scholarly journals Effect of M20 interleukin-1 inhibitor on normal and leukemic human myeloid progenitors

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1172-1177 ◽  
Author(s):  
T Peled ◽  
M Rigel ◽  
D Peritt ◽  
E Fibach ◽  
AJ Treves ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Interleukin 1 ◽  
Hematopoietic Cells ◽  
Myeloid Cell ◽  
Leukemic Cells ◽  
True Negative ◽  
In Vitro Proliferation ◽  
Gm Csf ◽  
Liquid Systems

Abstract This study aimed to assess the effect of the M20 interleukin-1 (IL-1) inhibitor on normal and leukemic hematopoietic cells. The M20-derived IL-1 inhibitor was found to inhibit the growth of various hematopoietic cells. The in vitro proliferation of myeloid cell lines in serum- containing medium or proliferation of these cells induced by IL-1 in serum-free medium (measured by 3H-TdR) were inhibited by the M20 IL-1 inhibitor. In addition, growth of normal progenitors and fresh leukemic cells stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) (as measured by colony and liquid systems) was also inhibited by this factor. After the removal of the IL-1 inhibitor at the peak of growth inhibition, leukemic and normal progenitor cells retain their ability to grow and develop into GM-CSF colonies. These results show that the growth inhibition phenomena were reversible and did not result from a cytotoxic effect. Our data suggest that the M20-derived IL-1 inhibitor might function as a true negative growth regulator of normal and leukemic hematopoietic cells.

scholarly journals Effect of M20 interleukin-1 inhibitor on normal and leukemic human myeloid progenitors

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1172-1177
Author(s):  
T Peled ◽  
M Rigel ◽  
D Peritt ◽  
E Fibach ◽  
AJ Treves ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Interleukin 1 ◽  
Hematopoietic Cells ◽  
Myeloid Cell ◽  
Leukemic Cells ◽  
True Negative ◽  
In Vitro Proliferation ◽  
Gm Csf ◽  
Liquid Systems

This study aimed to assess the effect of the M20 interleukin-1 (IL-1) inhibitor on normal and leukemic hematopoietic cells. The M20-derived IL-1 inhibitor was found to inhibit the growth of various hematopoietic cells. The in vitro proliferation of myeloid cell lines in serum- containing medium or proliferation of these cells induced by IL-1 in serum-free medium (measured by 3H-TdR) were inhibited by the M20 IL-1 inhibitor. In addition, growth of normal progenitors and fresh leukemic cells stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) (as measured by colony and liquid systems) was also inhibited by this factor. After the removal of the IL-1 inhibitor at the peak of growth inhibition, leukemic and normal progenitor cells retain their ability to grow and develop into GM-CSF colonies. These results show that the growth inhibition phenomena were reversible and did not result from a cytotoxic effect. Our data suggest that the M20-derived IL-1 inhibitor might function as a true negative growth regulator of normal and leukemic hematopoietic cells.

scholarly journals Interleukin-6 (IL-6) is an intermediate in IL-1-induced proliferation of leukemic human megakaryoblasts

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 1972-1979 ◽  
Author(s):  
MA Brach ◽  
B Lowenberg ◽  
L Mantovani ◽  
U Schwulera ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
Thymidine Incorporation ◽  
Interleukin 1 ◽  
Leukemic Cells ◽  
Megakaryoblastic Leukemia ◽  
Gm Csf ◽  
Endogenous Production ◽  
Neutralizing Monoclonal Antibody ◽  
In Vitro Effects ◽  
Stimulating Factor

Abstract We have examined the in vitro effects of recombinant human (rh) interleukin-1 (IL-1) on the growth of purified megakaryoblasts obtained from patients with acute megakaryoblastic leukemia. We demonstrate that both IL-1 alpha and IL-1 beta treatment of these cells led to stimulation of DNA synthesis (as shown by increase of 3H-thymidine incorporation up to 35-fold) and also resulted in colony formation of leukemic megakaryoblasts. However, the stimulatory effect of IL-1 was dependent on endogenous production of IL-6, because addition of neutralizing monoclonal antibody (MoAb) to IL-6 abrogated the stimulatory activity of IL-1. In contrast, neutralizing MoAbs to granulocyte (G)-colony stimulating factor (CSF), granulocyte-macrophage (GM)-CSF, and macrophage (M)-CSF failed to counteract the growth- enhancing effects of IL-1. Leukemic megakaryoblasts accumulated IL-6 mRNA and released IL-6 protein into their culture supernatant when exposed to rh IL-1 but failed to disclose transcripts for G-, GM-, and M-CSF under these conditions. Analysis of IL-6 receptor (IL-6R) transcript levels demonstrated that megakaryoblasts constitutively expressed IL-6R mRNA and that these transcripts are down-regulated to undetectable levels upon exposure to IL-1 and IL-6. Increase of 3H- thymidine incorporation by megakaryoblasts could be duplicated by exogenous IL-6 that could be blocked by neutralizing MoAb to IL-6. In conclusion, our results suggest that leukemic megakaryoblasts could produce and secrete IL-6, and express IL-6R, and that the growth- enhancing effect of IL-1 on these cells is indirect, via production of IL-6 by leukemic cells.

scholarly journals Vascular endothelial cells and granulopoiesis: interleukin-1 stimulates release of G-CSF and GM-CSF

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 99-103 ◽  
Author(s):  
KM Zsebo ◽  
VN Yuschenkoff ◽  
S Schiffer ◽  
D Chang ◽  
E McCall ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Interleukin 1 ◽  
Colony Growth ◽  
Mononuclear Phagocytes ◽  
Conditioned Media ◽  
Leukemic Cells ◽  
Gm Csf ◽  
Growth Assay

Abstract Cultured mononuclear phagocytes produce soluble factors that stimulate endothelial cells to release GM-colony-stimulating activity (GM-CSA). One such factor was recently identified as interleukin 1 (IL 1). Studies were designed to determine which types of granulopoietic factors are released by IL 1-stimulated endothelial cells. Supernatants from endothelial cells cultured for 3 days in medium containing IL 1 alpha and beta were tested in both murine and human CFU-GM colony growth assays. The effect of conditioned media on differentiation of WEHI-3B myelomonocytic leukemic cells was also examined. Control media containing IL 1 alone or unstimulated endothelial cell-conditioned media contained no detectable CSA in any bioassay. Medium conditioned by IL 1-stimulated endothelial cells stimulated the clonal growth of both human and murine CFU-GM and induced macrophage differentiation of WEHI-3B cells. Treatment of these conditioned media with a highly specific neutralizing monoclonal G-CSF antibody completely inhibited their activity in the murine CFU-GM assay, but only partially inhibited GM colony growth by human marrow. Treatment of the active conditioned media with a neutralizing rabbit anti-human GM-CSF antibody partially reduced the activity of the media in the human GM-colony growth assay. G-CSF radioimmunoassay of endothelial cell culture supernatants and Northern blot analysis of endothelial cell cytoplasmic RNA for GM-CSF gene transcripts confirmed that IL 1 induced expression of both G-CSF and GM-CSF genes. Because treatment of media with both antibodies abrogated all activity in the human GM colony growth assay, we conclude that IL 1-stimulated endothelial cells release both G and GM-CSF and that these are the only granulopoietic factors detectable in clonogenic assays released by these cells in vitro.

scholarly journals Differentiation state and responses to hematopoietic growth factors of murine myeloid cells transformed by myb

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2813-2822 ◽  
Author(s):  
TJ Gonda ◽  
EM Macmillan ◽  
PV Townsend ◽  
AJ Hapel
Keyword(s):  
Growth Factors ◽  
Hematopoietic Cells ◽  
Myeloid Cell ◽  
Surface Markers ◽  
Colony Stimulating Factor ◽  
Monocytic Differentiation ◽  
Hematopoietic Growth Factors ◽  
Gm Csf ◽  
Stimulating Factor

Murine hematopoietic cells can be transformed in vitro by recombinant retroviruses that express the myb oncogene, and hematopoietic growth factor (HGF)-dependent myeloid cell lines can be derived from these transformed primary cells. In this study, the differentiation state and responses of myb-transformed hematopoietic cells (MTHCs) have been investigated. We find that MTHCs exhibit properties of early myeloid progenitors including synergistic responses to combinations of HGFs and expression of certain surface markers. As reported previously, MTHCs respond well to granulocyte-macrophage colony-stimulating factor (GM- CSF) but can also respond to interleukin-3 (IL-3); the response to the latter factor depends on the mouse strain from which the cells are derived. Although these single factors stimulate MTHCs, combinations of these factors with colony-stimulating factor-1 (CSF-1 or M-CSF) or Steel factor (SLF or SCF) act synergistically to promote colony formation. The surface markers expressed by MTHCs include both granulocyte-macrophage lineage specific antigens Gr-1, 7/4, F4/80, and Mac-1, as well as two antigens found on early progenitors and stem cells--Thy-1 and Sca-1 (Ly6E). Expression of the latter markers is often heterogeneous and can be modulated by the growth factors to which the cells are exposed. Finally, we show that monocytic differentiation of MTHCs can be induced by exposure to tumor necrosis factor (TNF alpha). Taken together, these results suggest that MTHCs will be a useful model for studying HGF/cytokine responses in both proliferation and differentiation.

Autocrine secretion of GM-CSF in acute myeloblastic leukemia

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1178-1181 ◽  
Author(s):  
DC Young ◽  
JD Griffin
Keyword(s):  
Blot Hybridization ◽  
Cdna Probe ◽  
Constitutive Expression ◽  
Leukemic Cell ◽  
Acute Myeloblastic Leukemia ◽  
Leukemic Cells ◽  
Northern Blot Hybridization ◽  
In Vitro Proliferation ◽  
Gm Csf

Abstract Three cases of acute myeloblastic leukemia (AML) were identified in which clonogenic cells proliferated autonomously in vitro. Cells from two of these cases were found to secrete a colony-stimulating factor (CSF) that was immunologically and molecularly related to GM-CSF. Growth of AML-CFU could be blocked by the addition of a neutralizing antiserum to GM-CSF. Northern blot hybridization of leukemic cell mRNA with a cDNA probe for the GM-CSF gene revealed a 1-kb message identical in size to the normal GM-CSF message in stimulated T cells. No GM-CSF message was detected in the third case. These results indicate that constitutive expression of the GM-CSF gene, apparently by leukemic cells, can result in autonomous in vitro proliferation of AML-CFU in some cases of AML.

Differentiation state and responses to hematopoietic growth factors of murine myeloid cells transformed by myb

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2813-2822 ◽  
Author(s):  
TJ Gonda ◽  
EM Macmillan ◽  
PV Townsend ◽  
AJ Hapel
Keyword(s):  
Growth Factors ◽  
Hematopoietic Cells ◽  
Myeloid Cell ◽  
Surface Markers ◽  
Colony Stimulating Factor ◽  
Monocytic Differentiation ◽  
Hematopoietic Growth Factors ◽  
Gm Csf ◽  
Stimulating Factor

Abstract Murine hematopoietic cells can be transformed in vitro by recombinant retroviruses that express the myb oncogene, and hematopoietic growth factor (HGF)-dependent myeloid cell lines can be derived from these transformed primary cells. In this study, the differentiation state and responses of myb-transformed hematopoietic cells (MTHCs) have been investigated. We find that MTHCs exhibit properties of early myeloid progenitors including synergistic responses to combinations of HGFs and expression of certain surface markers. As reported previously, MTHCs respond well to granulocyte-macrophage colony-stimulating factor (GM- CSF) but can also respond to interleukin-3 (IL-3); the response to the latter factor depends on the mouse strain from which the cells are derived. Although these single factors stimulate MTHCs, combinations of these factors with colony-stimulating factor-1 (CSF-1 or M-CSF) or Steel factor (SLF or SCF) act synergistically to promote colony formation. The surface markers expressed by MTHCs include both granulocyte-macrophage lineage specific antigens Gr-1, 7/4, F4/80, and Mac-1, as well as two antigens found on early progenitors and stem cells--Thy-1 and Sca-1 (Ly6E). Expression of the latter markers is often heterogeneous and can be modulated by the growth factors to which the cells are exposed. Finally, we show that monocytic differentiation of MTHCs can be induced by exposure to tumor necrosis factor (TNF alpha). Taken together, these results suggest that MTHCs will be a useful model for studying HGF/cytokine responses in both proliferation and differentiation.

scholarly journals The nature and action of granulocyte-macrophage colony stimulating factors

Blood ◽  
1980 ◽  
Vol 56 (6) ◽  
pp. 947-958 ◽  
Author(s):  
AW Burgess ◽  
D Metcalf
Keyword(s):  
Progenitor Cells ◽  
Leukemic Cells ◽  
Mouse Lung ◽  
Target Cells ◽  
In Vitro Production ◽  
In Vitro Proliferation ◽  
Gm Csf ◽  
Macrophage Colony

Granulocyte-macrophage colony stimulating factor (GM-CSF) stimulates the in vitro proliferation and differentiation of granulocytic and macrophage cells. This regulator is now known to act at other levels of hemopoietic regulation. The heterogeneity of GM-CSFs is not only related to the tissue of origin and the in vitro production method, but also to functional subclasses of the molecule that have distinct biologic specificities. Most adult mouse organs produce GM-CSF (mol wt 23,000), but a macrophage (M)-CSF has been detected in fetal conditioned medium (CM) and isolated from L-cell CM. Murine endotoxin serum appears to contain a M-CSF, GM-CSF, and G-CSF, the last of which cofractionates with a differentiation factor active on leukemic cells. Human GM-CSFs, G-CSF, and EO-CSFs active on human cells have been detected in a variety of CM, but as yet none have been purified. Again, there are subclasses of progenitor cells that respond to particular forms of human active CSFs. GM-CSF isolated from mouse lung CM stimulates multipotential progenitor cells, the initial proliferatin of progenitors in the erythroid, eosinophil, and megakaryocyte series, as well as mature cells in the GM series. While GM-CSF is also able to stimulate the differentiation of myeloid leukemic cells, other factors appear to be more potent in this respect. Information on the regulation of GM-CSF production, on the modulators of its action on specific target cells, and on its role in vivo will be required before the physiologic function of this molecule can be properly assessed.

scholarly journals The nature and action of granulocyte-macrophage colony stimulating factors

Blood ◽  
1980 ◽  
Vol 56 (6) ◽  
pp. 947-958 ◽  
Author(s):  
AW Burgess ◽  
D Metcalf
Keyword(s):  
Progenitor Cells ◽  
Leukemic Cells ◽  
Mouse Lung ◽  
Target Cells ◽  
In Vitro Production ◽  
In Vitro Proliferation ◽  
Gm Csf ◽  
Macrophage Colony

Abstract Granulocyte-macrophage colony stimulating factor (GM-CSF) stimulates the in vitro proliferation and differentiation of granulocytic and macrophage cells. This regulator is now known to act at other levels of hemopoietic regulation. The heterogeneity of GM-CSFs is not only related to the tissue of origin and the in vitro production method, but also to functional subclasses of the molecule that have distinct biologic specificities. Most adult mouse organs produce GM-CSF (mol wt 23,000), but a macrophage (M)-CSF has been detected in fetal conditioned medium (CM) and isolated from L-cell CM. Murine endotoxin serum appears to contain a M-CSF, GM-CSF, and G-CSF, the last of which cofractionates with a differentiation factor active on leukemic cells. Human GM-CSFs, G-CSF, and EO-CSFs active on human cells have been detected in a variety of CM, but as yet none have been purified. Again, there are subclasses of progenitor cells that respond to particular forms of human active CSFs. GM-CSF isolated from mouse lung CM stimulates multipotential progenitor cells, the initial proliferatin of progenitors in the erythroid, eosinophil, and megakaryocyte series, as well as mature cells in the GM series. While GM-CSF is also able to stimulate the differentiation of myeloid leukemic cells, other factors appear to be more potent in this respect. Information on the regulation of GM-CSF production, on the modulators of its action on specific target cells, and on its role in vivo will be required before the physiologic function of this molecule can be properly assessed.

scholarly journals In vivo modulation with anti-interleukin-1 (IL-1) receptor (p80) antibody 35F5 of the response to IL-1. The relationship of radioprotection, colony-stimulating factor, and IL-6

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 57-62 ◽  
Author(s):  
R Neta ◽  
SN Vogel ◽  
JM Plocinski ◽  
NS Tare ◽  
W Benjamin ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Myeloid Cell ◽  
Natural Resistance ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Relationship Of ◽  
The Relationship ◽  
Stimulating Factor

Abstract Interleukin-1 (IL-1) is radioprotective and induces both circulating colony-stimulating factor(s) (CSF) and IL-6 in mice. We evaluated the relationship among these three responses to IL-1 using anti-IL-1 receptor antibody 35F5. This antibody in vitro blocks responses of T cells and fibroblasts, but not of B cells or myeloid cell lines, to IL- 1. Administration of 35F5 alone before irradiation reduced the number of surviving mice compared with those not treated with 35F5, demonstrating that endogenous IL-1 participates in the natural resistance to radiation. Thirty micrograms of 35F5 per mouse also reduced by 92% the survival of irradiated mice pretreated with 0.3 micrograms of IL-1. Similarly, 30 micrograms of 35F5 reduced by 96% to 98% the induction of IL-6 by IL-1. In contrast, 30 micrograms of 35F5 resulted in only moderate reduction of circulating CSF. Consequently, the level of circulating CSF after 35F5 treatment was still equivalent to levels of CSF that were induced by doses of IL-1 in the radioprotective range. Because treatment with 35F5 antibody resulted in the blocking of IL-1-reduced radioprotection, the above results suggest that circulating CSF, by itself, may not be sufficient for radioprotection. This conclusion supports our previous results which showed that granulocyte-macrophage CSF (GM-CSF) and G-CSF were radioprotective only when administered with suboptimal doses of IL-1.

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