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PubMed1992

[Function, molecular structure and gene expression regulation of receptor for D-factor/LIF].

Differentiation-stimulating factor (D-factor)/leukemia inhibitory factor (LIF) is a cytokine inducing differentiation of mouse myeloid leukemic M1 cells. IL-6, oncostatin M (OSM) and G-CSF also induce differentiation of M1 cells. These four cytokines are suggested to be members of a single cytokine family. The LIF receptor is structurally related to the gp130 signal-transducing component of the IL-6 receptor and to the G-CSF receptor. The high-affinity receptors for LIF, OSM and IL-6 share the common subunit, gp130. This provides an explanation for the functional redundancy of those cytokines.

Animals↗
PubMed1992

Oncostatin M is a differentiation factor for myeloid leukemia cells.

Oncostatin M (OSM) is a 28-kDa glycoprotein produced by stimulated macrophages and T lymphocytes that inhibits the proliferation of a number of different cell lines derived from solid tumors. Analysis of both amino acid sequence and gene structure has demonstrated that OSM is a member of a cytokine family that includes leukemia inhibitory factor (LIF), IL-6, and granulocyte colony-stimulating factor (G-CSF). We demonstrate that, like LIF, IL-6 and G-CSF, OSM can induce the differentiation of the myeloblastic M1 murine leukemia cells into macrophage-like cells. The morphologic and functional changes induced by OSM are more similar to those observed with LIF and IL-6 than those induced with G-CSF. OSM can also induce the differentiation of the histiocytic U937 human leukemia cells in the presence of granulocyte-macrophage CSF, a property shared with LIF and IL-6. In murine M1 cells, binding of labeled OSM is completely inhibited by excess LIF or OSM, reflecting the binding of OSM to the high affinity form of the murine LIF receptor. In contrast, the binding of labeled OSM to human U937 leukemia cells is inhibited by OSM, but the inhibition by LIF is significantly less. These results suggest that, in human leukemia cells, OSM may act through the LIF receptor and an OSM-specific receptor. The existence of an OSM-specific receptor was confirmed by both growth inhibition and competition binding assays on A375 human melanoma cells. The growth of human A375 cells was inhibited by OSM and IL-6 but not LIF or G-CSF. Neither LIF, G-CSF, nor IL-6 could compete with the binding of labeled OSM to A375 cells.

Animals↗
PubMed1992

Down-regulation of interleukin 6 receptors of mouse myelomonocytic leukemic cells by leukemia inhibitory factor.

We examined the effect of leukemia inhibitory factor (LIF) on the expression of interleukin 6 receptors (IL-6R) on mouse myelomonocytic leukemic M1 cells. Binding studies using 125I-labeled human and murine IL-6 revealed that LIF caused a decrease in IL-6 binding to M1 cells. The decrease became evident within 1 h, and the maximum decrease was observed at 3-6 h. Scatchard plot analysis revealed that M1 cells had a single class of high affinity receptors for IL-6 and that LIF-induced decrease in IL-6 binding was due to a decrease in the number of IL-6R on the cell surface and not to changes in their affinity. The affinity of IL-6R on M1 cells to human IL-6 (Kd = 2.25 nM) was about 10-fold lower than that to murine IL-6 (Kd = 200 pM). The amount of IL-6 secreted into culture media by M1 cells that were treated with LIF for up to 12 h was not enough to cause receptor down-regulation. Northern blot analysis demonstrated that IL-6R mRNA was down-regulated by LIF treatment, and similar regulation was also observed when the cells were treated with IL-6. The time course of the IL-6R mRNA level was similar to that of IL-6R expression on the cell surface, suggesting that the main mechanism responsible for the loss of high affinity IL-6R was the regulation of IL-6R mRNA. Although the half-life of IL-6R on the cell surface was about 30 min, the addition of LIF reduced it to 16 min, suggesting the existence of an additional mechanism responsible for the loss of high affinity IL-6R on the cell surface.

Animals↗
PubMed1992

Kinetic analyses of the binding of leukemia inhibitory factor to receptor on cells and membranes and in detergent solution.

The equilibrium and kinetic properties of leukemia inhibitory factor (LIF) binding to a range of cell types have been compared. When binding was examined at 4 degrees C, the majority of cells were found to express a single class of high affinity LIF receptor (KD = 20-100 pM; ka = 2-8 x 10(8) min-1 M-1; kd = 0.0004-0.0011 min-1). In contrast, certain activated macrophage populations expressed apparently independent classes of high and low affinity LIF receptor. The low affinity receptors differed from the high affinity receptors in terms of the dissociation rate of the receptor-ligand complex (KD = 1-2 nM; ka = 3-7 x 10(8) min-1 M-1; kd = 0.30-0.67 min-1). At 37 degrees C, the interaction of LIF with its high affinity receptor was more complicated, since occupied LIF receptors were internalized more rapidly than unoccupied receptors, internalized LIF was hydrolyzed and released from the cell, and new receptors were synthesized and expressed on the cell surface. Interestingly, when membranes were prepared from cells that expressed only high affinity receptors, both high and low affinity receptors were detected, while after detergent solubilization of membranes only low affinity receptors were apparent. These results are discussed in terms of a structural model for the LIF receptor in which interaction of a low affinity binding subunit and a second nonbinding subunit is required for the generation of the high affinity receptor.

3T3 Cells↗
PubMed1992

Reconstitution of high affinity leukaemia inhibitory factor (LIF) receptors in haemopoietic cells transfected with the cloned human LIF receptor.

cDNA clones encoding the human leukaemia inhibitory factor (hLIF) receptor were isolated by screening a placental cDNA expression library in COS-7 cells with 125I-hLIF. The cloned LIF receptor is a member of the haemopoietin receptor family and comprises a signal sequence (44 amino acids), an extracellular region of two haemopoietin receptor domains and three fibronectin type III domains (789 amino acids), a transmembrane domain (26 amino acids) and a cytoplasmic domain (238 amino acids). The LIF receptor is expressed in COS-7 cells as a 190 kDa glycoprotein that specifically binds human LIF with low affinity, but does not bind mouse LIF. Clones encoding a soluble form of the homologous mouse LIF receptor have been isolated, suggesting complex interactions between the various forms of LIF ligand and receptor in vivo. The LIF receptor is most related to the gp130 signal-transducing component of the IL-6 receptor, a feature that may provide a molecular basis for the intertwined biologies of LIF and IL-6 in the absence of obvious structural similarly between the ligands. Mouse B9 plasmacytoma cells transfected with the human LIF receptor display novel high affinity LIF receptors that are presumed to consist of transfected receptors in association with endogenous mouse high affinity-converting subunits. Unlike the low affinity human LIF receptor, the mixed species high affinity receptor is capable of binding mouse LIF.

Amino Acid Sequence↗
PubMed1992

Distribution and binding properties of receptors for leukaemia inhibitory factor.

The pleiotropic biological actions of leukaemia inhibitory factor (LIF) on haemopoietic cells (macrophages and megakaryocytes), hepatocytes, osteoblasts, pre-adipocytes, embryonic stem cells, myoblasts and neuronal cells must be mediated through the interactions of LIF with specific cellular receptors. The demonstration by equilibrium binding analysis and autoradiography of LIF receptors on all of the above cells and cell lines suggests that each of these pleiotropic effects of LIF is mediated by direct interactions with the responding cells rather than by the indirect release of secondary cytokines. Despite the differing biological effects of LIF on these cells, equilibrium binding, kinetic analyses and receptor internalization studies have all suggested that these cells display essentially identical high affinity LIF receptors. Nevertheless, there is evidence on some cell types (granulocyte-macrophage colony-stimulating factor [GM-CSF] transgenic peritoneal cells and F9 embryonal carcinoma cells) for a second class of low affinity LIF receptors (Kd = 1.5 nM versus Kd = 30 pM for high affinity receptors) which, LIF receptors (Kd = 1.5 nM versus Kd = 30 pM for high affinity receptors) which differ from the high affinity receptors only in kinetic dissociation rate. Moreover, the evidence suggests that low and high affinity receptors are structurally related and interconvertible, because detergent solubilization of LIF receptors from any cell type results in the quantitative conversion of high affinity receptors into low affinity receptors. As is the case for other related cytokine receptors, these data suggest that high affinity LIF receptors may be composed of two protein subunits--one responsible for LIF-specific low affinity binding and the other responsible for affinity conversion and cell signalling by the receptor. Such a model provides a possible explanation for the pleiotropy of LIF's biological actions.

Animals↗
PubMed1992

LIF: lots of interesting functions.

Leukaemia inhibitory factor (LIF) is one of a growing number of cytokines that cannot be readily categorized according to its functions. Rather, these pleiotropic hormones have diverse and often overlapping effects on a multitude of cell types: for example, LIF can inhibit the differentiation of embryonal stem cells on one hand and induce the differentiation of M1 leukaemic cells on the other. Recent work has shed light on the physiological effects of LIF, how these are limited, and the biochemical and biological properties of LIF and its receptor.

Amino Acid Sequence↗
PubMed1992

A major binding protein for leukemia inhibitory factor in normal mouse serum: identification as a soluble form of the cellular receptor.

A protein that specifically binds leukemia inhibitory factor (LIF) has been isolated from normal mouse serum by using four successive fractionation steps: chromatography on a LIF affinity matrix, anion-exchange chromatography, size-exclusion chromatography, and preparative native gel electrophoresis. The purified LIF-binding protein (LBP) is a glycoprotein with an apparent molecular mass of 90 kDa that specifically binds 125I-labeled murine LIF with an affinity comparable to that of the low-affinity cellular LIF receptor (Kd = 600 pM). N-terminal sequencing has identified this protein as a soluble truncated form of the alpha chain of the cellular LIF receptor. LBP is present in normal mouse serum at high levels (1 microgram/ml) and these levels are elevated in pregnant mice and reduced in neonatal mice. Since normal serum concentrations of LBP can block the biological actions of LIF in culture, LBP may serve as an inhibitor of the systemic effects of locally produced LIF.

Amino Acid Sequence↗
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↗
PubMed1992

Leukemia inhibitory factor--a puzzling polyfunctional regulator.

LIF seems likely to have important functions in the early developing embryo and in adult life can influence platelet formation, osteoblast and neuronal function, calcium and lipid metabolism and the production of acute-phase proteins. LIF appears usually to be produced and to function locally in various tissues, an arrangement that would minimize unwanted actions of this polyfunctional regulator. Nevertheless it remains puzzling what purpose is achieved by use of a regulator with potent actions on such a wide range of apparently unrelated tissues.

Animals↗
PubMed2026

Severe Suprasystemic Refractory Pulmonary Hypertension in a Neonate with Stüve-Wiedemann Syndrome Associated with Biallelic LIFR Variants: Molecular Insights and a Neonatal Case Report.

Stüve-Wiedemann syndrome (SWS) is an ultra-rare autosomal recessive skeletal dysplasia caused by loss-of-function variants in the leukemia inhibitory factor receptor (LIFR) gene. While characterized by bone deformities and dysautonomia, severe persistent pulmonary hypertension of the newborn (PPHN) significantly contributes to high early mortality. We report a neonate with genetically confirmed SWS who presented with severe, suprasystemic PPHN refractory to standard pulmonary vasodilators, including inhaled nitric oxide. This case provides a detailed longitudinal hemodynamic characterization of severe suprasystemic PPHN in genetically confirmed SWS, including serial assessment of pulmonary pressures, shunt direction, and right ventricular function during treatment. Rather than identifying PPHN as a novel manifestation of SWS, it extends the phenotypic and hemodynamic characterization of pulmonary vascular involvement in this rare disorder.

Humans↗
PubMed1992

Oncostatin M binds the high-affinity leukemia inhibitory factor receptor.

Oncostatin M (OSM) is a glycoprotein cytokine that was recently demonstrated to be structurally and functionally related to the leukemia inhibitory factor (LIF). We have investigated the binding of each cytokine to a variety of cellular receptors including those on solid tumor lines, leukemic cells, endothelial cells, macrophages, and cells transfected with the recently cloned low-affinity LIF receptor, and to a soluble form of the LIF receptor. LIF is incapable of binding either high- or low-affinity OSM receptors, yet OSM is capable of binding the high-affinity but not the low-affinity LIF receptor. Since the presence of high-affinity LIF receptors correlates with the biological activity of LIF on a wide range of target cells, we predict that OSM should have similar effects on LIF-responsive cells.

Animals↗
PubMed1992

Interleukin-11 and its receptor.

Interleukin (IL)-11 is a bone marrow fibroblast derived cytokine with a wide spectrum of activities in different biological systems. It has been shown that IL-11 supports the growth of certain types of plasmacytoma and hybridoma cells, enhances antigen-specific antibody responses, synergizes with IL-3 in supporting megakaryocyte colony formation, acts synergistically with IL-3 in shortening the G0 period of early progenitors, induces the synthesis of acute phase proteins, and inhibits lipoprotein lipase activity and adipocyte differentiation. The human IL-11 gene, which is localized at 19q13.3-13.4, consists of five exons and four introns. Initial biochemical characterization has identified a 151 kDa protein as the potential IL-11 binding subunit of the receptor complex. Because of the overlapping biological activities between IL-6 and IL-11, we compared the signal transduction pathways mediated by IL-6 or IL-11 in cell lines responsive to both cytokines. Results from protein tyrosine phosphorylation and immediate response gene expression suggest that there are convergent and divergent points along the signal transduction pathways utilized by IL-6 or IL-11. The IL-6 signal transducer, gp130, appears to be involved in the IL-11 mediated signaling. Other cytokines such as leukemia inhibitory factor, oncostatin M and ciliary neurotrophic factor have also been shown to utilize gp130 as a signal transducer. The significance of growth factor sharing common biological activities and signaling pathways will be discussed.

Animals↗
PubMed1992

Interleukin-6 signal transducer gp130 mediates oncostatin M signaling.

Oncostatin M (OM) is a multifunctional cytokine that is structurally and functionally related to interleukin 6 (IL-6) and leukemia inhibitory factor (LIF). The specific receptor for OM has been demonstrated (by chemical cross-linking) to be a 150-kDa protein in a number of cell lines. The IL-6 signal transducer, gp130, is also an affinity converter for the LIF receptor. It does not bind to either IL-6 or LIF, but associates with the alpha subunits of the receptors and transduces the signals. We examined the possible involvement of gp130 in OM binding and signaling. We demonstrate that: (a) anti-gp130 monoclonal antibodies (mAbs) block the inhibitory effect of OM on A375 cell growth, (b) the binding and cross-linking of 125I-OM to H2981 cells are completely abolished by anti-gp130 mAbs, (c) the cross-linked OM-receptor complex is immunoprecipitated by anti-gp130 mAbs, and (d) COS-7 cells transfected with the full-length cDNA encoding gp130 exhibit increased OM binding and cross-linking, which are also blocked by anti-gp130 mAbs. Therefore, we conclude that the 150-kDa OM binding protein previously characterized in a variety of cell lines is gp130. OM is the natural ligand for gp130 and gp130 mediates the biological responses of OM.

Animals↗
PubMed1992

Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins.

IL-6 is a major regulator of acute phase protein synthesis in the liver. It exerts its action via a plasma membrane receptor consisting of two subunits, a ligand binding 80-kDa glycoprotein and a 130-kDa glycoprotein involved in signal transduction. We genetically generated a soluble form of the 80-kDa subunit of the human IL-6R (shIL-6R) in mouse fibroblasts (NIH/3T3 cells). The shIL-6R added to human hepatoma cells (HepG2) amplified the induction of alpha 1-antichymotrypsin and haptoglobin by IL-6 at the mRNA and protein level. Moreover, a model for a liver permanently exposed to high IL-6 concentrations has been developed; HepG2 cells were stably transfected with human IL-6-cDNA; 10(6) of the transfected cells (HepG2-IL-6) synthesized and secreted 2 micrograms of IL-6 within 24 h. Incubation of these cells with endogenous or exogenous IL-6 did not result in acute-phase protein induction. However, these IL-6-desensitized cells responded to other cytokines such as leukemia inhibitory factor, transforming growth factor beta 1, and IFN-gamma, known to modulate acute phase protein synthesis in the liver. Incubation of HepG2-IL-6 cells with shIL-6R reconstituted their responsiveness to IL-6 in a dose- and time-dependent manner. The possible biologic role that might be played by the shIL-6R in disease is discussed.

Acute-Phase Proteins↗