Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130.

We analyzed the stimulatory effect of oncostatin M (OSM), leukemia inhibitory factor (LIF), interleukin 6 (IL-6), IL-11, and the inhibitory effect of anti-IL-6 antibody (Ab), anti-IL-6 receptor monoclonal antibody (mAb), and anti-gp130 mAb on the growth of human plasmacytoma cells freshly isolated from a patient with multiple myeloma. The purified cells showed a plasmacytoid morphology and expressed CD38, CD54, and CD56 antigens but no CD3, CD5, CD10, CD19, CD20, or very late antigen 5. IL-6 receptor (IL-6R) and its signal transducer, gp130, were expressed on their cell surface at a low level. Dose-dependent proliferation of the cells in response to OSM, LIF, and IL-6, but not to IL-11, was observed using [3H]TdR incorporation in vitro. Both anti-IL-6 Ab and anti-IL-6R mAb inhibited the growth of the cells in the presence or absence of exogenous IL-6. These cells release IL-6 but not OSM or LIF into the culture supernatant during short-term culture. Therefore, an autocrine growth mechanism mediated by IL-6, but not by OSM or LIF, was confirmed. Furthermore, anti-gp130 mAb completely inhibited the proliferation of the cells induced by OSM, LIF, as well as IL-6. These data indicate that OSM, LIF, and IL-6 can act as growth factors of human plasmacytoma cells through a common signal transducer, gp130, on their cell surface, and also suggest the potential therapeutic application of anti-gp130 mAb, as well as anti-IL-6R mAb against myeloma/plasmacytomas.

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Ciliary neurotropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130.

Journal of Experimental Medicine ◽

10.1084/jem.179.4.1337 ◽

1994 ◽

Vol 179 (4) ◽

pp. 1337-1342 ◽

Cited By ~ 172

Author(s):

X G Zhang ◽

J J Gu ◽

Z Y Lu ◽

K Yasukawa ◽

G D Yancopoulos ◽

...

Keyword(s):

Cell Lines ◽

Interleukin 6 ◽

Leukemia Inhibitory Factor ◽

Biological Activities ◽

Myeloma Cell ◽

Oncostatin M ◽

Inhibitory Factor ◽

Signal Transducer ◽

Neurotropic Factor ◽

Human Myeloma Cell

Interleukin 6 (IL-6) is a major growth factor for tumor plasma cells involved in human multiple myeloma (MM). In particular, human myeloma cell lines (HMCL), whose growth is completely dependent on addition of exogenous IL-6, can be obtained reproducibly from every patient with terminal disease. Four cytokines, ciliary neurotropic factor (CNTF), IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OM), use the same transducer chain (signal transducer gp130) as IL-6 and share numerous biological activities with this IL. We found that these four cytokines stimulated proliferation and supported the long-term growth of two out of four IL-6-dependent HMCL obtained in our laboratory. Half-maximal proliferation was obtained with cytokine concentrations ranging from 0.4 to 1.2 ng/ml for IL-11, LIF, and OM. CNTF worked at high concentrations only (90 ng/ml), but addition of soluble CNTF receptor increased sensitivity to CNTF 30-fold. The growth-promoting effect of these four cytokines was abrogated by anti-gp130 antibodies, contrary to results for anti-IL-6 receptor or anti-IL-6 antibodies. No detectable changes in the morphology and phenotype were found when myeloma cells were cultured with one of these four cytokines instead of IL-6. Concordant with their IL-6-dependent growth, the four HMCL expressed membrane IL-6R and gp130 detected by FACS analysis. LIF-binding chain gene (LIFR) was expressed only in the two HMCL responsive to LIF and OM.

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The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin m in rheumatoid arthritis

Arthritis & Rheumatism ◽

10.1002/art.1780400614 ◽

1997 ◽

Vol 40 (6) ◽

pp. 1096-1105 ◽

Cited By ~ 151

Author(s):

Hideyuki Okamoto ◽

Masahiro Yamamura ◽

Yoshitaka Morita ◽

Seishi Harada ◽

Hirofumi Makino ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Interleukin 6 ◽

Leukemia Inhibitory Factor ◽

Serum Levels ◽

Oncostatin M ◽

Inhibitory Factor ◽

Interleukin 11

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Oncostatin M, leukaemia-inhibitory factor and interleukin 6 trigger different effects on α1-proteinase inhibitor synthesis in human lung-derived epithelial cells

Biochemical Journal ◽

10.1042/bj3290335 ◽

1998 ◽

Vol 329 (2) ◽

pp. 335-339 ◽

Cited By ~ 26

Author(s):

Joanna CICHY ◽

Stefan ROSE-JOHN ◽

James TRAVIS

Keyword(s):

Epithelial Cells ◽

Interleukin 6 ◽

Proteinase Inhibitor ◽

Human Lung ◽

Biological Activities ◽

Oncostatin M ◽

Inhibitory Factor ◽

Leukaemia Inhibitory Factor ◽

Common Signal

Interleukin 6 (IL-6), oncostatin M (OSM) and leukaemia-inhibitory factor (LIF) share a common signal-transducing subunit in each of their receptors and thus mediate an overlapping spectrum of biological activities. Although all of these cytokines stimulate the production of α1-proteinase inhibitor (α1-PI) in hepatocyte-derived cells, only OSM is able to up-regulate levels of this inhibitor in epithelial cells originating from the lung. In this study we characterized human lung-derived epithelial-like HTB58 cells for their ability to synthesize α1-PI after treatment with IL-6, OSM and LIF. The results demonstrate that the resistance of HTB58 cells to the effects of IL-6 and LIF was not because of a lack of their individual functional receptors and suggest that OSM utilizes two different receptors, gp130/LIF receptor and gp130/OSM receptor, in lung-derived epithelial cells.

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Different epitopes are required for gp130 activation by interleukin-6, oncostatin M and leukemia inhibitory factor

FEBS Letters ◽

10.1016/s0014-5793(00)01205-9 ◽

2000 ◽

Vol 468 (2-3) ◽

pp. 120-124 ◽

Cited By ~ 14

Author(s):

Andreas Timmermann ◽

Stefan Pflanz ◽

Joachim Grötzinger ◽

Andrea Küster ◽

Ingo Kurth ◽

...

Keyword(s):

Interleukin 6 ◽

Leukemia Inhibitory Factor ◽

Oncostatin M ◽

Inhibitory Factor

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STIMULATION OF OSTEOCLAST DIFFERENTIATION IN VITRO BY MOUSE ONCOSTATIN M, LEUKAEMIA INHIBITORY FACTOR, CARDIOTROPHIN-1 AND INTERLEUKIN 6: SYNERGY WITH DEXAMETHASONE

Cytokine ◽

10.1006/cyto.1999.0635 ◽

2000 ◽

Vol 12 (6) ◽

pp. 613-621 ◽

Cited By ~ 80

Author(s):

Carl D Richards ◽

Carrie Langdon ◽

Paula Deschamps ◽

Diane Pennica ◽

Stephen G Shaughnessy

Keyword(s):

Interleukin 6 ◽

Osteoclast Differentiation ◽

Oncostatin M ◽

Inhibitory Factor ◽

Leukaemia Inhibitory Factor ◽

Stimulation Of

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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 ◽

10.1182/blood.v85.2.379.bloodjournal852379 ◽

1995 ◽

Vol 85 (2) ◽

pp. 379-390 ◽

Cited By ~ 3

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.

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Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells.

Journal of Clinical Investigation ◽

10.1172/jci118432 ◽

1996 ◽

Vol 97 (2) ◽

pp. 431-437 ◽

Cited By ~ 120

Author(s):

T Bellido ◽

N Stahl ◽

T J Farruggella ◽

V Borba ◽

G D Yancopoulos ◽

...

Keyword(s):

Bone Marrow ◽

Interleukin 6 ◽

Neurotrophic Factor ◽

Leukemia Inhibitory Factor ◽

Ciliary Neurotrophic Factor ◽

Oncostatin M ◽

Inhibitory Factor ◽

Osteoblastic Cells ◽

Interleukin 11

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Leukemia inhibitory factor (LIF) inhibits angiogenesis in vitro

Journal of Cell Science ◽

10.1242/jcs.108.1.73 ◽

1995 ◽

Vol 108 (1) ◽

pp. 73-83 ◽

Cited By ~ 3

Author(s):

M.S. Pepper ◽

N. Ferrara ◽

L. Orci ◽

R. Montesano

Keyword(s):

Growth Factor ◽

Leukemia Inhibitory Factor ◽

Collagen Gel ◽

Plasminogen Activator Inhibitor ◽

Inhibitory Effect ◽

Inhibitory Factor ◽

Tumor Promoter ◽

Endothelial Cell Proliferation ◽

Plasminogen Activator Inhibitor 1

Using an in vitro model in which endothelial cells can be induced to invade a three-dimensional collagen gel to form capillary-like tubular structures, we demonstrate that leukemia inhibitory factor (LIF) inhibits angiogenesis in vitro. The inhibitory effect was observed on both bovine aortic endothelial (BAE) and bovine microvascular endothelial (BME) cell, and occurred irrespective of the angiogenic stimulus, which included basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), the synergistic effect of the two in combination, or the tumor promoter phorbol myristate acetate. LIF inhibited bFGF- and VEGF-induced proliferation in BAE and BME cells. In addition, LIF inhibited BAE but not BME cell migration in a conventional two-dimensional assay. Finally, LIF decreased the proteolytic activity of BAE and BME cells and increased their expression of plasminogen activator inhibitor-1. These results demonstrate that LIF inhibits angiogenesis in vitro, an effect that can be correlated with a LIF-mediated decrease in endothelial cell proliferation, migration and extracellular proteolysis.

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