Production of IL-5 and granulocyte-macrophage colony-stimulating factor by naive human mast cells activated by high-affinity IgE receptor ligation

1997 ◽  
Vol 99 (4) ◽  
pp. 508-514 ◽  
Author(s):  
R BRESSLER ◽  
J LESKO ◽  
M JONES ◽  
M WASSERMAN ◽  
R DICKASON ◽  
...  
Keyword(s):  
Mast Cells ◽  
Colony Stimulating Factor ◽  
Ige Receptor ◽  
High Affinity ◽  
Human Mast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
High Affinity Ige Receptor ◽  
Receptor Ligation ◽  
Stimulating Factor

Reconstituted human granulocyte-macrophage colony-stimulating factor receptor transduces growth-promoting signals in mouse NIH 3T3 cells: comparison with signalling in BA/F3 pro-B cells

1993 ◽  
Vol 13 (3) ◽  
pp. 1440-1448
Author(s):  
S Watanabe ◽  
A L Mui ◽  
A Muto ◽  
J X Chen ◽  
K Hayashida ◽  
...  
Keyword(s):  
Colony Stimulating Factor ◽  
3T3 Cells ◽  
Gm Csf ◽  
High Affinity ◽  
Macrophage Colony Stimulating Factor ◽  
Growth Promoting ◽  
Macrophage Colony ◽  
Nih 3T3 ◽  
Stimulating Factor ◽  
Nih 3T3 Cells

Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical role in growth and differentiation of myeloid cells. We previously reconstituted high-affinity human GM-CSF receptor (hGM-CSFR) in a pro-B cell line, BA/F3, by cotransfecting alpha- and beta-chain cDNA clones and showed that the reconstituted receptor could transduce growth-promoting signals. The high-affinity hGM-CSFR was also reconstituted in mouse NIH 3T3 cells, but its ability to transduce signals in fibroblasts remained undetermined. In the present study, we further characterized signal transduction by the reconstituted hGM-CSFR in both NIH 3T3 cells and BA/F3 cells. We found that the reconstituted hGM-CSFR transduces signals in NIH 3T3 fibroblasts and BA/F3 cells in response to hGM-CSF to activate transcription of the c-fos, c-jun, and c-myc proto-oncogenes. hGM-CSF also induces protein tyrosine phosphorylation and DNA synthesis in both cell types. These results indicated that hGM-CSFR is functional in fibroblasts, that signal transduction via hGM-CSFR in fibroblasts involves tyrosine kinase(s), and that association of hGM-CSFR with a factor(s) specific to hematopoietic cell lineage is not essential to transduce growth-promoting signals.

scholarly journals Differential activation of leukotriene biosynthesis by granulocyte- macrophage colony-stimulating factor and interleukin-5 in an eosinophilic substrain of HL-60 cells

Blood ◽  
1995 ◽  
Vol 86 (9) ◽  
pp. 3507-3516 ◽  
Author(s):  
KA Scoggan ◽  
AW Ford-Hutchinson ◽  
DW Nicholson
Keyword(s):  
Binding Sites ◽  
Affinity Binding ◽  
Colony Stimulating Factor ◽  
High Affinity Binding ◽  
Interleukin 5 ◽  
Gm Csf ◽  
High Affinity ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Cytokines can stimulate eosinophils to produce cysteinyl leukotrienes (LTs) in the lung that provoke tissue destruction associated with asthma. Priming of an eosinophilic substrain of HL-60 cells (HL-60#7) with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) before ionophore challenge was found to produce an apparent 45% increase in total LT production in a dose-dependent manner (ED50 = 150 pmol/L) that could be accounted for by a decrease in the time required for maximal formation of LTs. GM-CSF had no effect on the kinetic parameters of LTC4 synthase and therefore probably acts upstream of this catalytic event. Incubation with interleukin-5 (IL-5), however, had no effect on LT biosynthesis. This differential priming ability was not a consequence of different receptor populations or differences in the affinity or stability of the ligand-receptor complexes of GM-CSF and IL-5. GM-CSF and IL-5 each displayed similar populations of high-affinity binding sites and neither GM-CSF nor IL-5 were able to cross-compete for the other's receptor binding sites. Analysis of phosphotyrosine patterns suggest that IL-5 is incapable of transducing a signal in eosinophilic HL-60#7 cells even though IL-5 and GM-CSF receptors mediate signal transduction via a common beta-chain component that is also necessary for high-affinity binding. Overall, this unique system may permit the dissection of distinct events responsible for specific intracellular signals transduced separately by GM-CSF or IL-5.

Simultaneous Antagonism of Interleukin-5, Granulocyte-Macrophage Colony-Stimulating Factor, and Interleukin-3 Stimulation of Human Eosinophils by Targetting the Common Cytokine Binding Site of Their Receptors

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1943-1951 ◽  
Author(s):  
Q. Sun ◽  
K. Jones ◽  
B. McClure ◽  
B. Cambareri ◽  
B. Zacharakis ◽  
...  
Keyword(s):  
Affinity Binding ◽  
Colony Stimulating Factor ◽  
High Affinity Binding ◽  
Receptor Dimerization ◽  
Interleukin 5 ◽  
Gm Csf ◽  
High Affinity ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Human interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3 are eosinophilopoietic cytokines implicated in allergy in general and in the inflammation of the airways specifically as seen in asthma. All 3 cytokines function through cell surface receptors that comprise a ligand-specific  chain and a shared subunit (βc). Although binding of IL-5, GM-CSF, and IL-3 to their respective receptor  chains is the first step in receptor activation, it is the recruitment of βc that allows high-affinity binding and signal transduction to proceed. Thus, βc is a valid yet untested target for antiasthma drugs with the added advantage of potentially allowing antagonism of all 3 eosinophil-acting cytokines with a single compound. We show here the first development of such an agent in the form of a monoclonal antibody (MoAb), BION-1, raised against the isolated membrane proximal domain of βc. BION-1 blocked eosinophil production, survival, and activation stimulated by IL-5 as well as by GM-CSF and IL-3. Studies of the mechanism of this antagonism showed that BION-1 prevented the high-affinity binding of125I–IL-5, 125I–GM-CSF, and125I–IL-3 to purified human eosinophils and that it bound to the major cytokine binding site of βc. Interestingly, epitope analysis using several βc mutants showed that BION-1 interacted with residues different from those used by IL-5, GM-CSF, and IL-3. Furthermore, coimmunoprecipitation experiments showed that BION-1 prevented ligand-induced receptor dimerization and phosphorylation of βc, suggesting that ligand contact with βc is a prerequisite for recruitment of βc, receptor dimerization, and consequent activation. These results demonstrate the feasibility of simultaneously inhibiting IL-5, GM-CSF, and IL-3 function with a single agent and that BION-1 represents a new tool and lead compound with which to identify and generate further agents for the treatment of eosinophil-dependent diseases such as asthma.

Simultaneous Antagonism of Interleukin-5, Granulocyte-Macrophage Colony-Stimulating Factor, and Interleukin-3 Stimulation of Human Eosinophils by Targetting the Common Cytokine Binding Site of Their Receptors

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1943-1951 ◽  
Author(s):  
Q. Sun ◽  
K. Jones ◽  
B. McClure ◽  
B. Cambareri ◽  
B. Zacharakis ◽  
...  
Keyword(s):  
Affinity Binding ◽  
Colony Stimulating Factor ◽  
High Affinity Binding ◽  
Receptor Dimerization ◽  
Interleukin 5 ◽  
Gm Csf ◽  
High Affinity ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Human interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3 are eosinophilopoietic cytokines implicated in allergy in general and in the inflammation of the airways specifically as seen in asthma. All 3 cytokines function through cell surface receptors that comprise a ligand-specific  chain and a shared subunit (βc). Although binding of IL-5, GM-CSF, and IL-3 to their respective receptor  chains is the first step in receptor activation, it is the recruitment of βc that allows high-affinity binding and signal transduction to proceed. Thus, βc is a valid yet untested target for antiasthma drugs with the added advantage of potentially allowing antagonism of all 3 eosinophil-acting cytokines with a single compound. We show here the first development of such an agent in the form of a monoclonal antibody (MoAb), BION-1, raised against the isolated membrane proximal domain of βc. BION-1 blocked eosinophil production, survival, and activation stimulated by IL-5 as well as by GM-CSF and IL-3. Studies of the mechanism of this antagonism showed that BION-1 prevented the high-affinity binding of125I–IL-5, 125I–GM-CSF, and125I–IL-3 to purified human eosinophils and that it bound to the major cytokine binding site of βc. Interestingly, epitope analysis using several βc mutants showed that BION-1 interacted with residues different from those used by IL-5, GM-CSF, and IL-3. Furthermore, coimmunoprecipitation experiments showed that BION-1 prevented ligand-induced receptor dimerization and phosphorylation of βc, suggesting that ligand contact with βc is a prerequisite for recruitment of βc, receptor dimerization, and consequent activation. These results demonstrate the feasibility of simultaneously inhibiting IL-5, GM-CSF, and IL-3 function with a single agent and that BION-1 represents a new tool and lead compound with which to identify and generate further agents for the treatment of eosinophil-dependent diseases such as asthma.

scholarly journals Production of granulocyte-macrophage colony-stimulating factor by Abelson virus-induced tumorigenic mast cell lines

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1074-1081
Author(s):  
SW Chung ◽  
PM Wong ◽  
G Shen-Ong ◽  
S Ruscetti ◽  
T Ishizaka ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Lines ◽  
Colony Formation ◽  
Northern Analysis ◽  
Pokeweed Mitogen ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

We have recently described a system that supports the development of continuously growing and tumorigenic cell lines after infection of individual multilineage hematopoietic colonies with Abelson murine leukemia virus (A-MuLV). We now provide definitive evidence that these transformed lines express features characteristic of mast cells. Although these lines have been maintained in some cases for more than a year in the absence of exogenous growth factors other than those present in fetal calf serum, colony formation could consistently after 2 months, and variably after 5 months, be shown to be increased several fold when pokeweed mitogen-stimulated spleen cell conditioned medium (CM) was added to the cultures. CM from the A-MuLV-transformed lines was then tested for its ability to stimulate hematopoietic colony formation by cells from both fetal and adult tissues. Four of four randomly selected cell lines produced factors that were active on erythropoietic, granulopoietic, and in some cases pluripotent progenitors. Removal of viral particles from the CM from one of the lines (27d1) by either heat inactivation or high-speed centrifugation did not alter the colony-stimulating activity detected. When CM from 27d1 cells was tested for its ability to stimulate the proliferation of interleukin 3 (IL3) granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent FDC-P1 cells, a positive result was obtained. This stimulatory activity was not reduced in the presence of neutralizing anti-IL 3 immunoglobulin (Ig), suggesting that the activity detected was GM-CSF and not IL 3. This was confirmed by the lack of expression of the IL 3 gene in 27d1 cells as determined by Northern analysis of 27d1 cell RNA. Furthermore, S1 analysis of mRNA from 27d1 cells as well as two other lines indicated that the GM-CSF gene in all three was transcriptionally active. Taken together, these data suggest that A- MuLV transformation of normal mast cells or their precursors under certain conditions commonly activates the production of GM-CSF.

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