Mapping of the human gene encoding the mutual signal-transducing subunit (?-chain) of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) receptor complexes to chromosome 22q13.1

1994 ◽  
Vol 93 (2) ◽  
Author(s):  
S. Takai ◽  
K. Yamada ◽  
N. Hirayama ◽  
A. Miyajima ◽  
T. Taniyama
Keyword(s):  
Human Gene ◽  
Colony Stimulating Factor ◽  
Gene Encoding ◽  
Interleukin 5 ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Receptor Complexes ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Identification through chemical cross-linking of distinct granulocyte- macrophage colony-stimulating factor and interleukin-3 receptors on myeloid leukemic cells, KG-1

Blood ◽  
1989 ◽  
Vol 74 (8) ◽  
pp. 2652-2656 ◽  
Author(s):  
T Gesner ◽  
RA Mufson ◽  
KJ Turner ◽  
SC Clark
Keyword(s):  
Binding Proteins ◽  
Myelogenous Leukemia ◽  
Cross Linking ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Chemical Cross Linking

Abstract Granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) each bind specifically to a small number of high- affinity receptors present on the surface of the cells of the acute myelogenous leukemia line, KG-1. Through chemical cross-linking of IL-3 and GM-CSF to KG-1 cells, we identified distinct binding proteins for each of these cytokines with approximate molecular masses of 69 and 93 Kd, respectively. Although these two binding proteins are distinct, GM- CSF and IL-3 compete with each other for binding to KG-1 cells. Other cell lines, which express receptors for either factor but not for both do not display this cross-competition for binding with IL-3 and GM-CSF. These findings imply that distinct IL-3 and GM-CSF binding proteins are expressed on the cell surface and that an association exists between these proteins on KG-1 cells.

scholarly journals A Truncated Isoform of the Human β Chain Common to the Receptors for Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-3 (IL-3), and IL-5 With Increased mRNA Expression in Some Patients With Acute Leukemia

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 54-63 ◽  
Author(s):  
Rosemary E. Gale ◽  
Robin W. Freeburn ◽  
Asim Khwaja ◽  
Rajesh Chopra ◽  
David C. Linch
Keyword(s):  
Amino Acids ◽  
Acute Leukemia ◽  
Myeloid Cells ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Β Chain ◽  
Stimulating Factor

We report here a naturally occurring isoform of the human β chain common to the receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 (GMRβC) with a truncated intracytoplasmic tail caused by deletion of a 104-bp exon in the membrane-proximal region of the chain. This β intracytoplasmic truncated chain (βIT) has a predicted tail of 46 amino acids, instead of 432 for βC, with 23 amino acids in common with βC and then a new sequence of 23 amino acids. In primary myeloid cells, βIT comprised approximately 20% of the total β chain message, but was increased up to 90% of total in blast cells from a significant proportion of patients with acute leukemia. Specific anti-βITantibodies demonstrated its presence in primary myeloid cells and cell lines. Coexpression of βIT converted low-affinity GMRα chains (KD 2.5 nmol/L) to higher-affinity αβ complexes (KD 200 pmol/L). These could bind JAK2 that was tyrosine-phosphorylated by stimulation with GM-CSF. βITdid not support GM-CSF–induced proliferation when cotransfected with GMRα into CTLL-2 cells. Therefore, it may interfere with the signal-transducing properties of the βC chain and play a role in the pathogenesis of leukemia.

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.

scholarly journals A mutation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and IL-5 that leads to ligand independence and tumorigenicity

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2802-2808 ◽  
Author(s):  
R D'Andrea ◽  
J Rayner ◽  
P Moretti ◽  
A Lopez ◽  
GJ Goodall ◽  
...  
Keyword(s):  
Large Family ◽  
Mutant Form ◽  
Sequence Motifs ◽  
Colony Stimulating Factor ◽  
Interleukin 5 ◽  
Interleukin 3 ◽  
Conserved Sequence ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The cytokines interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor bind with high affinity to a receptor complex that contains a ligand-specific alpha-chain and a common beta-chain, h beta c. We report here the isolation of a mutant form of h beta c, from growth factor-independent cells, that arose spontaneously after infection of a murine factor-dependent hematopoietic cell line (FDC-P1) with a retroviral h beta c expression construct. Analysis of this h beta c mutation shows that a small (37 amino acid) duplication of extracellular sequence that includes two conserved sequence motifs is sufficient to confer ligand-independent growth on these cells and lead to tumourigenicity. Because this is a conserved region in the cytokine receptor superfamily, our results suggest that the large family of cytokine receptors has the capacity to become oncogenically active.

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.

scholarly journals The Human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF ) Receptor Exists as a Preformed Receptor Complex That Can Be Activated by GM-CSF, Interleukin-3, or Interleukin-5

Blood ◽  
1997 ◽  
Vol 90 (8) ◽  
pp. 3005-3017 ◽  
Author(s):  
Joanna M. Woodcock ◽  
Barbara J. McClure ◽  
Frank C. Stomski ◽  
Michael J. Elliott ◽  
Christopher J. Bagley ◽  
...  
Keyword(s):  
Myeloid Cell ◽  
Cytokine Receptor ◽  
Activation Mechanism ◽  
Receptor Complex ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The granulocyte-macrophage colony-stimulating factor (GM-CSF ) receptor is expressed on normal and malignant hematopoietic cells as well as on cells from other organs in which it transduces a variety of functions. Despite the widespread expression and pleiotropic nature of the GM-CSF receptor, little is known about its assembly and activation mechanism. Using a combination of biochemical and functional approaches, we have found that the human GM-CSF receptor exists as an inducible complex, analogous to the interleukin-3 (IL-3) receptor, and also as a preformed complex, unlike the IL-3 receptor or indeed other members of the cytokine receptor superfamily. We found that monoclonal antibodies to the GM-CSF receptor α chain (GMRα) and to the common β chain of the GM-CSF, IL-3, and IL-5 receptors (βc ) immunoprecipitated both GMRα and βc from the surface of primary myeloid cells, myeloid cell lines, and transfected cells in the absence of GM-CSF. Further association of the two chains could be induced by the addition of GM-CSF. The preformed complex required only the extracellular regions of GMRα and βc , as shown by the ability of soluble βc to associate with membrane-anchored GMRα or soluble GMRα. Kinetic experiments on eosinophils and monocytes with radiolabeled GM-CSF, IL-3, and IL-5 showed association characteristics unique to GM-CSF. Significantly, receptor phosphorylation experiments showed that not only GM-CSF but also IL-3 and IL-5 stimulated the phosphorylation of GMRα-associated βc . These results indicate a pattern of assembly of the heterodimeric GM-CSF receptor that is unique among receptors of the cytokine receptor superfamily. These results also suggest that the preformed GM-CSF receptor complex mediates the instantaneous binding of GM-CSF and is a target of phosphorylation by IL-3 and IL-5, raising the possibility that some of the biologic activities of IL-3 and IL-5 are mediated through the GM-CSF receptor complex.

Sequential administration of interleukin-3 and granulocyte-macrophage colony-stimulating factor following standard-dose combination chemotherapy with etoposide, ifosfamide, and cisplatin.

1992 ◽  
Vol 10 (9) ◽  
pp. 1452-1459 ◽  
Author(s):  
W Brugger ◽  
J Frisch ◽  
G Schulz ◽  
K Pressler ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
Standard Dose ◽  
Colony Stimulating Factor ◽  
Platelet Recovery ◽  
Neutrophil Recovery ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Sequential Administration ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE To combine the benefits of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on neutrophil recovery and recombinant human interleukin-3 (rhIL-3) on platelet recovery, we applied standard-dose chemotherapy with the combined administration of IL-3 and GM-CSF to investigate their efficacy and toxicity. PATIENTS AND METHODS Thirty-six patients with advanced malignancies were treated with etoposide (VP16) 500 mg/m2, ifosfamide 4 g/m2, and cisplatin 50 mg/m2 (VIP), followed by the sequential administration of IL-3 (days 1 to 5 subcutaneously [SC]) and GM-CSF (day 6 to 15 SC). Control patients received GM-CSF alone or were treated without hematopoietic growth factors. RESULTS Subcutaneous IL-3 and GM-CSF treatment was well tolerated; low-grade fever (World Health Organization grade 1 to 2) was the only consistent clinical symptom. Neutrophil recovery documented that the duration of neutropenia less than 0.1 x 10(9)/L or less than 0.5 x 10(9)/L was identical in GM-CSF as well as IL-3 and GM-CSF-treated patients, but was shortened significantly when compared with patients who were treated without cytokines. Overall platelet recovery was not different significantly in the three treatment groups. The biologic activity of IL-3 in this cytokine combination was reflected in a variety of effects, which included an increase in basophil and eosinophil counts and the induction of circulating hematopoietic progenitor cells. CONCLUSION We conclude that after conventional-dose VIP chemotherapy, a shortened treatment course of IL-3 (5 days) sequentially followed by GM-CSF (10 days) combines the benefits of prolonged single GM-CSF treatment on WBC count recovery in all patients and an accelerated platelet recovery only in some intensively pretreated patients.

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