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Results for “Leukemia Inhibitory Factor”

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At least 19 recordsLinked to original sources

PubMed2000

Leukemia inhibitory factor, leukemia inhibitory factor receptor, and glycoprotein 130 in rhesus monkey uterus during menstrual cycle and early pregnancy.

This goal of this study was to examine immunohistochemical distribution of leukemia inhibitory factor (LIF), LIF receptor (LIFR), and glycoprotein (gp) 130 in rhesus monkey uterus during the menstrual cycle and early pregnancy. Pregnancy rate was significantly reduced in the control group from 66.7% (12 of 18) to 22.2% (4 of 18) with an injection of goat anti-human recombinant LIF immunoglobulin G into the uterine lumen on Day 8 of pregnancy. LIF was mainly localized in glandular and luminal epithelium. LIF immunostaining during the luteal phase was stronger than it was during the proliferative phase. LIF staining gradually increased from Day 3 of pregnancy and reached its highest level on Day 9. LIFR was mainly localized in the glandular and luminal epithelium. LIFR staining during the luteal phase was stronger than it was during the proliferative phase. LIFR staining began to increase from Day 3 of pregnancy and reached a high level on Days 9 and 11. Gp130, a signal-transducing receptor component of LIF, was mainly localized in the glandular epithelium. A high level of gp130 was found on Days 16 and 20 of menstrual cycle, and from Days 5 to 11 of pregnancy. These results suggest that LIF may play an important role in monkey implantation, as it does in mice.

Animals↗

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↗

PubMed1999

Muscle protection following motor nerve repair in combination with leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) has been shown to stimulate growth of muscle and nerve cells. In this rat study, in which the nerve to the medial head of the gastrocnemius was divided and repaired and slow-release LIF was administered at the repair site, we evaluated recovery by measuring the force of muscle contraction and of muscle bulk. Thirty-five male Sprague-Dawley rats (325-375 g) were randomly divided into 5 different groups according to type of treatment: denervated, end-to-end nerve repair, end-to-end nerve repair with LIF, neurotization, and neurotization with LIF. The contralateral side served as a nonoperated control group. Leukemia inhibitory factor was administered for 28 days to the site of the nerve repair via an implanted osmotic infusion pump. Muscle mass and muscular function were evaluated at 6 weeks using electrophysiologic techniques. The medial gastrocnemius muscle mass of the repair + LIF group was greater than the repair-alone group. The peak twitch, relative twitch, relative tetanic, and tetanic forces generated from the repair + LIF group were also significantly higher than those in the repair-alone group. Although neurotization was almost as effective as end-to-end nerve repair for reinnervating muscle, LIF had no increased effect on neurotization. These data suggest that LIF protects muscular function and reduces denervation atrophy following end-to-end nerve repair.

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↗

PubMed2003

The unsolved enigmas of leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a polyfunctional glycoprotein cytokine whose inducible production can occur in many, perhaps all, tissues. LIF acts on responding cells by binding to a heterodimeric membrane receptor composed of a low-affinity LIF-specific receptor and the gp130 receptor chain also used as the receptor for interleukin-6, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. LIF is essential for blastocyst implantation and the normal development of hippocampal and olfactory receptor neurons. LIF is used extensively in experimental biology because of its key ability to induce embryonic stem cells to retain their totipotentiality. LIF has a wide array of actions, including acting as a stimulus for platelet formation, proliferation of some hematopoietic cells, bone formation, adipocyte lipid transport, adrenocorticotropic hormone production, neuronal survival and formation, muscle satellite cell proliferation, and acute phase production by hepatocytes. Unwanted actions of LIF can be minimized by circulating soluble LIF receptors and by intracellular suppression by suppressors of cytokine-signaling family members. However, the outstanding problems remain of how the induction of LIF is mediated in response to demands from such a heterogeneity of target tissues and why it makes design sense to use LIF in the regulation of such a diverse and unrelated series of biological processes.

Animals↗

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↗

PubMed2005

Retinoic acid-induced neural differentiation of P19 embryonal carcinoma cells is potentiated by leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a cytokine that exhibits proliferation, survival and differentiation in a wide range of cell types. Here we show that LIF potentiates retinoic acid-mediated neural induction in pluripotent P19 embryonal carcinoma cells. This activity of LIF was demonstrated by a profounded neural morphology followed by increased expression of neural-specific proteins (N-CAM, III beta-tubulin, and GAP-43), up-regulation of early neural lineage-specific gene Mash-1, and down-regulation of early endoderm-specific genes -fetoprotein and GATA-4. Moreover, LIF also slows growth and increases the level of apoptosis in differentiating cells.

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↗

PubMed1998

Analysis of neuronal and glial phenotypes in brains of mice deficient in leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) can regulate the survival and differentiation of certain neurons and glial cells in culture. To determine the role of this cytokine in the central nervous system in vivo, we examined the brains of young and adult mice in which the LIF gene was disrupted. Immunohistochemical staining of neurons for choline acetyltransferase, tyrosine hydroxylase, serotonin, parvalbumin, calbindin, neuropeptide Y, vasoactive intestinal polypeptide, and calcitonin gene-related peptide revealed no significant differences between null mutant and wild-type (WT) brains. In contrast, analysis of glial phenotypes demonstrated striking deficits in the LIF-knockout brain. Staining with several anti-glial fibrillary acidic protein (GFAP) antibodies showed that the number of GFAP-positive cells in various regions of the hippocampus in the female mutant is much lower than in the WT. The null male hippocampus also displays a significant, though less marked deficit. The number of astrocytes in the mutant hippocampus, as determined by S-100 staining, is not, however, significantly different from WT. In addition, quantification of immunohistochemical staining of female, but not male, mutants reveals a significant deficit in myelin basic protein content in three brain regions, suggesting alterations in oligodendrocytes as well. Thus, while overall brain histology appears normal, the absence of LIF in vivo leads to specific, sexually dimorphic alterations in glial phenotype.

Animals↗

PubMed1999

Inhibitory roles for SHP-1 and SOCS-3 following pituitary proopiomelanocortin induction by leukemia inhibitory factor.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that stimulates the hypothalamo-pituitary-adrenal (HPA) axis through JAK-STAT activation. We show here that LIF-induced JAK2 and STAT3 tyrosine phosphorylation is transient, disappearing within 20 and 40 minutes, respectively. LIF activates the SH2 domain-containing tyrosine phosphatase, SHP-1, with maximal stimulation observed at 30 minutes. SHP-1 is constitutively associated with JAK2, and LIF induces recruitment of phosphorylated STAT3 to this complex. Overexpression of wild-type or dominant negative forms of SHP-1 shows decreased or increased LIF-induced proopiomelanocortin (POMC) promoter activity, respectively. LIF-induced JAK2 and STAT3 dephosphorylation is delayed until after 60 minutes in cells that overexpress the mutant SHP-1. In addition, SOCS-3, a negative regulator of LIF signaling, binds to JAK2 after 60 minutes of LIF stimulation, after which the complex is degraded by the proteasome. SOCS-3 overexpression blocks LIF-induced JAK2 tyrosine phosphorylation, confirming a role for SOCS-3 in deactivating JAK2 by direct association. Using SOCS-3 fusion proteins, we also define regions of the SOCS-3 protein that are critical for inhibition of LIF-induced POMC promoter activity. Corticotrophic signaling by LIF is thus subject to 2 forms of negative autoregulation: dephosphorylation of JAK2 and STAT3 by the SHP-1 tyrosine phosphatase, and SOCS-3-dependent inactivation of JAK2.

Animals↗

PubMed1996

Regulation of oligodendrocyte cell survival and differentiation by ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, and interleukin-6.

The regulation and maintenance of developmental lineages by trophic factors, both cell-mediated and soluble, is a key aspect of cellular differentiation in the nervous system. In this review we focus on oligodendrocytes and their progenitors and how differentiation and survival are regulated by four neuropoietic cytokines: ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, and interleukin-6 (IL-6). We discuss how these cytokines act as "broad spectrum" factors. That is, how, even within a specific cell lineage, a given cytokine may have different effects on the target cells at various stages of differentiation.

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↗

PubMed1997

An antagonist for the leukemia inhibitory factor receptor inhibits leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M.

The leukemia inhibitory factor receptor (LIF-R) is activated not only by LIF, but also by cardiotrophin-1, ciliary neurotrophic factor with its receptor, and oncostatin M (OSM). Each of these cytokines induces the hetero-oligomerization of LIF-R with gp130, a signal-transducing subunit shared with interleukin-6 and interleukin-11. The introduction of mutations into human LIF that reduced the affinity for gp130 while retaining affinity for LIF-R has generated antagonists for LIF. In the current study, a LIF antagonist that was free of detectable agonistic activity was tested for antagonism against the family of LIF-R ligands. On cells that express LIF-R and gp130, all LIF-R ligands were antagonized. On cells that also express OSM receptor, OSM was not antagonized, demonstrating that the antagonist is specific for LIF-R. Ligand-triggered tyrosine phosphorylation of both LIF-R and gp130 was blocked by the antagonist. The antagonist is therefore likely to work by preventing receptor oligomerization.

Cell Division↗

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↗

PubMed2001

Expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR alpha, LIFR beta, IL-6R alpha, and gp130) in human peripheral neuropathies.

The mRNA levels of neuropoietic cytokines, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6), and their receptor components (CNTFR alpha, LIFR beta, IL-6R alpha, and gp130) were examined in seventy-six patients with various peripheral neuropathies to determine the extent of expression of these cytokines and receptors, and their relationship to nerve fiber pathology and cell infiltration in the diseased nerves. The CNTF mRNA levels were significantly decreased in the diseased nerves and were correlated to residual myelinated fiber population. In contrast, the mRNA levels of LIF, IL-6 and the ligand-binding receptor components (CNTFR alpha, LIFR beta and IL-6R alpha) were elevated to variable extent in the diseased nerves. The CNTFR alpha, LIFR beta, and IL-6R alpha mRNA levels showed a weak positive correlation with the extent of demyelinating pathology and their levels were related to each other. Moreover, the CNTF and LIF mRNA levels were inversely proportional to the extent of macrophage invasion, whereas the CNTFR alpha and IL-6R alpha mRNA expressions were correlated to the increase in macrophage infiltration. The neuropoietic cytokine family and its receptor expressions in the diseased human nerves are regulated by an underlying pathology-related process rather than type of diseases, and could play a role in peripheral nerve regeneration and repair.

Adult↗