Different epitopes are required for gp130 activation by interleukin-6, oncostatin M and leukemia inhibitory 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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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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Influence of Subunit Combinations on Signaling by Receptors for Oncostatin M, Leukemia Inhibitory Factor, and Interleukin-6

Journal of Biological Chemistry ◽

10.1074/jbc.272.24.15135 ◽

1997 ◽

Vol 272 (24) ◽

pp. 15135-15144 ◽

Cited By ~ 47

Author(s):

Karen K. Kuropatwinski ◽

Cyr De Imus ◽

David Gearing ◽

Heinz Baumann ◽

Bruce Mosley

Keyword(s):

Interleukin 6 ◽

Leukemia Inhibitory Factor ◽

Oncostatin M ◽

Inhibitory Factor

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Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)78174-5 ◽

1994 ◽

Vol 269 (15) ◽

pp. 11648-11655

Author(s):

T.G. Boulton ◽

N. Stahl ◽

G.D. Yancopoulos

Keyword(s):

Growth Factors ◽

Tyrosine Phosphorylation ◽

Interleukin 6 ◽

Neurotrophic Factor ◽

Leukemia Inhibitory Factor ◽

Ciliary Neurotrophic Factor ◽

Oncostatin M ◽

Inhibitory Factor

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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.v85.2.379.379 ◽

1995 ◽

Vol 85 (2) ◽

pp. 379-390 ◽

Cited By ~ 37

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.

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