scholarly journals Induction of differentiation of WEHI-3B D+ leukemic cells transfected with differentiation-stimulating factor/leukemia inhibitory factor receptor cDNA

Blood ◽  
1995 ◽  
Vol 85 (1) ◽  
pp. 217-221 ◽  
Author(s):  
M Tomida
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Leukemia Inhibitory Factor Receptor ◽  
Transfected Cells ◽  
Receptor Cdna ◽  
Induction Of Differentiation ◽  
Stimulating Factor

Differentiation-stimulating factor (D-factor)/leukemia inhibitory factor can induce the differentiation of mouse myeloid leukemia M1 cells and also stimulate proliferation of the interleukin-3 (IL-3)- dependent cell line, DA-1a. To determine whether D-factor can induce the differentiation of leukemia cells other than M1 cells, WEHI-3B D+ mouse myelomonocytic leukemia cells were transfected with a plasmid containing mouse D-factor receptor cDNA. Expression of D-factor receptor in transfected cells was determined by binding of [125]D- factor and analyzed by Scatchard's method. The transfected cells had high-affinity D-factor receptors with a dissociation constant of 100 to 200 pmol/L and binding sites per cell varied from 67 to 1,500 among several clones. The cells expressing a high level of D-factor receptor were induced to differentiate by D-factor; about 60% of the cells exhibited the ability to reduce nitroblue tetrazolium and expression of the differentiation antigen Mac-1 (CD11b) on the cell surface increased. The effect of cytokines, which induce the differentiation of M1 cells, on the transfected WEHI-3B cells was examined. The sensitivity to oncostatin M was identical to that against D-factor in the cells of each clone. Expression of D-factor receptor in WEHI-3B cells promoted sensitivity to IL-6 and granulocyte colony-stimulating factor (G-CSF). Induction of differentiation of the cells accompanied the suppression of proliferation. Treatment of the cells with D-factor for longer than 5 days resulted in 50% inhibition of growth. These results indicate that the stimulating effect of D-factor on the differentiation of malignant myeloid cells is not unique to M1 cells.

scholarly journals Concomitant Activation of OSM and LIF Receptor by a Dual-Specific hlOSM Variant Confers Cardioprotection after Myocardial Infarction in Mice

2021 ◽  
Vol 23 (1) ◽  
pp. 353
Author(s):  
Holger Lörchner ◽  
Juan M. Adrian-Segarra ◽  
Christian Waechter ◽  
Roxanne Wagner ◽  
Maria Elisa Góes ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Leukemia Inhibitory Factor ◽  
Structural Integrity ◽  
Strain Analysis ◽  
Immunoblot Analysis ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Leukemia Inhibitory Factor Receptor ◽  
Beneficial Effects ◽  
Inflammatory Phase

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) signaling protects the heart after myocardial infarction (MI). In mice, oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) are selectively activated by the respective cognate ligands while OSM activates both the OSMR and LIFR in humans, which prevents efficient translation of mouse data into potential clinical applications. We used an engineered human-like OSM (hlOSM) protein, capable to signal via both OSMR and LIFR, to evaluate beneficial effects on cardiomyocytes and hearts after MI in comparison to selective stimulation of either LIFR or OSMR. Cell viability assays, transcriptome and immunoblot analysis revealed increased survival of hypoxic cardiomyocytes by mLIF, mOSM and hlOSM stimulation, associated with increased activation of STAT3. Kinetic expression profiling of infarcted hearts further specified a transient increase of OSM and LIF during the early inflammatory phase of cardiac remodeling. A post-infarction delivery of hlOSM but not mOSM or mLIF within this time period combined with cardiac magnetic resonance imaging-based strain analysis uncovered a global cardioprotective effect on infarcted hearts. Our data conclusively suggest that a simultaneous and rapid activation of OSMR and LIFR after MI offers a therapeutic opportunity to preserve functional and structural integrity of the infarcted heart.

scholarly journals Differential regulation of macrophage differentiation in response to leukemia inhibitory factor/oncostatin-M/interleukin-6: the effect of enforced expression of the SCL transcription factor

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 379-390 ◽  
Author(s):  
T Tanigawa ◽  
N Nicola ◽  
GA McArthur ◽  
A Strasser ◽  
CG Begley
Keyword(s):  
Growth Factors ◽  
Interleukin 6 ◽  
Leukemia Inhibitory Factor ◽  
Differential Regulation ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Macrophage Phenotype ◽  
Colony Stimulating Factor ◽  
Macrophage Differentiation ◽  
Stimulating Factor

The physiologic program of macrophage differentiation normally proceeds in a coordinated manner in response to several different growth factors. Although the utilization of common receptor subunits may explain in part overlapping biologic functions, mechanisms by which unique actions are mediated remain obscure. We examined growth factor- induced macrophage differentiation in M1 leukemia cells that simultaneously display receptors for interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and Oncostatin-M (OSM). Differentiation induced by all three factors was associated with decreased expression of transcription factors myb and SCL, increased expression of macrophage markers, and suppression of proliferation. Cell lines were established in which SCL expression was enforced. In the absence of growth factors, cells were indistinguishable from parental cells. However, LIF (or OSM)- induced macrophage differentiation was perturbed; there was failure to undergo morphologic differentiation, disturbed expression of lysozyme and Mac1 alpha, and failure to suppress proliferation. Surprisingly the perturbation of macrophage differentiation did not apply to induced expression of macrophage colony-stimulating factor (M-CSF) or granulocyte colony stimulating factor (G-CSF) receptors. This dissociation of elements normally coordinated in a macrophage differentiation program applied at a clonal level. There was no disturbance of IL-6-induced macrophage differentiation. These data directly implicate SCL in components of the macrophage differentiation program (suggesting that LIF receptor/gp130 heterodimers utilize an SCL- inhibitable pathway while gp130 homodimers do not) and demonstrate differential-regulation of components of the mature macrophage phenotype.

scholarly journals Differential regulation of macrophage differentiation in response to leukemia inhibitory factor/oncostatin-M/interleukin-6: the effect of enforced expression of the SCL transcription factor

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 379-390 ◽  
Author(s):  
T Tanigawa ◽  
N Nicola ◽  
GA McArthur ◽  
A Strasser ◽  
CG Begley
Keyword(s):  
Growth Factors ◽  
Interleukin 6 ◽  
Leukemia Inhibitory Factor ◽  
Differential Regulation ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Macrophage Phenotype ◽  
Colony Stimulating Factor ◽  
Macrophage Differentiation ◽  
Stimulating Factor

Abstract The physiologic program of macrophage differentiation normally proceeds in a coordinated manner in response to several different growth factors. Although the utilization of common receptor subunits may explain in part overlapping biologic functions, mechanisms by which unique actions are mediated remain obscure. We examined growth factor- induced macrophage differentiation in M1 leukemia cells that simultaneously display receptors for interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and Oncostatin-M (OSM). Differentiation induced by all three factors was associated with decreased expression of transcription factors myb and SCL, increased expression of macrophage markers, and suppression of proliferation. Cell lines were established in which SCL expression was enforced. In the absence of growth factors, cells were indistinguishable from parental cells. However, LIF (or OSM)- induced macrophage differentiation was perturbed; there was failure to undergo morphologic differentiation, disturbed expression of lysozyme and Mac1 alpha, and failure to suppress proliferation. Surprisingly the perturbation of macrophage differentiation did not apply to induced expression of macrophage colony-stimulating factor (M-CSF) or granulocyte colony stimulating factor (G-CSF) receptors. This dissociation of elements normally coordinated in a macrophage differentiation program applied at a clonal level. There was no disturbance of IL-6-induced macrophage differentiation. These data directly implicate SCL in components of the macrophage differentiation program (suggesting that LIF receptor/gp130 heterodimers utilize an SCL- inhibitable pathway while gp130 homodimers do not) and demonstrate differential-regulation of components of the mature macrophage phenotype.

scholarly journals Oncostatin M Regulates the Synthesis and Turnover of gp130, Leukemia Inhibitory Factor Receptor α, and Oncostatin M Receptor β by Distinct Mechanisms

2001 ◽  
Vol 276 (50) ◽  
pp. 47038-47045 ◽  
Author(s):  
Frédéric Blanchard ◽  
Yanping Wang ◽  
Erin Kinzie ◽  
Laurence Duplomb ◽  
Anne Godard ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Ligand Binding ◽  
Leukemia Inhibitory Factor ◽  
Human Fibroblasts ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Receptor Protein ◽  
Cytokine Signaling ◽  
Leukemia Inhibitory Factor Receptor ◽  
Oncostatin M Receptor

The cytokine receptor subunits gp130, leukemia inhibitory factor receptor α (LIFRα), and oncostatin M receptor β (OSMRβ) transduce OSM signals that regulate gene expression and cell proliferation. After ligand binding and activation of the Janus protein-tyrosine kinase/STAT and mitogen-activated protein kinase signal transduction pathways, negative feedback processes are recruited. These processes attenuate receptor action by suppression of cytokine signaling and by down-regulation of receptor protein expression. This study demonstrates that in human fibroblasts or epithelial cells, OSM first decreases the level of gp130, LIFRα, and OSMRβ by ligand-induced receptor degradation and then increases the level of the receptors by enhanced synthesis. The transcriptional induction of gp130 gene by OSM involves STAT3. Various cell lines expressing receptor subunits to the different interleukin-6 class cytokines revealed that only LIFRα degradation is promoted by activated ERK and that degradation of gp130, OSMRβ, and a fraction of LIFRα involves mechanisms that are separate from signal transduction. These mechanisms include ligand-mediated dimerization, internalization, and endosomal/lysosomal degradation. Proteosomal degradation appears to involve a fraction of receptor subunit proteins that are ubiquitinated independently of ligand binding.

scholarly journals Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice

2010 ◽  
Vol 120 (2) ◽  
pp. 582-592 ◽  
Author(s):  
Emma C. Walker ◽  
Narelle E. McGregor ◽  
Ingrid J. Poulton ◽  
Melissa Solano ◽  
Sueli Pompolo ◽  
...  
Keyword(s):  
Bone Formation ◽  
Leukemia Inhibitory Factor ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Leukemia Inhibitory Factor Receptor

Cytoplasmic Domains of the Leukemia Inhibitory Factor Receptor Required for STAT3 Activation, Differentiation, and Growth Arrest of Myeloid Leukemic Cells

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 1934-1941 ◽  
Author(s):  
Mikio Tomida ◽  
Toshio Heike ◽  
Takashi Yokota
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Growth Arrest ◽  
Point Mutations ◽  
Cytoplasmic Domain ◽  
Dominant Negative ◽  
Inhibitory Factor ◽  
Leukemic Cells ◽  
Leukemia Inhibitory Factor Receptor ◽  
Macrophage Differentiation ◽  
D Cells

Leukemia inhibitory factor (LIF) induces growth arrest and macrophage differentiation of mouse myeloid leukemic cells through the functional LIF receptor (LIFR), which comprises a heterodimeric complex of the LIFR subunit and gp130. To identify the regions within the cytoplasmic domain of LIFR that generate the signals for growth arrest, macrophage differentiation, and STAT3 activation independently of gp130, we constructed chimeric receptors by linking the transmembrane and intracellular regions of mouse LIFR to the extracellular domains of the human granulocyte macrophage colony-stimulating factor receptor (hGM-CSFR)  and βc chains. Using the full-length cytoplasmic domain and mutants with progressive C-terminal truncations or point mutations, we show that the two membrane-distal tyrosines with the YXXQ motif of LIFR are critical not only for STAT3 activation, but also for growth arrest and differentiation of WEHI-3B D+ cells. A truncated STAT3, which acts in a dominant negative manner was introduced into WEHI-3B D+ cells expressing GM-CSFR-LIFR and GM-CSFRβc-LIFR. These cells were not induced to differentiate by hGM-CSF. The results indicate that STAT3 plays essential roles in the signals for growth arrest and differentiation mediated through LIFR.

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