Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6.

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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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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Expression of the fusion protein recombinant human granulocyte-macrophage colony stimulating factor and leukemia inhibitory factor in a baculovirus vector system

Journal of Industrial Microbiology & Biotechnology ◽

10.1038/sj.jim.2900699 ◽

1999 ◽

Vol 23 (2) ◽

pp. 103-105

Author(s):

X-W Zhang ◽

X-Y Zeng ◽

T Sun ◽

X Liu ◽

D-X Gu

Keyword(s):

Fusion Protein ◽

Leukemia Inhibitory Factor ◽

Inhibitory Factor ◽

Vector System ◽

Colony Stimulating Factor ◽

Baculovirus Vector ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Interleukin-6 and the Granulocyte Colony-Stimulating Factor Receptor Are Major Independent Regulators of Granulopoiesis In Vivo But Are Not Required for Lineage Commitment or Terminal Differentiation

Blood ◽

10.1182/blood.v90.7.2583.2583_2583_2590 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2583-2590 ◽

Cited By ~ 8

Author(s):

Fulu Liu ◽

Jennifer Poursine-Laurent ◽

Huai Yang Wu ◽

Daniel C. Link

Keyword(s):

Interleukin 6 ◽

Terminal Differentiation ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Normal Numbers ◽

Stimulating Factor ◽

Deficient Mice ◽

Additional Loss

Multiple hematopoietic cytokines can stimulate granulopoiesis; however, their relative importance in vivo and mechanisms of action remain unclear. We recently reported that granulocyte colony-stimulating factor receptor (G-CSFR)-deficient mice have a severe quantitative defect in granulopoiesis despite which phenotypically normal neutrophils were still detected. These results confirmed a role for the G-CSFR as a major regulator of granulopoiesis in vivo, but also indicated that G-CSFR independent mechanisms of granulopoiesis must exist. To explore the role of interleukin-6 (IL-6) in granulopoiesis, we generated IL-6 × G-CSFR doubly deficient mice. The additional loss of IL-6 significantly worsened the neutropenia present in young adult G-CSFR–deficient mice; moreover, exogenous IL-6 stimulated granulopoiesis in vivo in the absence of G-CSFR signals. Near normal numbers of myeloid progenitors were detected in the bone marrow of IL-6 × G-CSFR–deficient mice and their ability to terminally differentiate into mature neutrophils was observed. These results indicate that IL-6 is an independent regulator of granulopoiesis in vivo and show that neither G-CSFR or IL-6 signals are required for the commitment of multipotential progenitors to the myeloid lineage or for their terminal differentiation.

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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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Effects of Interleukin-6 and Granulocyte Colony-stimulating Factor on the Proliferation of Leukemic Blast Progenitors from Acute Myeloblastic Leukemia Patients

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1990.tb03335.x ◽

1990 ◽

Vol 81 (10) ◽

pp. 979-986 ◽

Cited By ~ 16

Author(s):

Toshiya Suzuki ◽

Tomohiro Morio ◽

Shuji Tohda ◽

Kaoru Nagata ◽

Yoko Yamashita ◽

...

Keyword(s):

Interleukin 6 ◽

Acute Myeloblastic Leukemia ◽

Leukemic Blast ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor

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

Blood ◽

10.1182/blood.v85.1.217.bloodjournal851217 ◽

1995 ◽

Vol 85 (1) ◽

pp. 217-221 ◽

Cited By ~ 8

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.

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