Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Leukemia Inhibitory Factor”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2000

Protein-tyrosine phosphatase PTPepsilon C inhibits Jak-STAT signaling and differentiation induced by interleukin-6 and leukemia inhibitory factor in M1 leukemia cells.

We engineered and expressed both a wild-type and mutant cytosolic isoform of PTPepsilon (PTPepsilonC) in murine M1 leukemic cells, which can be induced to growth arrest and monocytic differentiation by interleukin (IL)-6 and leukemia inhibitory factor (LIF). Forced expression of PTPepsilonC inhibited IL-6- and LIF-induced monocytic differentiation and apoptosis in M1 cells, whereas expression of PTPepsilonM, a transmembrane isoform of PTPepsilon, did not. PTPepsilonC expression resulted in lower levels of IL-6-induced tyrosine phosphorylation of Jak1, Tyk2, gp130, and Stat3 compared with parent cells. In M1 transfectants expressing an inactive mutant of PTPepsilonC, both tyrosine phosphorylation and apoptosis induced by IL-6 and LIF were potentiated rather than inhibited. These results suggest an important role for PTPepsilonC in negative regulation of IL-6- and LIF-induced Jak-STAT signaling.

Animals↗
PubMed1998

Synergistic effects of colony-stimulating factor 1 and leukemia inhibitory factor in inducing early myeloid cell differentiation.

Cells of the M1D+ murine myeloid leukemic cell line differentiate into macrophages in response to either leukemia inhibitory factor (LIF) or interleukin 6. Previously, it was shown that LIF treatment of M1D+ cells leads to an increased expression of colony-stimulating factor (CSF) receptor mRNA encoded by c-fms. CSF-1, a macrophage growth factor, induces the survival, growth, and differentiation of mononuclear phagocytes but has not been implicated in the regulation of early myeloid cell differentiation. Here we show that low-dose LIF treatment of M1D+ cells results in CSF-1 secretion and CSF-1 receptor up-regulation. CSF-1, when applied alone, induces some M1D+ adherence and the up-regulation of lysozyme M, a macrophage-specific marker. Finally, we show that when applied together, LIF and CSF-1 act synergistically to induce macrophage morphology, phagocytosis, and the expression of the macrophage-specific markers CD11b/Mac-1 alpha chain, lysozyme M, FcgammaRII, and JE/MCP.1. These results indicate that instead of being part of exclusive pathways, as thought until this work, LIF and CSF-1 can function synergistically to further stimulate the early stages of myeloid differentiation.

Animals↗
PubMed1994

Ciliary neurotropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130.

Interleukin 6 (IL-6) is a major growth factor for tumor plasma cells involved in human multiple myeloma (MM). In particular, human myeloma cell lines (HMCL), whose growth is completely dependent on addition of exogenous IL-6, can be obtained reproducibly from every patient with terminal disease. Four cytokines, ciliary neurotropic factor (CNTF), IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OM), use the same transducer chain (signal transducer gp130) as IL-6 and share numerous biological activities with this IL. We found that these four cytokines stimulated proliferation and supported the long-term growth of two out of four IL-6-dependent HMCL obtained in our laboratory. Half-maximal proliferation was obtained with cytokine concentrations ranging from 0.4 to 1.2 ng/ml for IL-11, LIF, and OM. CNTF worked at high concentrations only (90 ng/ml), but addition of soluble CNTF receptor increased sensitivity to CNTF 30-fold. The growth-promoting effect of these four cytokines was abrogated by anti-gp130 antibodies, contrary to results for anti-IL-6 receptor or anti-IL-6 antibodies. No detectable changes in the morphology and phenotype were found when myeloma cells were cultured with one of these four cytokines instead of IL-6. Concordant with their IL-6-dependent growth, the four HMCL expressed membrane IL-6R and gp130 detected by FACS analysis. LIF-binding chain gene (LIFR) was expressed only in the two HMCL responsive to LIF and OM.

Antigens, CD↗
PubMed2001

Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy.

Human disuse muscle atrophy frequently accompanies orthopedic injury, arthritis, or bed rest, and recovery is often incomplete despite current rehabilitation programs. We have studied the vastus lateralis muscle in 12 patients with chronic disuse atrophy associated with chronic osteoarthritis of the hip both preoperatively and after total hip arthroplasty. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated an increase in the level of expression of myostatin, insulin-like growth factor-1 (IGF-1) and leukemia inhibitory factor (LIF) mRNAs compared to healthy control muscle. In all patients there was a significant correlation preoperatively between increasing myostatin mRNA expression and reduction in type 2A and 2B fiber area. In the 8 female patients there was a significant correlation between increased myostatin mRNA expression and the atrophy factor calculated for 2A and 2B fiber types preoperatively. We hypothesize that a complex interaction occurs between muscle growth regulating factors in the genesis of muscle wasting. Our results indicate that myostatin is a muscle-wasting factor contributing to type 2B and 2A atrophy. Other muscle growth factors, such as IGF-1 and LIF, may be upregulated in a counterregulatory fashion or may be involved in the fiber type switching seen in disuse muscle wasting.

Adult↗
PubMed1994

Proliferative responses and binding properties of hematopoietic cells transfected with low-affinity receptors for leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor.

Specific low-affinity receptors for leukemia inhibitory factor (LIF), oncostatin M (OSM; gp130), and ciliary neurotrophic factor (CNTF; receptor alpha, CNTFR alpha) may be utilized in various combinations to generate high-affinity binding sites and signal transduction. We have tested the ability of combinations of these receptors to transduce a proliferative signal in BAF-B03 cells. Coexpression of the LIF receptor and gp130 in these cells conferred high-affinity LIF and OSM binding and responsiveness to LIF and OSM. These cells also responded to CNTF in the absence of detectable binding. The further addition of CNTFR alpha conferred high-affinity CNTF binding and enhanced responsiveness to CNTF but did not modify responses to LIF or OSM. Coexpression of LIF receptor and CNTFR alpha resulted in a nonfunctional high-affinity binding site. These data are consistent with a role for the CNTFR alpha in enhancing CNTF action but the CNTFR alpha is not absolutely required for CNTF action and suggest a wider range of targets for CNTF.

Animals↗
PubMed1995

Hematologic effects of stem cell factor (SCF) and leukemia inhibitory factor (LIF) in vivo: LIF-induced thrombocytosis in SCF-primed mice.

Stem cell factor (SCF) administered as daily bolus injections in dose-response experiments in mice causes a progressive and dramatic dose-dependent panleukocytosis characterized by neutrophilia, eosinophilia, monocytosis, and lymphocytosis. SCF causes circulating platelet numbers to be dose-dependently increased after 2 weeks of daily injections. Leukemia inhibitory factor (LIF) administered as daily bolus injections in mice causes a peripheral leukopenia that is largely due to peripheral lymphopenia. LIF causes thrombocytosis peaking after approximately 1 w. Coinjection of SCF and LIF for 1 to 2 wk in mice does not cause a much greater thrombocytosis than the maximum thrombocytosis achievable with SCF or LIF alone. On the other hand, daily injection of SCF for 5 days followed by daily injection of LIF for 5 to 6 d in mice causes a very substantial increase in platelets that was lineage-specific in terms of not being accompanied by a generalized leukocytosis. In contrast, only a very modest thrombocytosis was noted in SCF-primed LIF-treated rats. LIF causes a large increase in the cytoplasmic volume of splenic megakaryocytes in mice, but not in rats. In conclusion, SCF-induced priming followed by LIF-induced maturation of megakaryocytes causes a substantial selective increase in the numbers of circulating platelets in mice.

Animals↗
PubMed1996

Binding interactions of leukemia inhibitory factor and ciliary neurotrophic factor with the different subunits of their high affinity receptors.

Leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) share common components in their multimeric receptors. Both cytokine receptors contain gp130/interleukin-6-receptor transducer as well as gp190/low affinity LIF receptor. For CNTF, addition of a third subunit, or alpha subunit, defines the high-affinity CNTF receptor. In the present study, we analyzed the binding interactions of LIF and CNTF in human cell lines and showed a mutual displacement for LIF and CNTF toward the trimeric high-affinity CNTF receptor. Similar results were obtained in the JEG cell line, which only expressed the gp130/gp190 high-affinity LIF receptor, by adding a soluble form of the alpha CNTF receptor to the system to reconstitute the high-affinity-type CNTF receptor. The different receptor subunits were then expressed separately in transfected cells and their binding capacities analyzed. The results showed that the heterocomplex CNTF/alpha CNTF receptor bound to gp130 with an affinity of 3-5 x 10(-10)M, whereas LIF interacted mainly with gp190. In summary, the observed competition between LIF and CNTF does not result from the binding to a common site or receptor subunit, but rather to the interaction of the three receptor components to create a conformational site common to both LIF and CNTF.

Animals↗
PubMed1996

Role of leukemia inhibitory factor during mammalian development.

Leukemia inhibitory factor (LIF) is a cytokine that exhibits proliferative, survival and differentiation activities on a wide range of cell types. A role for LIF in embryonic development is suggested by: i) its ability to stimulate the proliferation of embryonic stem (ES) cells in vitro, while maintaining their totipotency and ii) by both its maternal and embryonic expression at the time of blastocyst implantation. Functional studies of LIF and its receptor during mouse embryogenesis have been performed using the techniques of targeted gene replacement and transgene expression in ES cells to produce transgenic mice bearing either loss- or gain-of-function mutations for LIF activity. Whereas, the phenotype observed in the LIF gain-of-function mutant mice supports a role for LIF in early embryogenesis, the loss-of-function phenotypes point to more specialized functions for LIF in development and further reveal the redundant feature of the LIF cytokine/receptor family.

Animals↗
PubMed1998

Leukemia inhibitory factor regulates proopiomelanocortin transcription.

Leukemia inhibitory factor (LIF), a pleiotropic cytokine, is expressed in both fetal and adult pituitary tissue, and LIF immunoreactivity is found in functional human pituitary tumors. LIF induces basal, and augments CRH-induced, POMC mRNA and ACTH secretion from AtT20 cells. Therefore, we examined LIF signaling and LIF regulation of POMC expression in AtT20 cells. Immunoneutralization studies demonstrated the dependence of LIF action on both the specific LIF receptor (35% inhibition; p < 0.05) and also the gpl30 affinity converter (41% inhibition; p < 0.05). These antisera also attenuate basal ACTH secretion without added LIF. LIF rapidly induced tyrosyl phosphorylation of both STAT 1 alpha, and STAT beta and also induced phosphorylation of a novel STAT 1 alpha related protein p115. LIF induced POMC transcription (-706/+64) and strikingly potentiated CRH action (up to 18-fold induction). This synergy involved cAMP-dependent pathways, as forskolin action was also potentiated by LIF. Deletion of the major CRH-responsive region in POMC (-323/-166) abolished both CRH and LIF action on POMC transcription. Thus LIF action in pituitary corticotrophs is dependent on LIF receptor heterodimerisation with gpl30 and involves STAT protein tyrosyl phosphorylation. LIF enhances POMC transcription and strongly potentiates the well-documented action of CRH on the POMC gene. These results define a subcellular mechanism for an immuno-neuroendocrine interface between peripheral afferent signals and the HPA axis.

Adrenocorticotropic Hormone↗
PubMed1994

Tumor necrosis factor alpha stimulates production of leukemia inhibitory factor in human dermal fibroblast cultures.

Leukemia inhibitory factor (LIF) is a recently described cytokine with a variety of actions including a possible involvement in immune responses. We determined whether human dermal fibroblast cultures could produce LIF after they were treated with tumor necrosis factor alpha (TNF alpha), a cytokine that is produced as an early inflammatory response of activated monocytes. We found that treatment of the cultures with as little as 0.5 units/ml (1.5 pM) caused a detectable increase in both LIF message and protein as measured by Northern blot assay and ELISA, respectively. Furthermore, increasing concentrations of TNF alpha produced a dose-dependent increase in both steady-state LIF mRNA and protein levels up to a maximum response with 500 units/ml (1.5 nM). Increases in LIF mRNA levels were rapid and could be detected 1 hr after treatment with 500 units/ml of TNF alpha. However, this effect was transient. It reached a maximum at 2 hr and returned almost to baseline at 24 hr. In contrast, levels of LIF protein in the conditioned media of the cultures increased progressively over 24 hr. The LIF produced by these cultures was biologically active and was inhibited by a polyclonal antibody to human LIF in a bioassay. These results demonstrate that LIF is produced by human dermal fibroblasts in response to treatment with TNF alpha, a mediator of acute inflammation. Furthermore, they suggest that production of LIF by these cells may be involved in the development of both the local and generalized immune response.

Cells, Cultured↗
PubMed1997

Production and characterization of monoclonal antibodies against the leukemia inhibitory factor low affinity receptor, gp190.

Leukemia inhibitory factor (LIF), oncostatin-M (OSM), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT1) act through transmembrane receptors which share the gp190 glycoprotein chain. The understanding of its involvement in the biology of these cytokines is of importance since these systems have recently been shown to participate in major inflammatory and neoplastic processes such as myelomatosis (Rose-John, S., Heinrich, P.C., 1994. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem. J. 300, 281). In addition, this family of receptors also shares the gp130 transducing chain, with the IL6 and IL11 receptors. Because IL6 and gp130 were the first members to be discovered, most of the available reagents are directed at them. In this respect, monoclonal antibodies have played a major role in elucidating these receptor/ligand interactions and exploring the pathophysiological aspects of their biology. So far, no such reagents have been described for the gp190. We now report the production and characterization of 16 monoclonal antibodies directed against human gp190. They were obtained using recombinant chimeric or truncated proteins produced in a eukaryotic CHO cell line. One was able to block the biological activity of LIF. Because gp190 comprises two hematopoietin binding domains, crude epitope mapping was possible using the same reagents. While more of these antibodies are required, the present set validate the technological approach used for their preparation and should improve our understanding of this class of cytokines.

Animals↗
PubMed1998

Testicular leukemia inhibitory factor (LIF) and LIF receptor mediate phosphorylation of signal transducers and activators of transcription (STAT)-3 and STAT-1 and induce c-fos transcription and activator protein-1 activation in rat Sertoli but not germ cells.

Increasing amounts of evidence suggest noninflammatory roles for growth factor and cytokines in development and differentiation. Leukemia inhibitory factor (LIF) belongs to a gp130 pleiotropic family of growth factors that has recently been shown to enhance the survival of rat testicular gonocytes and Sertoli cells. In this study, we show the expression of gp130 and LIF messenger RNAs (mRNAs) in the somatic (the Sertoli and Leydig cells) and specific germ cells (spermatogonia, pachytene, round, and elongated spermatids) of rodent testis, suggestive of cell-specific LIF-mediated functions. LIF receptor mRNA was demonstrated in rat somatic cells, rat elongating spermatids, and all of the mouse germ cells. In addition, we characterized the effects of LIF on the signal transducers and activators of transcription (STAT)-3 and STAT-1, c-fos gene expression, and activator protein-1 regulation in primary rat Sertoli cells. Electrophoretic mobility shift assay and Western blot analysis demonstrated that LIF translocates STAT-3 (and to a lesser extent STAT-1) transcription factor(s) to the nucleus within 2 min of exposure in a tyrosine but not serine/threonine phosphorylation-dependent pathway. Quantitative solution hybridization analysis revealed a transient increase in c-fos mRNA levels by 20-fold following 30-45 min of LIF treatment, an effect that was inhibited by the tyrosine, as well as serine/threonine kinase inhibitors, genistein, and H7. Subsequently, LIF treatment of the Sertoli cells increased nuclear activator protein-1 binding proteins at 2 h after its addition, an effect that was also sensitive to genistein and H7 pretreatments. In contrast, LIF treatment of primary rat germ cells did not alter c-fos mRNA levels. Species specificity in the expression of LIF receptor as well as ligand binding may play a role in LIF signaling in these germ cells. Thus, using a primary Sertoli cell model, we demonstrated that the testicular LIF signaling pathway is contingent on the phosphorylation of latent transcription factors. Our data are consistent with LIF-mediated signaling events involving both somatic and germ cells during spermatogenesis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Infection with human T-lymphotropic viruses leads to constitutive expression of leukemia inhibitory factor and interleukin-6.

Leukemia inhibitory factor (LIF), similar to interleukin-6 (IL-6), is a glycoprotein growth factor and differentiation regulator that has pleiotropic activity in several cellular systems. Recent reports of constitutive IL-6 production from spontaneously proliferating cells from human T-cell leukemia virus (HTLV)-infected individuals led us to examine the expression of IL-6 and LIF during HTLV infection. In vitro infection of peripheral blood lymphocytes with HTLV-I was associated with production of both soluble LIF and IL-6 in conjunction with the increasing HTLV antigen concentration. Northern blot analysis of T-cell lines generated from individuals infected with HTLV-I (MT-2, HuT-102, FS, EG, SP) and HTLV-II (Mo-T, H2A, H2E) demonstrated a marked increase in constitutive expression of LIF and IL-6 transcripts, as compared with uninfected cell lines (HuT-78, Jurkat). The constitutive expression of LIF and IL-6 was independent of presence of IL-2 in the culture medium, as both IL-2-independent (MT-2, HuT-102, SP, Mo-T) and IL-2-dependent (FS, EG, H2A, H2E) cell lines expressed LIF and IL-6 transcripts. Furthermore, LIF and IL-6 RNA expression in an HTLV-I-infected cell line (MT-2) was enhanced by phorbol ester stimulation via mechanisms that appear to be dependent on the posttranscriptional regulatory controls. These results show that both LIF and IL-6 are produced by HTLV-I- and HTLV-II-infected cells, which could potentially alter the transcriptional regulation of HTLV gene expression by inducing certain early response genes.

Cell Line↗
PubMed2005

Endogenous leukemia inhibitory factor attenuates endotoxin response.

Leukemia inhibitory factor (LIF) is induced in inflammation and likely plays a regulatory role. Using LIF-deficient mice (LIF-/-), we report here that endogenous LIF has a protective role in endotoxic shock and host defence. LIF-/- mice have heightened sensitivity to LPS in a LPS/D-galactosamine (D-Gal) sensitization model compared to wild-type mice (LIF+/+), enhanced thrombocytopenia and leukopenia, with increased hepatic necrosis, neutrophil sequestration in the lung and accelerated mortality. These findings correlated with 10-fold higher tumour necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6) serum levels and reduced IL-10 production in LIF-/- mice in response to LPS. Therefore, endogenous LIF attenuates the endotoxic shock response, enhances the expression of basal acute phase proteins and IL-10 production, which downregulates TNFalpha synthesis and release and thereby confers partial protection to endotoxemia.

Acute-Phase Reaction↗
PubMed1993

Close proximity of the genes for leukemia inhibitory factor and oncostatin M.

Leukemia inhibitory factor (LIF) and oncostatin M (OSM) are structurally related cytokines that share a common receptor complex. The genes for LIF and OSM have previously been reported to be on human chromosome 22. We report here the isolation of a single 73 kbp human genomic yeast artificial chromosome clone that contains the LIF and OSM genes. The two genes lie within 19 kbp of each other and are transcribed in opposite directions.

Base Sequence↗
PubMedDate not supplied

Enhancement of in vitro murine embryo development by recombinant leukemia inhibitory factor.

OBJECTIVE: Human recombinant leukemia inhibitory factor (rLIF) has been shown to stimulate hatching of murine and ovine embryos in vitro. The temporal and dose-dependent effects of murine rLIF (mrLIF) and human rLIF (hrLIF) on embryo development in two different mouse strains were investigated in this work. METHODS: Two-cell embryos were recovered from the fallopian tubes of superovulated/mated females and cultured in Krebs medium plus bovine serum albumin in microdroplets under oil. RESULTS: In the B6CBF1 strain, mrLIF significantly stimulated blastocyst formation and decreased embryo fragmentation/degeneration when added simultaneously at the initiation of culture or 24 hours thereafter. Human rLIF also had a positive effect on development. In the CD1 strain (lower fecundity), mrLIF dose-dependent effects were observed, with enhanced developmental stimulation achieved with higher doses. CONCLUSIONS: These findings confirm that hrLIF stimulates mouse embryo development in vitro and that different mouse strains show distinct responses to the cytokine. In addition, mrLIF enhances blastocyst formation and decreases embryo fragmentation when added to the embryo culture as early as the two-cell stage.

Animals↗
PubMed2003

PI 3-kinase-Akt-p70 S6 kinase in hypertrophic responses to leukemia inhibitory factor in cardiac myocytes.

Leukemia inhibitory factor (LIF) is a member of interleukin-6 related cytokines, which induces cardiac hypertrophy through glycoprotein (gp) 130. In this study, the role of phosphatidylinositol (PI) 3-kinase, Akt/protein kinase B (Akt/PKB), and p70 S6 kinase activation in LIF-induced hypertrophic responses such as stimulation of protein synthesis, atrial natriuretic peptide (ANP) gene expression, and reorganization of actin filaments into sarcomeric units was investigated in cultured cardiac myocytes. Treatment of cells with LIF resulted in sequential activation of PI 3-kinase, Akt/PKB, and p70 S6 kinase. Using inhibitors for PI 3-kinase and p70 S6 kinase activation, and adenovirus-mediated expression of dominant negative mutants of PI 3-kinase and Akt/PKB, we showed that PI 3-kinase activation was essential for stimulation of protein synthesis, ANP gene expression, and sarcomeric reorganization induced by LIF, while Akt/PKB activation was indispensable for ANP expression and stimulation of protein synthesis, but not for sarcomeric reorganization. Activation of p70 S6 kinase was necessary for stimulation of protein synthesis, but not for ANP gene expression or sarcomeric reorganization. These results indicated the essential role of PI 3-kinase-Akt/PKB-p70 S6 kinase pathway in the LIF-induced hypertrophic responses in cardiac myocytes.

Blotting, Northern↗
PubMed1993

Reconstitution of the response to leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in hepatoma cells.

Ciliary neurotrophic factor (CNTF) has been described as a neuro-active cytokine that shares functional similarities with the leukemia inhibitory factor (LIF). We demonstrate here that, like LIF, CNTF stimulates expression of acute phase plasma proteins in rat H-35 hepatoma cells. Transfection of the LIF receptor into Hep3B hepatoma cells reconstituted LIF and oncostatin M regulation of acute phase plasma protein genes. Co-expression of the LIF receptor and the CNTF receptor, but not expression of either subunit alone, generated CNTF responsiveness in Hep3B cells, suggesting cooperativity of these receptor subunits. Evidence is presented for direct interaction of the LIF receptor with the intracellular signal transduction machinery.

Acute-Phase Proteins↗