required for leukemia inhibitory factor-stimulated M2 muscarinic acetylcholine receptor promoter activityJOURNAL OF NEUROCHEMISTRY, Issue 4 2006George S. Laszlo Abstract Treatment of neuronal cells with leukemia inhibitory factor (LIF) results in increased M2 muscarinic acetylcholine receptor promoter activity. We demonstrate here that multiple promoter elements mediate LIF stimulation of M2 gene transcription. We identify a LIF inducible element (LIE) in the M2 promoter with high homology to a cytokine-inducible ACTG-containing sequence in the vasoactive intestinal peptide promoter. Mutagenesis of both a STAT (signal transducers and activators of transcription) element and the LIE in the M2 promoter is required to attenuate stimulation of M2 promoter activity by LIF completely. Mobility shift assays indicate that a LIF-stimulated complex binds to a 70 base pair M2 promoter fragment. Furthermore, a STAT element within this fragment can bind to LIF-stimulated nuclear STAT1 homodimers in vitro. Mutagenesis experiments show that cytokine-stimulated activation of M2 promoter activity requires tyrosine residues on glycoprotein 130 (gp130) that are also required for both STAT1 and STAT3 activation. Dominant negative STAT1 or STAT3 can block LIF-stimulated M2 promoter activity. Real-time RT-PCR analysis indicates that LIF-stimulated induction of M2 mRNA is partially dependent on protein synthesis. These results show that regulation of M2 gene transcription in neuronal cells by LIF occurs through a complex novel mechanism that is dependent on LIE, STAT and de novo protein synthesis. [source] An Insight to Pituitary Folliculo-Stellate CellsJOURNAL OF NEUROENDOCRINOLOGY, Issue 6 2008S. Devnath Folliculo-stellate cells (FS-cells) are star-shaped and follicle-forming cells in the anterior pituitary gland that were first identified by electron microscopy as non-endocrine agranular cells. Light microscopy has revealed many of their cytophysiological features and the FS-cell is known to be positive for S-100 protein, a marker for FS-cells. So far, functions ascribed to FS-cells include the formation of an extensive and complex tridimentional network, scavenger activity by engulfing degenerated cells, paracrine regulation of endocrine cells by producing various growth factors and cytokines, such as interleukin-6, leukemia inhibitory factor, basic fibroblastic growth factor, vascular endothelial cell growth factor and follistatin, and large-scale inter-cellular communication by means of their long cytoplasmic processes and gap junctions. Moreover, their multi-potential characteristics and other cytological features support the possibility of them becoming organ-specific stem cells. This concept is yet to be resolved, however. In this review, we focus on these features of FS-cells along with some futuristic approaches. [source] Effects of Ethanol on Mouse Embryonic Stem CellsALCOHOLISM, Issue 12 2009Alla Arzumanyan Background:, Fetal alcohol syndrome (FAS) reflects a constellation of congenital abnormalities caused by excess maternal consumption of alcohol. It is likely that interference with embryonic development plays a role in the pathogenesis of the disorder. Ethanol-induced apoptosis has been suggested as a causal factor in the genesis of FAS. Mouse embryonic stem (mES) cells are pluripotent cells that differentiate in vitro to cell aggregates termed embryoid bodies (EBs), wherein differentiation capacity and gene expression profile are similar to those of the early embryo. Methods:, To investigate the effects of ethanol during differentiation, mES cells were cultured on a gelatin surface in the presence of leukemia inhibitory factor which maintains adherent undifferentiated cells or in suspension to promote formation of EBs. All cells were treated (1,6 days) with 80 mM ethanol. The pluripotency and differentiation of mES cells were evaluated by western blotting of stage-specific embryonic antigen (SSEA-1), transcription factors Oct-3/4, Sox-2, and Nanog, using alkaline phosphatase staining. Apoptosis (early to late stages) was assessed by fluorescence-activated cell sorting using TdT-mediated biotin,dUTP nick-end labelling assay and fluorescein isothiocyanate-Annexin V/propidium iodide staining. Results:, Ethanol increased apoptosis during in vitro differentiation of mES cells to EBs, whereas undifferentiated cells were not affected. Ethanol exposure also interfered with pluripotency marker patterns causing an upregulation of SSEA-1 under self-renewal conditions. In EBs, ethanol delayed the downregulation of SSEA-1 and affected the regulation of transcription factors during differentiation. Conclusion:, Our findings suggest that ethanol may contribute to the pathogenesis of FAS by triggering apoptotic pathways during differentiation of embryonic stem cells and deregulating early stages of embryogenesis. [source] Properties of murine embryonic stem cells maintained on human foreskin fibroblasts without LIF,MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 4 2008G.L. Meng Abstract In embryonic stem (ES) cells, leukemia inhibitory factor (LIF)/STAT3, wnt and nodal/activin signaling are mainly active to control pluripotency during expansion. To maintain pluripotency, ES cells are typically cultured on feeder cells of varying origins. Murine ES cells are commonly cultured on murine embryonic fibroblasts (MEFs), which senesce early and must be frequently prepared. This process is laborious and leads to batch variation presenting a challenge for high-throughput ES cell expansion. Although some cell lines can be sustained by exogenous LIF, this method is costly. We present here a novel and inexpensive culture method for expanding murine ES cells on human foreskin fibroblast (HFF) feeders. After 20 passages on HFFs without LIF, ES cell lines showed normal expression levels of pluripotency markers, maintained a normal karyotype and retained the ability to contribute to the germline. As HFFs do not senesce for at least 62 passages, they present a vast supply of feeders. Mol. Reprod. Dev. 75: 614,622, 2008. © 2007 Wiley-Liss, Inc. [source] Proteomic analysis of membrane proteins expressed specifically in pluripotent murine embryonic stem cellsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 1 2009Atsushi Intoh Abstract Embryonic stem cells (ESCs) are established from the inner cell mass of preimplantation embryos, are capable of self-renewal, and exhibit pluripotency. Given these unique properties, ESCs are expected to have therapeutic potential in regenerative medicine and as a powerful tool for in vitro differentiation studies of stem cells. Various growth factors and extracellular matrix components regulate the pluripotency and differentiation of ESC progenies. Thus, the cell surface receptors that bind these regulatory factors are crucial for the precise regulation of stem cells. To identify membrane proteins that are involved in the regulation of pluripotent stem cells, the membrane proteins of murine ESCs cultured with or without leukemia inhibitory factor (LIF) were purified and analyzed by quantitative proteomics. 2-D PAGE-based analysis using fluorescently labeled proteins and shotgun-based analysis with isotope-labeled peptides identified 338 proteins, including transmembrane, membrane-binding, and extracellular proteins, which were expressed specifically in pluripotent or differentiated murine ESCs. Functions of the identified proteins revealed cell adhesion molecules, channels, and receptors, which are expected to play important roles in the maintenance of murine ESC pluripotency. Membrane proteins that are expressed in pluripotent ESCs but not in differentiated cells such as Slc16a1 and Bsg could be useful for the selection of the stem cells in vitro. [source] 1141636674 Differential serine and tyrosine phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in Jeg-3 choriocarcinoma cell linesAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2006J Roediger Background:, Signal Transducer and Activator of Transcription 3 (STAT3) is an intracellular signalling molecule, which is used by several cytokines, including leukemia inhibitory factor (LIF), epithelial growth factor (EGF), and interleukin-6 (IL-6). It induces a variety of gene transcripts and cell functions. In trophoblast cells and in tumor cells, its tyrosine phosphorylation is directly linked to their invasiveness. The regulation and function of STAT3 serine phosphorylation is still widely unclear. Material and Methods:, Jeg-3 choriocarcinoma cells were stimulated with different concentrations of EGF, IL-6 and LIF. STAT3 serine (727) and tyrosine (705) phosphorylation were analyzed 5,60 min after stimulation by SDS-PAGE electrophoresis followed by Western blotting. Results:, Jeg-3 cells display spontaneous STAT3 serine phosphorylation. 100 ng/mL EGF induces a time-dependent reduction starting 15 min after stimulation. Tyrosine phosphorylation does not occur spontaneously, but is strongly induced by EGF at all analyzed time points. LIF induces tyrosine phosphorylation, but affects serine phosphorylation only very slightly. IL-6 did not influence neither serine phosphorylation nor tyrosine phosphorylation. Discussion:, The EGF induced STAT3 tyrosine phosphorylation may be responsible for its invasion triggering capacities. The parallel reduction of serine phosphorylation may enhance this effect. LIF was formerly shown to enhance trophoblast invasion via STAT3 tyrosine phosphorylation. IL-6 displays very little effects on STAT3 and seems to use other pathways for signalling. [source] Supplementation-dependent differences in the rates of embryonic stem cell self-renewal, differentiation, and apoptosisBIOTECHNOLOGY & BIOENGINEERING, Issue 5 2003Sowmya Viswanathan Abstract Although it is known that leukemia inhibitory factor (LIF) supports the derivation and expansion of murine embryonic stem (ES) cells, it is unclear whether this is due to inhibitory effects of LIF on ES cell differentiation or stimulatory effects on ES cell survival and proliferation. Using an ES cell line transgenic for green fluorescent protein (GFP) expression under control of the Oct4 promoter, we were able to simultaneously track the responses of live Oct4-GFP-positive (ES) and -negative (differentiated) fractions to LIF, serum, and other growth factors. Our findings show that, in addition to inhibiting differentiation of undifferentiated cells, the administration of LIF resulted in a distinct dose-dependent survival and proliferation advantage, thus enabling the long-term propagation of undifferentiated cells. Competitive responses from the differentiated cell fraction could only be elicited upon addition of serum, fibroblast growth factor-4 (FGF-4), or insulin-like growth factor-1 (IGF-1). The growth factors did not induce additional differentiation of ES cells, but rather they significantly improved the proliferation of already differentiated cells. Our analyses show that, by adjusting culture conditions, including the type and amount of growth factors or cytokines present, the frequency of media exchange, and the presence or absence of serum, we could selectively and specifically alter the survival, proliferation, and differentiation dynamics of the two subpopulations, and thus effectively control population outputs. Our findings therefore have important applications in engineering stem cell culture systems to predictably generate desired stem cells or their derivatives for various regenerative therapies. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng84: 505,517, 2003. [source] Expression of LIF and LIF receptor beta in Alzheimer's and Parkinson's diseasesACTA NEUROLOGICA SCANDINAVICA, Issue 1 2010M. Soilu-Hänninen Background,,, Signaling through the leukemia inhibitory factor (LIF) receptor (LIFR) is crucial for nervous system development. There are few studies concerning the expression of LIF and LIFR in normal and degenerating adult human brain. Objectives,,, To study the expression of LIF and LIFR in Alzheimer's disease (AD), Parkinson's disease (PD), and control brains. Patients and methods,,, LIF and LIFR mRNA copy numbers were determined by quantitative real-time RT-PCR from four brain regions of 34 patients with AD, 40 patients with PD, and 40 controls. Immunohistochemistry was performed in seven PD and in four AD patients and in seven normal controls. Results,,, In general, the LIF copy numbers were 1 log higher than the LIFR copy numbers. In the AD brains, LIF expression was higher than in the controls in the hippocampus and in the temporal cortex, and in the PD brains in the hippocampus and in the anterior cingulated cortex. Expressions of LIF and LIFR in different brain regions were opposite except for the AD hippocampus and PD anterior cingulated cortex, where the expression patterns were parallel. Conclusions,,, Co-operative expression of LIF and LIFR in AD hippocampus and PD anterior cingulated cortex may indicate a role for LIF in neuronal damage or repair in these sites. [source] Human epithelial ovarian carcinoma cell-derived cytokines cooperatively induce activated CD4+CD25,CD45RA+ naïve T cells to express forkhead box protein 3 and exhibit suppressive ability in vitroCANCER SCIENCE, Issue 11 2009Xiaofeng Zhao Regulatory T cells play an important role in tumor escape from host antitumor immunity. Increased frequencies of CD4+CD25+ regulatory T cells have been documented in the tumor sites, malignant effusions, and peripheral blood of patients with ovarian carcinoma. However, the mechanism involved remains unclear. In the present study, we collected high-purity human CD4+CD25,CD45RA+ naïve T cells by microbead cell separation. These cells did not express FOXP3 by single-cell analysis, and few cells expressed FOXP3 when they were activated with anti-CD3/CD28 dual signal. However, more cells expressed FOXP3 when the supernatant of human epithelial ovarian carcinoma cell culture was added, yet not the supernatant of normal human ovarian surface epithelia cell culture. Neutralization assays revealed that neutralizing antibody against transforming growth factor , (TGF-,), interleukin-10, and interleukin-4 did not abrogate elevated FOXP3 expression induced by carcinoma cell culture supernatant, whereas neutralizing leukemia inhibitory factor (LIF) partially abrogated FOXP3 expression, but LIF alone could not increase FOXP3 expression in activated naïve T cells. Further, an in vitro coculture suppression assay showed that these cells could suppress the proliferation of autologous CD4+CD25,CD45RA, T cells. In summary, our findings show that ovarian carcinoma cells are able to induce expression of FOXP3 and exhibit suppressive ability in activated naïve T cells by producing soluble substances, and multiple cytokines involve in the induction of FOXP3 expression. (Cancer Sci 2009) [source] | |||||||||||||||||||||||||