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 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 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

scholarly journals Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells.

1995 ◽  
Vol 182 (6) ◽  
pp. 1801-1806 ◽  
Author(s):  
D Chauhan ◽  
S M Kharbanda ◽  
A Ogata ◽  
M Urashima ◽  
D Frank ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Leukemia Inhibitory Factor ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Janus Kinase ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Leukemia Inhibitory Factor Receptor ◽  
Myeloma Cells ◽  
Human Multiple Myeloma

Oncostatin M (OSM) is a 28-kD glycoprotein recently identified as a growth factor for human multiple myeloma cells. It belongs to a family of distantly related cytokines that includes interleukin 6, ciliary neurotrophic factor, leukemia-inhibitory factor, and interleukin 11. These cytokines initiate signaling by inducing either homodimerization of gp130 or heterodimerization of gp130 with leukemia-inhibitory factor receptor beta components. Such dimerization in turn activates receptor-associated tyrosine kinases. In the present study using U266B1 human multiple myeloma cells, we show that OSM induces tyrosine phosphorylation and activation of JAK2, but not JAK1 or Tyk2, kinases. The results also demonstrate that OSM induces direct interaction of JAK2 kinase with Grb2, an SH2/SH3 domain containing adaptor protein. The SH2 domain of Grb2 is directly associated with tyrosine-phosphorylated JAK2. Furthermore, the presence of Sos in the JAK2-Grb2 complex suggests a role for Ras in OSM-transduced signaling.

Oncostatin M is a growth factor for ewing sarcoma: Potent role of the leukemia inhibitory factor receptor

Bone ◽  
2011 ◽  
Vol 48 ◽  
pp. S254
Author(s):  
E. David ◽  
P. Guihard ◽  
F. Tirode ◽  
K. Laud ◽  
O. Delattre ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ewing Sarcoma ◽  
Leukemia Inhibitory Factor ◽  
Oncostatin M ◽  
Inhibitory Factor ◽  
Leukemia Inhibitory Factor Receptor
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