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PubMed1996

Macrophage-derived tumor necrosis factor and tumor-derived of leukemia inhibitory factor and interleukin-6: possible cellular mechanisms of cancer cachexia.

BACKGROUND: The cellular basis for augmented cytokine production in the tumor-bearing host is not known. Recently leukemia inhibitory factor (LIF) and interleukin (IL)-6, produced by a variety of tumors, have been implicated as mediators of cachexia. METHODS: Five murine tumor cell lines were tested for the production of these cytokines. 4JK tumor was further tested to determine if IL-1, tumor necrosis factor (TNF), or cocultivation with RAW 264 cells augmented IL-6 or LIF production. RESULTS: 4JK from in vivo tumors produced significantly more IL-6 than did 4JK from culture, indicating that tumor production of IL-6 and LIF is potentially augmented by infiltrating macrophages. When 4JK was cocultured with RAW 264 cells, TNF, or IL-1 in vitro, a three- to 15-fold increase in tumor production of LIF and IL-6 was noted (p2 < or = 0.03). Conversely, in coculture experiments performed with a neutralizing TNF antibody, a 50% reduction in tumor production of LIF ad IL-6 was noted (p2 < 0.04). Resting RAW cells produced only minimal quantities of TNF; however, when RAW cells were exposed to tumor-conditioned supernatant from 4JK, their TNF production was markedly increased. CONCLUSIONS: In the tumor microenvironment, host macrophages may be activated and produce inflammatory cytokines such as TNF. Local TNF then appears to act on tumor cells to stimulate production of IL-6 and LIF. Enhanced tumor production of cytokine mediators may contribute to deleterious effects of neoplastic growth on the host.

Animals↗

PubMed2001

Evaluation of leukemia inhibitory factor as a marker of ectopic pregnancy.

OBJECTIVE: Our purpose was to determine the utility of measuring serum leukemia inhibitory factor, a cytokine expressed in the process of pregnancy implantation, for the diagnosis of ectopic pregnancy. STUDY DESIGN: Serum samples from 40 patients with positive serum quantitative beta-human chorionic gonadotropin levels were used for leukemia inhibitory factor determination. The serum leukemia inhibitory factor concentration was determined by enzyme-linked immunosorbent assay in the following 4 groups: (1) normal intrauterine pregnancies, (2) threatened abortions, (3) spontaneous abortions, and (4) ectopic pregnancies. RESULTS: All patients had detectable concentrations of leukemia inhibitory factor in serum, ranging from 2.44 to 8.25 pg/mL. Mean leukemia inhibitory factor concentrations for ectopic pregnancy were significantly lower (P <.05) than those of both the spontaneous abortion and threatened abortion groups by 1-way analysis of variance. When a cutoff point of serum leukemia inhibitory factor <6.2 pg/mL is assigned as diagnostic of ectopic pregnancy, leukemia inhibitory factor in patients with ectopic pregnancies versus all other groups predicted ectopic pregnancy with a sensitivity of 73%, specificity of 72%, positive predictive value of 50%, and negative predictive value of 88%. CONCLUSION: Serum leukemia inhibitory factor concentration is lowest in patients with ectopic pregnancy. A cutoff point of 6.2 pg/mL maximizes the sensitivity and specificity of the test; however, it is not sufficiently discriminatory to be used clinically for the diagnosis of ectopic pregnancy.

Abortion, Spontaneous↗

PubMed2004

Leukemia inhibitory factor (LIF) and its biological activity.

Leukemia inhibitory factor (LIF) is a pleiotropic glycoprotein belonging to the IL-6 family of cytokines. It shows a wide range of biologic activities that include the growth promotion and cell differentiation of different types of target cells, influence on bone metabolism, cachexia, neural development, embryogenesis and inflammation. LIF has potent proinflammatory property, being the inducer of the acute phase protein synthesis and affecting the cell recruitment into the area of damage or inflammation. LIF is also one of the cytokines that are capable to regulate the differentiation of embryonic stem cells, hematopoietic and neuronal cells. Due to its polyfunctional activities, LIF is involved in the pathogenic events and development of many diseases of various origin.

Animals↗

PubMed2002

ATP induces leukemia inhibitory factor mRNA in cultured rat astrocytes.

Leukemia inhibitory factor (LIF) is a cytokine involved in the survival and differentiation of the neural cells in the central and peripheral nervous systems. In the present study, we examined the effects of various neurotransmitter receptor agonists on LIF mRNA expression in cultured rat astrocytes, microglia and neurons to elucidate the cell types producing LIF and to clarify the neurotransmitter(s) regulating the mRNA expression. The results demonstrated that the expression of LIF mRNA was intensely induced by ATP in the cultured astrocytes. Experiments using ATP, UTP and related compounds showed the involvement of P2Y2 and P2Y4 purinoceptors in the expression induced by ATP.

Adenosine Diphosphate↗

PubMed2004

Leukemia inhibitory factor stimulates vasopressin release in rats.

Leukemia inhibitory factor (LIF) is a cytokine of the interleukin-6 family exhibiting diverse physiological functions during inflammatory stress. It is well known that syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is often associated with inflammatory disease, and cytokines produced at inflammatory foci are thought to stimulate arginine vasopressin (AVP) release. In the present study, we investigated the effects of centrally administered LIF on AVP release in conscious rats. Intracerebroventricular administration of LIF (0.01-1.0 microg/rat) significantly increased the plasma AVP concentration, and its effect was observed from 5 to 60 min after the injection. LIF did not cause significant changes in plasma Na+, total protein and blood pressure. There were no significant changes in the plasma AVP concentration after intravenous injection of LIF (1.0, 3.0 microg/rat). These results indicate that LIF plays a stimulatory role in the regulation of AVP release, and suggest the possibility that LIF may be involved in the pathogenesis of SIADH.

Animals↗

PubMed2002

In vivo gene transfer of leukemia inhibitory factor (LIF) into mouse endometrium.

PURPOSE: Leukemia inhibitory factor (LIF) is important for embryogenesis and implantation. We aimed to transfect LIF gene into the mouse endometrium. MATERIALS AND METHODS: Expression plasmids carried LIF and luciferase genes for transfer. After superovulation, 100 ICR mice were mated with vasectomized mice. Then LIF-liposome (Group 1) and luciferase-liposome complexes (Group 2) were injected into their uterine lumen (Day 0). Endometrial LIF and luciferase expressions were detected by reverse transcription-polymerase chain reaction on Days 0-4 post gene transfer. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control to normalize the gene transfection. RESULTS: LIF mRNA and luciferase activities reached the peak expression on Day 3. In Group 1, the ratios of LIF/GADPH on Days 1-4 were 0.414, 1.096, 1.162, and 0.782. In Group 2. LIF/GADPH on Days 1-4 were 0.24, 0.22, 0.35, and 0.32. CONCLUSIONS: Mouse endometrium could be effectively transfected with liposome-DNA mixtures. Endometrial LIF transfer via liposome may be effective in human.

Animals↗

PubMed2004

Leukocyte subpopulations in the uteri of leukemia inhibitory factor knockout mice during early pregnancy.

Leukemia inhibitory factor (LIF) is transiently expressed on Day (D) 1 of pregnancy by the uterine epithelium and on D4 specifically by the glandular epithelium. The Lif knockout female mice are infertile because of uterine defects that affect embryo implantation, but pregnancy can be rescued in these mice by injections of LIF on D4 of pregnancy. Many of the specific actions of LIF in the uterus are unknown, especially with regard to uterine cell biology. Leukocytes, such as macrophages, natural killer (NK) cells, and eosinophils, are present in the pregnant uterus and are thought to be beneficial, because alterations in their proportions can adversely affect pregnancy. Immunocytochemistry and cell counting were used to compare the distributions and dynamics of leukocyte subpopulations in wild-type and Lif knockout mice. The percentage of macrophages was reduced by more than half in the Lif knockout mice on D3 of pregnancy, and their distribution was disrupted, suggesting that LIF is a chemokine for these cells. The NK cells were detected as early as D3 of pregnancy, but the Lif knockout mice had double the percentage of NK cells compared to wild-type mice at this time, indicating that LIF restricts the migration of NK cells to the uterus. The Lif knockout mice also had significantly higher percentages of eosinophils in the outer stroma on D3, and in the midstroma on D4, of pregnancy, suggesting that LIF also may restrict eosinophil migration to the uterus. These alterations of the uterine leukocyte subpopulations in Lif knockout mice may disrupt pregnancy and contribute to failure of implantation.

Animals↗

PubMed2005

Effects of leukemia inhibitory factor on 3T3-L1 adipocytes.

Leukemia inhibitory factor (LIF) is a member of the gp130 cytokine family and signals through the receptor complex of gp130 and the LIF receptor (LIFR) to activate the JAK/STAT signaling cascade. Since LIF activates STATs 1 and 3 in adipocytes, we examined the effects of LIF on 3T3-L1 adipocytes. Our studies clearly demonstrate that LIF treatment had minimal effects on adipocyte differentiation as judged by marker gene expression, but did inhibit triacylglyceride (TAG) accumulation during adipogenesis. Acute treatment with LIF resulted in increased expression of suppressors of cytokine signaling-3 (SOCS3) and CCAAT/enhancer-binding protein-delta (C/EBPdelta) mRNA in 3T3-L1 adipocytes. Moreover, the upregulation of C/EBPdelta correlated with binding to three sites in the C/EBPdelta promoter by LIF-activated protein complexes that contained STAT1 and not STAT3. Chronic treatment with LIF resulted in decreased protein levels of sterol regulatory element binding protein-1 (SREBP1) and fatty acid synthase (FAS), but had no effect on the expression of other adipocyte marker proteins or on TAG levels in mature 3T3-L1 adipocytes. LIF had a small effect on insulin-stimulated glucose uptake in 3T3-L1 adipocytes, but did not cause insulin resistance following chronic treatment. These findings indicate that LIF has similar and distinct effects in comparison with the effects of other gp130 cytokines on cultured fat cells. In summary, our results support a role for LIF in the regulation of proteins involved in lipid synthesis and in the modulation of signal transduction pathways in 3T3-L1 adipocytes.

3T3-L1 Cells↗

PubMed1998

Measurement of leukemia inhibitory factor in biological fluids by radioimmunoassay.

Leukemia inhibitory factor (LIF) exhibits multiple biological activities in various tissues, and we have shown that LIF activates POMC gene transcription in response to immune signals. As higher serum levels of LIF have been reported in septicemia, we measured LIF values in biological fluids by RIA. Immunoreactive LIF was detected in 303 of 428 human serum samples. Circulating LIF detection rates were 69% in acute inflammatory diseases, 83% in chronic inflammatory diseases, 61% in noninflammatory diseases, and 90% in cancer patients. Serum concentrations of human LIF was higher in patients with inflammatory disease than in noninflammatory disease (0.80 +/- 0.10 vs. 0.53 +/- 0.02 ng/mL; P < 0.05) or in cancer patients (0.44 +/- 0.06; P < 0.05). Higher serum human LIF levels were found in septicemia (0.78 +/- 0.14 ng/mL), pneumonia (0.80 +/- 0.10 ng/mL), acute bronchitis (0.88 +/- 0.09 ng/mL), other infections (1.01 +/- 0.17 ng/mL), and systemic lupus erythematosus (SLE; 0.79 +/- 0.06 ng/mL). In 7 septicemia patients, Gram-negative infection was associated with higher LIF levels (1.06 +/- 0.16 ng/mL) than was Gram-positive infection (0.58 +/- 0.14 ng/mL). In patients with acute inflammatory disease, serum LIF levels decreased within several days after hospitalization. To test circulating mouse (m) LIF changes in response to inflammatory stress, lipopolysaccharide (LPS) was injected ip to mice. LPS increased serum mLIF values concordantly with ACTH levels. After i.p. injection of 80 microg LPS, serum mLIF increased by 144% (P < 0.05), 173% (P < 0.05), and 134% at 30, 90, and 120 min respectively. In vitro, however, LPS did not increase ACTH and mLIF secretion from dispersed mouse primary pituitary cells. These results suggest that LIF is an important participant in the pathogenesis of the acute inflammatory response. The elevated serum LIF levels observed in inflammation do not appear to originate from the pituitary.

Animals↗

PubMed1991

Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro.

Receptors for murine leukemia inhibitory factor (LIF) were demonstrated on immature and mature murine megakaryocytes. LIF alone had no effects in culture on the survival or proliferation of normal murine megakaryocytes or their precursors. However, combination of LIF with multipotential-colony-stimulating factor (Multi-CSF) (interleukin-3) enhanced the megakaryocyte colony formation able to be stimulated by Multi-CSF; the enhancement involved all types of megakaryocyte colony and resulted in the formation of increased numbers of megakaryocytes. These observations provide a possible basis for the observation that, when LIF is injected in vivo, elevations are observed in megakaryocyte numbers and platelet levels.

Animals↗

PubMed2003

Gene expression of leukemia inhibitory factor (LIF) and macrophage colony stimulating factor (M-CSF) in bovine endometrium during early pregnancy.

Leukemia inhibitory factor (LIF) and macrophage colony stimulating factor (M-CSF), members of the group of hemopoietic cytokines, play a primary role in the control of embryo development and implantation and in the growth of the placenta in humans and mice. Gene expressions of LIF and M-CSF were investigated using quantitative RT-PCR in bovine endometrial tissues during early and mid-pregnancy (Days 16-17, 20-21, 30-36, 48-49 and 74-140) and during the estrous cycle (Days 13-14). Leukemia inhibitory factor and M-CSF genes were expressed in all samples examined. Significant differences were found between the gene expression patterns of LIF and M-CSF. Leukemia inhibitory factor expression level at Days 48-49 was the highest in caruncular endometrium, however, the large variability negated any significant differences. Leukemia inhibitory factor expression levels in intercaruncular endometrium at Days 48-49 and 74-140 of pregnancy were greater than at Days 13-14 of the estrous cycle and at other days of pregnancy. No significant change was recognized in M-CSF expression levels in caruncular endometrium. Macrophage colony stimulating factor expression level in intercaruncular endometrium at Days 74-140 was greater than those of the other samples. These results suggest that LIF and M-CSF are produced in the endometrium and may play different roles in early and mid-pregnancy.

Animals↗

PubMed1997

Molecular cloning of rat leukemia inhibitory factor receptor alpha-chain gene and its expression during pregnancy.

Leukemia inhibitory factor (LIF) is a secreted glycoprotein and a pluripotent growth factor that acts on diverse cell systems. LIF transmits its effects via binding to transmembrane receptors, of which both high- and low-affinity forms have been identified. In this study, we analyzed the structure and expression of rat LIF receptor alpha-chain (rLIFR alpha) cDNA. A full-length clone of the cDNA encoding the membrane-bound form of rLIFR alpha protein was prepared by a combination of LA-PCR and 5' RACE using DNA reverse-transcribed from total RNA isolated from the livers of day-12 and day-14 pregnant rats as templates. The nucleotide sequence of a full-length clone was determined and further confirmed by analysis of shorter DNA fragment prepared by PCR using pfu polymerase. The gene for rLIFR alpha encodes a 1093 amino acid residue protein. The rLIFR alpha protein shows a high degree of similarity to mouse and human LIF receptor alpha-chain protein (89% and 76% amino acid sequence identities, respectively). Only one molecular species of mRNA for the rLIFR alpha gene was detected in the liver and placenta. rLIFR alpha was expressed in liver of both non-pregnant and pregnant rats. The level of mRNA for the rLIFR alpha gene in placenta was maximum on day 16 of pregnancy.

Amino Acid Sequence↗

PubMed1990

The effects of leukemia inhibitory factor (LIF) on the blast stem cells of acute myeloblastic leukemia.

Leukemia inhibitory factor (LIF) was tested using three established acute myelocytic leukemia (AML) cell lines. In growth assays in two of the three lines, we found that the addition of LIF increased the doubling time of the clonogenic population but not the total population as assessed by nucleated cell counts. Similarly, tritiated thymidine uptake into total AML populations was not affected by LIF, but the percentage of clonogenic cells killed by exposure to high specific activity 3HTdR was reduced in LIF-treated cultures compared to controls. We interpret these results to indicate that LIF prolongs the cell cycle of stem cells in some AML lines, possibly by increasing the time spent in the G2-M-G1 parts of the cycle. Consistent with this interpretation, we observed a decrease in ara-C sensitivity in LiF treated cultures. Variable results were obtained when freshly obtained AML blasts were exposed to LIF.

Cell Cycle↗

PubMed1999

Complex conserved organization of the mammalian leukemia inhibitory factor gene: regulated expression of intracellular and extracellular cytokines.

Leukemia inhibitory factor (LIF) is a member of the IL-6 family of pleiotropic cytokines, which are extensively involved in modulating hematopoiesis and immunity. We have undertaken a detailed analysis of LIF genomic organization and gene transcription and investigated the proteins expressed from alternate transcripts. Previously unidentified LIF transcripts, containing alternate first exons spliced onto common second and third exons, were cloned from murine embryonic stem cells, human embryonal carcinoma cells, and primary porcine fibroblasts. Based on sequence homology and position within the genomic sequence, this confirmed the existence of the LIF-M transcript in species other than the mouse and identified a new class of transcript, designated LIF-T. Thus, a complex genomic organization of the LIF gene, conserved among eutherian mammals, results in the expression of three LIF transcripts (LIF-D, LIF-M, and LIF-T) differentially expressed from alternate promoters. The first exon of the LIF-T transcript contained no in-frame AUG, causing translation to initiate downstream of the secretory signal sequence at the first AUG in exon two, producing a truncated LIF protein that was localized within the cell. Enforced secretion of this protein demonstrated that it could act as a LIF receptor agonist. Regulated expression of biologically active intracellular and extracellular LIF cytokine could thus provide alternate mechanisms for the modulation of hematopoiesis and immune system function.

Alternative Splicing↗

PubMed2006

Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination.

Enhancement of oligodendrocyte survival through activation of leukemia inhibitory factor receptor (LIFR) signaling is a candidate therapeutic strategy for demyelinating disease. However, in other cell types, LIFR signaling is under tight negative regulation by the intracellular protein suppressor of cytokine signaling 3 (SOCS3). We, therefore, postulated that deletion of the SOCS3 gene in oligodendrocytes would promote the beneficial effects of LIFR signaling in limiting demyelination. By studying wild-type and LIF-knockout mice, we established that SOCS3 expression by oligodendrocytes was induced by the demyelinative insult, that this induction depended on LIF, and that endogenously produced LIF was likely to be a key determinant of the CNS response to oligodendrocyte loss. Compared with wild-type controls, oligodendrocyte-specific SOCS3 conditional-knockout mice displayed enhanced c-fos activation and exogenous LIF-induced phosphorylation of signal transducer and activator of transcription 3. Moreover, these SOCS3-deficient mice were protected against cuprizone-induced oligodendrocyte loss relative to wild-type animals. These results indicate that modulation of SOCS3 expression could facilitate the endogenous response to CNS injury.

Animals↗

PubMed2002

Mapping and microsatellite marker development for the porcine leukemia inhibitory factor receptor (LIFR) and epidermal growth factor receptor (EGFR) genes.

Leukemia inhibitory factor receptor (LIFR), epidermal growth factor receptor (EGFR), and their respective ligands have been implicated in regulating growth and development of the early pig conceptus. We isolated a PAC clone containing the porcine gene for LIFR and a BAC clone with the porcine EGFR gene, respectively. On each of these clones one microsatellite marker was identified by sequencing a collection of subclones. These gene-associated markers were evaluated by genotyping of 202 unrelated boars of four different breeds. Based on fluorescence in situ hybridization and radiation hybrid mapping, the porcine LIFR gene was assigned to SSC16q13-->q14. The EGFR gene mapped to SSC9q26.

Animals↗

PubMed1993

Regulation of cytokine expression in osteoblasts by parathyroid hormone: rapid stimulation of interleukin-6 and leukemia inhibitory factor mRNA.

PTH and other hormones that stimulate resorption affect osteoclasts indirectly by modulating cytokine production by osteoblasts. However, the identity and role of the osteoblast-derived cytokines involved in this process are unclear. To examine which cytokines are regulated by PTH, we assessed cytokine mRNA levels in osteoblasts using the reverse transcription-polymerase chain reaction technique. Of the 16 cytokines we examined, unstimulated MC3T3-E1 osteoblastic cells expressed mRNA for interleukins 5, 6, and 7, macrophage and granulocyte-macrophage colony-stimulating factors, transforming growth factor beta 1, and leukemia inhibitory factor. PTH specifically increased expression of interleukin-6 (approximately 50-fold) and leukemia inhibitory factor (approximately 10-fold). Levels of both IL-6 and LIF mRNA peaked 30-60 minutes after addition of PTH and returned to baseline by 4-6 h. This rapid and transient mRNA response, which resembles that of immediate early genes, was also observed in primary rat osteoblasts. The transient mRNA response was accompanied by increased secretion of IL-6 protein. Lipopolysaccharide, another stimulator of resorption, increased mRNA levels of a group of cytokines that were not induced by PTH, namely interleukin-1 alpha, tumor necrosis factor alpha, and granulocyte-macrophage and granulocyte colony-stimulating factors. We conclude that osteoblasts produce complex networks of cytokines that (1) are regulated by bone-resorptive agents and (2) may be involved in controlling bone resorption.

3T3 Cells↗

PubMed2004

The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element.

We found that human melanoma SEKI and neuroepithelioma NAGAI cells, which are known to secrete high concentrations of leukemia inhibitory factor (LIF), also secrete high levels of hepatocyte growth factor (HGF). We therefore examined the role of LIF in HGF expression and examined the human HGF promoter. The expression of both LIF and HGF mRNA is very low in HEK293 cells. Treatment of these cells with LIF stimulated the expression of HGF mRNA. The cis-acting regulatory element of the HGF promoter in SEKI and 293 cells was analysed by means of a transient expression assay. By deletion analysis, we showed that the region comprising the -181 to -73 bp was required for full activity of the HGF promoter in SEKI cells and for LIF responsiveness of 293 cells. This region contains putative consensus sequences for the Stat and NF-IL6 (C/EBP beta) transcription factors. The activity of the HGF promoter was abolished by mutation of the Stat site at -99/-91, while the activity only slightly decreased on mutation of the NF-IL6 site. Treatment with anti-LIF antibodies or interruption of Stat3 signaling by dominant-negative Stat3 also reduced the HGF promoter activity. Stat3 activation was constitutive in SEKI cells and induced on treatment of 293 cells with LIF. These results suggest that cytokines, growth factors and oncogenes (v-Src, etc.) that activate Stat3 are important regulators of HGF expression.

Base Sequence↗