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At least 19 recordsLinked to original sources
PubMed1989

The pleiotropic actions of leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a glycoprotein regulator that induces the differentiation and suppresses the clonogenicity of M1 myeloid leukemic cells. M1 cells require only a brief exposure to LIF to become irreversibly committed to differentiation. In combination with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, LIF is also able to suppress HL-60 and U937 cell proliferation. Normal monocytes and macrophages have LIF receptors, but the function of LIF on such cells is unclear. Recently it was discovered that LIF also acts on embryonic stem (ES) cells, where its continuous presence is required to prevent ES cell differentiation.

Animals↗
PubMed1993

Pathology induced by leukemia inhibitory factor.

Leukemia inhibitory factor is a glycoprotein growth and differentiation factor with pleiotropic activity. LIF has potent effects on the hematopoietic system, including megakaryocyte progenitor cells. In addition, LIF has bone regeneration activity, induces cachexia and acute-phase response in hepatocytes, and inhibits adipogenesis, to mention the more important activities. In vivo LIF treatment in monkeys and rodents was followed by signs of general toxicity, cachexia, acute-phase reaction, and stimulation of hematopoiesis. The safety margin for possible therapeutic effects on hematopoiesis seems to be very narrow.

Acute-Phase Reaction↗
PubMed1992

The modulatory hematopoietic activities of leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a multi-potential cytokine which has been implicated in the hematopoietic regulatory machinery. For example, we have found that LIF is constitutively expressed in marrow stroma. Other investigators have reported that LIF affects remodeling of bone, and that, in concert with other growth factors, it stimulates hematopoietic stem cell proliferation. Moreover, in vivo animal trials reveal that, at high doses, administration of LIF induces myelosclerosis whereas, at lower doses, megakaryocytosis and thrombocytosis with reduced bone marrow cellularity and marrow lymphopenia are observed. Therefore, the role of LIF in the pathogenesis of myeloproliferative disorders such as myelofibrosis and sclerosis merits investigation. Further, its megakaryocytic stimulatory properties suggest that LIF may be exploitable in the clinic to enhance platelet production.

Animals↗
PubMed1993

Crystallization and preliminary X-ray analysis of leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a polyfunctional molecule with significant and diverse biological activities. LIF is a glycoprotein secreted by a number of different cell types in vitro. It is induced in fibroblasts, lymphocytes, monocytes and astrocytes by various inducers such as serum, TNF, interleukin-IP and EGF. Due to extensive and variable glycosylation the molecular weight can range from 38 to 67 kDA. The biological functions of LIF are mediated through a receptor and a signal transducer, gp130, which is also used by factors like interleukin-6 (IL-6), cilliary neurotropic factor (CNTF), and oncostatin M (OSM). Here, we report the crystallization of the non-glycosylated human-like LIF expressed in E. coli. The present crystals diffract to 2.0 A using synchrotron radiation. They belong to the monoclinic space group C2, and the cell dimensions are a = 61.5 A, b = 45.3 A, c = 77.7 A and beta = 112.3 degrees.

Cloning, Molecular↗
PubMed1992

Inhibited gastrulation in mouse embryos overexpressing the leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a cytokine active in vitro on different target cells. It is detected in vivo during mouse gestation in both extraembryonic membranes and maternal tissues. Two isoforms have been described maintaining embryonic stem cells in culture in a pluripotent state. However, overexpression of their cDNAs in chimeric mouse embryos observed between 6.5 and 9.5 days postcoitus gave strikingly different phenotypes. Embryos overexpressing the diffusible form of LIF cDNA looked essentially normal. Chimerae expressing LIF associated with the extracellular matrix cDNA showed an abnormal proliferation of tissues and the absence of differentiated mesoderm. They have not undertaken the normal pathway of gastrulation.

Animals↗
PubMedDate not supplied

In vitro myoblast to myotube transformations in the presence of leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine which exerts a variety of effects on many cell types including neuronal cells, and is a potent mitogen for myoblasts. At concentrations of 0.1-0.3 ng/ml, the peptide stimulates a maximal increase in cell number. LIF initiates a prolonged proliferative response lasting up to 13 days, when myoblasts are exposed to it in culture. LIF expression can be detected in vivo during development of limb muscle and in adult regenerating skeletal muscle tissue. Here, we studied the levels of expression of alpha-bungarotoxin-binding sites as a measure of acetylcholine receptors (AChRs), myosin light chain pattern and rate of myotube formation in fused, control and LIF-treated muscle cultures derived from mouse hind-limb muscles. We found that both the level of expression of AChRs and myosin light chain pattern, are normal, following exposure of the cells to LIF. There was no difference in the rate of myotube formation between LIF-stimulated and control myoblasts over a 10-fold concentration range (0.3-3.0 ng/ml) as determined by nuclei counts. Taken together, these results suggest that LIF, in combination with other cytokines, may act in vivo to stimulate rapid growth, without significant differentiation, during the early phases of myogenesis.

Animals↗
PubMed1993

Combined action of stem cell factor, leukemia inhibitory factor, and cAMP on in vitro proliferation of mouse primordial germ cells.

In the present paper we investigated the effects of stem cell factor/mastocyte growth factor (SCF/MGF), leukemia inhibitory factor/differentiating inhibitory activity (LIF/DIA) (two growth factors known to affect primordial germ cell growth in vitro) and forskolin (FRSK) (an activator of adenylate cyclase in many cell types) alone or in combination on the survival and proliferation of primordial germ cells (PGCs) obtained from 8.5, 10.5, and 11.5 days post coitum (dpc) mouse embryos and cultured without pre-formed cell feeder layers. The results showed that both at 1 and 3 days of culture the addition of 100 ng/ml SCF, 20 microM FRSK, or in some instances 20 ng/ml LIF alone caused a significant increase of PGC number as compared with controls. The highest effects were obtained when SCF and/or LIF were used together with FRSK. Moreover, we found that FRSK elevated cAMP levels in purified 11.5 dpc PGCs and that this compound, but not SCF and LIF, stimulated PGC proliferation, as assessed by 5-bromo-2'-deoxyuridin (BrdU) incorporation. These results suggest a mechanism of combined action of cAMP with SCF and/or LIF in the control of proliferation of mouse PGCs in vitro.

Animals↗
PubMed1991

Recombinant cholinergic differentiation factor (leukemia inhibitory factor) regulates sympathetic neuron phenotype by alterations in the size and amounts of neuropeptide mRNAs.

The cholinergic differentiation factor (CDF) in heart cells is identical to leukemia inhibitory factor (LIF). Recombinant CDF/LIF was shown to alter dramatically neurotransmitter production as well as the levels of several neuropeptides in cultured rat sympathetic neurons. Here it is shown that these changes are likely to be caused by alterations in the mRNA for these proteins and peptides. Growth in 1 nM recombinant CDF/LIF induces mRNA for acetyl CoA: choline-O-acetyltransferase [EC 2.3.1.6; choline acetyltransferase (ChAT)], somatostatin (SOM), substance P, and vasoactive intestinal polypeptide while lowering mRNA levels of tyrosine hydroxylase (EC 1.14.16.2) and neuropeptide Y (NPY). In addition, the sizes of the mRNAs for ChAT, SOM, and NPY are larger after recombinant CDF/LIF treatment.

Animals↗
PubMed1989

Human differentiation-stimulating factor (leukemia inhibitory factor, human interleukin DA) gene maps distal to the Ewing sarcoma breakpoint on 22q.

The human gene encoding differentiation-stimulating factor (D-factor) has previously been isolated and shown to be identical to leukemia inhibitory factor (LIF). We have determined a fine structure map of approximately 20-kb surrounding the D-factor/LIF gene. Southern blot analysis using a somatic cell hybrid panel shows that the gene maps to chromosome 22. D-factor/LIF was further sublocalized to 22q11.2----q13.1, distal to a Ewing sarcoma (ES) breakpoint, using a second somatic cell hybrid panel. Probes to the 5' and 3' regions of the locus and the cDNA were used to screen for restriction fragment length polymorphisms, but none were detected. Analysis by pulsed field gel electrophoresis suggests that D-factor/LIF is not near the ES breakpoint.

Animals↗
PubMed1992

Inhibition of differentiation in a murine F9 embryonal carcinoma cell subline by leukemia inhibitory factor (LIF).

Leukemia inhibitory factor (LIF) is a cytokine previously shown to maintain pluripotent embryonic stem cells in their undifferentiated state. We have examined the effects of LIF in nullipotent embryonal carcinoma cell lines, and have found that LIF blocks differentiation induced by retinoic acid and at low temperature in OTF9 cells. LIF did not block differentiation in a parent F9 cell line. For OTF9 cells, LIF acts early in differentiation, inhibiting the appearance of parietal endoderm-type product cells. However, it acts subsequent to retinoic acid, and at least one early retinoic acid-induced event is unaltered in the presence of LIF. This finding provides both a means of dissecting the cascade of events leading to EC cell differentiation, and a well-characterised target cell type for studying the mechanism of action of LIF.

Animals↗
PubMed1994

Coordinate regulation of choline acetyltransferase, tyrosine hydroxylase, and neuropeptide mRNAs by ciliary neurotrophic factor and leukemia inhibitory factor in cultured sympathetic neurons.

The neurotransmitter phenotype switch that occurs in cultures of rat superior cervical ganglion neurons after treatment with leukemia inhibitory factor or ciliary neurotrophic factor is a useful model permitting investigation of the mechanisms of cytokine-mediated differentiation. Recently the actions of leukemia inhibitory factor and ciliary neurotrophic factor have been linked through their interactions with related receptor complexes. Here we compare the effects of these two cytokines on gene expression in sympathetic neuronal cultures and begin to investigate their mechanisms. We report that, as has been shown for leukemia inhibitory factor, ciliary neurotrophic factor regulates peptides and classical transmitters in these cultures at the mRNA level. In addition, we find that the induction of substance P mRNA by these cytokines is rapid, dependent on protein synthesis, and occurs in 40-50% of superior cervical ganglion neurons in dissociated culture.

Animals↗
PubMed1991

The leukemia inhibitory factor (LIF).

Leukemia inhibitory factor (LIF) is a glycoprotein able to enforce differentiation and/or suppress clonogenic self-renewal in a number of myeloid leukemic cell lines. When acting on normal embryonic stem cells, it has the opposite action of preventing differentiation commitment. LIF is not a proliferative factor when acting alone on normal hemopoietic cells, but can potentiate the action of interleukin 3 on blast cell and megakaryocyte precursors. When injected in vivo, LIF stimulates rises in megakaryocyte numbers and platelet levels. LIF also exhibits striking functional effects on a wide range of other cells including hepatic parenchymal cells, neurones, adipocytes, osteoblasts and gonadal cells. The polyfunctionality of LIF suggests strongly that it is normally intended to be produced locally and act as a local regulator. Despite its wide range of actions, LIF remains a promising candidate for clinical use in thrombocytopenia and myeloid leukemia.

Animals↗
PubMed1993

The cholinergic stimulating effects of ciliary neurotrophic factor and leukemia inhibitory factor are mediated by protein kinase C.

The intracellular mechanisms through which two trophic factors, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), regulate cholinergic development were examined in sympathetic neuron cultures. Treatment with CNTF or LIF increased levels of choline acetyltransferase (ChAT) activity by 375 and 350%, respectively. However, in neuronal cultures depleted of protein kinase C (PKC) activity by chronic phorbol ester treatment, neither CNTF nor LIF elevated ChAT activity. Further, the stimulation of ChAT due to increased cell density was not observed in PKC-depleted sympathetic neurons. The inhibition of CNTF-stimulated ChAT by phorbol ester occurred in a dose-dependent manner and chronic phorbol ester treatments did not alter the levels of the catecholamine biosynthetic enzyme tyrosine hydroxylase. Moreover, increased levels of diacylglycerol, an endogenous activator of PKC, were observed in sympathetic neurons treated with CNTF. However, neither CNTF nor LIF stimulated the hydrolysis of phosphatidylinositol 4,5-bisphosphate. These observations suggest that a common PKC-dependent pathway, which is independent of phosphatidylinositol 4,5-bisphosphate hydrolysis, mediates the cholinergic stimulating effects of CNTF, LIF, and cell-cell contact in cultured sympathetic neurons.

Animals↗
PubMed1995

C/EBP-related sites in addition to a STAT site are necessary for ciliary neurotrophic factor-leukemia inhibitory factor-dependent transcriptional activation by the vasoactive intestinal peptide cytokine response element.

The neuropoietic cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) regulate VIP gene expression through a cytokine response element (CyRE) which interacts with members of the STAT transcription factor family. The CyRE STAT site is, however, insufficient to mediate full transcriptional activation by CNTF/LIF, suggesting that other sequences and nuclear proteins are also important. As C/EBP proteins participate in the transcriptional effects of the related cytokine, interleukin-6, we investigated the role of possible C/EBP-binding sites in the response of the VIP CyRE to CNTF/LIF. Using DNase I footprinting, transactivation studies, DNA mobility shift assays, and mutational analysis, three sites within the VIP CyRE were identified as C/EBP-related binding sites and shown to be important to CNTF/LIF-mediated transcriptional activation. The CyRE C/EBP-related sites interact with nuclear proteins from the human neuroblastoma cell line, NBFL, including a novel, protein synthesis-dependent, nuclear protein complex, induced by CNTF treatment. These nuclear proteins are not, however, recognized by antisera to known C/EBP proteins. Therefore, other nuclear proteins regulated by independent pathways act in concert with the JAK-STAT pathway to mediate CNTF/LIF regulation of VIP gene expression through the CyRE.

Base Sequence↗
PubMed1993

Effects of the recombinant hematopoietic growth factors interleukin-3, interleukin-6, stem cell factor, and leukemia inhibitory factor on the megakaryocytic differentiation of CD34+ cells.

Using a liquid culture system and human CD34+ marrow cells, we examined the effects of recombinant interleukin (IL)-3, IL-6, stem cell factor (SCF), and leukemia inhibitory factor (LIF) on megakaryocyte (MK) growth, endoreplication, and maturation. MK proliferation, ploidy distribution, and volume were studied by flow cytometry. IL-3 was the only cytokine that, alone, induced a marked increase in MK proliferation. At a high CD34+ cell concentration, addition of IL-6, SCF, and LIF to IL-3--containing medium increased the number of MK (approximately 20%). At a low CD34+ cell concentration, IL-3 alone was a less potent inducer of MK growth, but IL-6, SCF, and their combination had a marked effect, increasing the number of MK by a factor 1.7, 2.9, and 4.4, respectively. These differences may be related to the endogenous release of cytokines in the culture. The effects of these cytokines were subsequently tested on a more mature type of MK progenitor (CD34+ cells isolated after 6 days of incubation in liquid culture). IL-3 remained the most potent cytokine, but IL-6 or SCF alone also increased MK number in comparison to unstimulated cultures. The ploidy distribution of MKs grown with IL-3 was not markedly changed by the addition of the other cytokines, with the exception of SCF, which induced a significant increase in the mean ploidy. However, in all cultures, glycoprotein (GP)IIIa+ 2N and 4N cells were present in large but variable numbers (35% to 75%). The number of these low-ploidy MKs directly correlated with MK proliferation. Therefore, we subsequently explored the absolute number of polyploid MK produced in culture. SCF, IL-6, or their combination, in association with IL-3, increased the number of polyploid MK up to fourfold. In addition, they improved the maturation of MK grown in the presence of IL-3, leading to the synthesis of demarcation membranes and platelet shedding. A similar effect of growth factors on the maturation of day 6 CD34+ cells was observed. We conclude that IL-6 and SCF have a broad range of activities on megakaryocytopoiesis, acting both on the early and late stages. However, the proliferative properties of these cytokines largely predominate in our cultures. Therefore, in the absence of a specific MK regulator, this study further extends the need for a combination of growth factors to maximize megakaryocytopoiesis.

Adult↗
PubMed1993

Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis).

Proliferating primordial germ cells (PGCs) isolated from mouse embryos soon after their arrival in the genital ridges would only survive in vitro at temperature of less than 30 degrees C (De Felici, M. and McLaren, A. (1983). Exp. Cell. Res. 144, 417-427; Wabik-Sliz, B. and McLaren, A. (1984). Exp. Cell. Res. 154, 530-536) or when co-cultured on cell feeder layers (Donovan, P. J., Stott, D., Godin, I., Heasman, J. and Wylie, C. C. (1986). Cell 44, 831-838; De Felici, M. and Dolci, S. (1991). Dev. Biol. 147, 281-284). In the present paper we report that mouse PGC death in vitro occurs with all the hallmarks of programmed cell death or apoptosis. We found that after 4-5 hours in culture many PGCs isolated from 12.5 dpc fetal gonads assumed a nuclear morphology and produced membrane bound fragments (apoptotic bodies) typical of apoptotic cells. In addition, PGCs in culture accumulated high level of tissue transglutaminase (tTGase; an enzyme that is induced and activated during apoptosis) and showed extensive degradation of DNA to oligonucleosomal fragments, which is characteristic of apoptosis. The physiological relevance of this mechanism of PGC death is supported by the finding that some PGCs undergoing apoptosis, as revealed by the high level of tTGase expression, were detected in the embryo. Most importantly, we show that the addition of stem cell factor (SCF) or leukemia inhibitory factor (LIF) to the culture medium, two cytokines known to favour PGC survival and/or proliferation in vitro, markedly reduced the occurrence of apoptosis in PGCs during the first hours in culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Molecular basis of the soluble and membrane-bound forms of the murine leukemia inhibitory factor receptor alpha-chain. Expression in normal, gestating, and leukemia inhibitory factor nullizygous mice.

The murine leukemia inhibitory factor receptor alpha-chain (mLIFR) exists in a membrane-bound and a soluble form. The two major classes of mRNA transcript correspond to either the soluble or membrane-bound form of the mLIFR. In this study we have identified a complex and heterogeneous pattern of expression of mRNA transcripts for this receptor in normal mouse tissues and cell lines. In order to understand the molecular basis of these transcripts, genomic clones encompassing the region of divergence from the soluble to the membrane-bound form of the receptor were isolated. cDNAs encoding the membrane-bound form of the mLIFR were generated by an alternative splicing event where an exon that is specific to the soluble mLIFR was skipped. The membrane-bound form of the mLIFR was heterogeneously polyadenylated with at least five different sites of polyadenylation. The mRNA transcript encoding the soluble form of the mLIFR contained a region highly homologous to a murine B2 repetitive element, thus providing a possible explanation for the genesis of this transcript. The different forms of the mLIFR were analyzed in a wide range of mouse tissues in pseudopregnant mice and in mice at various stages of pregnancy. Only liver, placenta, and uterus showed an increase in the levels of mLIFR mRNA expression during pregnancy, indicating an important role for the LIFR in this process. However, somewhat surprisingly, there was no detectable difference in mLIFR mRNA levels or levels of soluble protein in leukemia inhibitory factor nullizygous mice when compared with normal mice.

Animals↗
PubMed1996

Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists.

Ciliary neurotrophic factor (CNTF) drives the sequential assembly of a receptor complex containing the ligand-specific alpha-receptor subunit (CNTFR alpha) and the signal transducers gp130 and leukemia inhibitory factor receptor-beta (LIFR). The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR. The functional importance of these residues was assessed by alanine mutagenesis. Substitution of either F152 or K155 with alanine was found to specifically inhibit cytokine interaction with LIFR without affecting binding to CNTFR alpha or gp130. The resulting variants behaved as partial agonists with varying degrees of residual bioactivity in different cell-based assays. Simultaneous alanine substitution of both F152 and K155 totally abolished biological activity. Combining these mutations with amino acid substitutions in the D-helix, which enhance binding affinity for the CNTFR alpha, gave rise to a potent competitive CNTF receptor antagonist. This protein constitutes a new tool for studies of CNTF function in normal physiology and disease.

Amino Acid Sequence↗