The interleukin-5 (IL-5) receptor is a heterodimer that consists of an IL-5 specific alpha subunit and a common ssc chain that is shared with the receptors for granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-3 (IL-3). In contrast to IL-5, which acts mainly as an eosinophil lineage specific factor in vivo, IL-3 and GM-CSF stimulate the survival, proliferation and development of various hematopoietic cell lineages and also multipotent progenitor cells. IL-5 has little effect on the survival or proliferation of the multipotent stem cell line FDCP-Mix A4 but does promote some eosinophil development. To investigate whether the lineage specificity of IL-5 is due to the restricted expression of the IL-5 receptor alpha subunit we transfected the FDCP-Mix A4 cells with a retroviral vector containing this alpha subunit. The ectopic expression of the IL-5 receptor alpha subunit in the FDCP-Mix cells did not increase the observed eosinophilic development but did stimulate survival and proliferation of the transfected cells when IL-5 was added. IL-5 thus acts like IL-3 in these cells, promoting proliferation and survival. The results suggest that IL-5, whilst having a capacity to promote proliferation, does not influence eosinophilic lineage commitment in these multipotent cells. The results further argue that the observed lineage specificity of IL-5 is probably due to factors in addition to the restricted expression of the IL-5 receptor alpha subunit.
REFERENCES
Bagley
C. J.
, Woodcock
J. M.
, Stomski
F. C.
, Lopez
A. F.
(1997
). The structural and functional basis of cytokine receptor activation: lessons from the common beta subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors.
Blood
89
, 1471
–1482
Fairbairn
L. J.
, Cowling
G. J.
, Reipert
B. M.
, Dexter
T. M.
(1993
). Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors.
Cell
74
, 823
–832
Gasson
J. C.
(1991
). Molecular physiology of granulocyte-macrophage colony-stimulating factor.
Blood
77
, 1131
–1145
Gearing
D. P.
, King
J. A.
, Gough
N. M.
, Nicola
N. A.
(1989
). Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor.
EMBO J
8
, 3667
–3676
Gorman
D. M.
, Itoh
N.
, Jenkins
N. A.
, Gilbert
D. J.
, Copeland
N. G.
, Miyajima
A.
(1992
). Chromosomal localization and organization of the murine genes encoding the beta subunits (AIC2A and AIC2B) of the interleukin 3, granulocyte/macrophage colony-stimulating factor, and interleukin 5 receptors.
J. Biol. Chem
267
, 15842
–15848
Hara
T.
, Miyajima
A.
(1992
). Two distinct functional high affinity receptors for mouse interleukin-3 (IL-3).
EMBO J
11
, 1875
–1884
Heldin
C. H.
(1995
). Dimerization of cell surface receptors in signal transduction.
Cell
80
, 213
–223
Heyworth
C. M.
, Dexter
T. M.
, Kan
O.
, Whetton
A. D.
(1990
). The role of hemopoietic growth factors in self-renewal and differentiation of IL-3-dependent multipotential stem cells.
Growth Factors
2
, 197
–211
Heyworth
C. M.
, Dexter
T. M.
, Nicholls
S. E.
, Whetton
A. D.
(1994
). Combinations of colony-stimulating factors promote enhanced proliferative potential in enriched granulocyte-macrophage colony-forming cells.
Exp. Hematol
22
, 1089
–1094
Hitoshi
Y.
, Yamaguchi
N.
, Mita
S.
, Sonoda
E.
, Takaki
S.
, Tominaga
A.
, Takatsu
K.
(1990
). Distribution of IL-5 receptor-positive B cells. Expression of IL-5 receptor on Ly-1(CD5)+B cells.
J. Immunol
144
, 4218
–4225
Hu
M.
, Krause
D.
, Greaves
M.
, Sharkis
S.
, Dexter
T. M.
, Heyworth
C. M.
, Enver
T.
(1997
). Multilineage gene expression preceeds commitment in the haemopoietic system.
Genes Dev
14
, 512
–524
Itoh
N.
, Yonehara
S.
, Schreurs
J.
, Gorman
D. M.
, Maruyama
K.
, Ishii
A.
, Yahara
I.
, Arai
K.
, Miyajima
A.
(1990
). Cloning of an interleukin-3 receptor gene: a member of a distinct receptor gene family.
Science
247
, 324
–327
Johnson
G. R.
, Metcalf
D.
(1980
). Detection of a new type of mouse eosinophil colony by Luxol-fast-blue staining.
Exp. Hematol
8
, 549
–561
Just
U.
, Stocking
C.
, Spooncer
E.
, Dexter
T. M.
, Ostertag
W.
(1991
). Expression of the GM-CSF gene after retroviral transfer in hematopoietic stem cell lines induces synchronous granulocyte-macrophage differentiation.
Cell
64
, 1163
–1173
Karasuyama
H.
, Melchers
F.
(1988
). Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors.
Eur. J. Immunol
18
, 97
–104
Kinoshita
T.
, Yokota
T.
, Arai
K.
, Miyajima
A.
(1995
). Suppression of apoptotic death in hematopoietic cells by signalling through the IL-3/GM-CSF receptors.
EMBO J
14
, 266
–275
Kitamura
T.
, Sato
N.
, Arai
K.
, Miyajima
A.
(1991
). Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors.
Cell
66
, 1165
–1174
Kopf
M.
, Brombacher
F.
, Hodgkin
P. D.
, Ramsay
A. J.
, Milbourne
E. A.
, Dai
W. J.
, Ovington
K. S.
, Behm
C. A.
, Kohler
G.
, Young
I. G.
, et al. (1996
). IL-5-deficient mice have a developmental defect in CD5+B-1cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses.
Immunity
4
, 15
–24
Laker
C.
, Stocking
C.
, Bergholz
U.
, Hess
N.
, De Lamarter
J. F.
, Ostertag
W.
(1987
). Autocrine stimulation after transfer of the granulocyte/macrophage colony-stimulating factor gene and autonomous growth are distinct but interdependent steps in the oncogenic pathway.
Proc. Nat. Acad. Sci. USA
84
, 8458
–8462
Lin
C. S.
, Lim
S. K.
, Dagati
V.
, Costantini
F.
(1996
). Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis.
Genes Dev
10
, 154
–164
Markowitz
D.
, Goff
S.
, Bank
A.
(1988
). Construction and use of a safe and efficient amphotropic packaging cell line.
Virology
167
, 400
–406
Markowitz
D.
, Goff
S.
, Bank
A.
(1988
). A safe packaging line for gene transfer: separating viral genes on two different plasmids.
J. Virol
62
, 1120
–1124
Mckinstry
W. J.
, Li
C. L.
, Rasko
J. E.
, Nicola
N. A.
, Johnson
G. R.
, Metcalf
D.
(1997
). Cytokine receptor expression on hematopoietic stem and progenitor cells.
Blood
89
, 65
–71
Metcalf
D.
, Burgess
A. W.
(1982
). Clonal analysis of progenitor cell commitment of granulocyte or macrophage production.
J. Cell Physiol
111
, 275
–283
Mire-Sluis
A.
, Page
L. A.
, Wadhwa
M.
, Thorpe
R.
(1995
). Evidence for a signaling role for the alpha chains of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors: divergent signaling pathways between GM-CSF/IL-3 and IL-5.
Blood
86
, 2679
–2688
Mui
A. L.
, Miyajima
A.
(1994
). Cytokine receptors and signal transduction.
Prog. Growth Factor Res
5
, 15
–35
Nishinakamura
R.
, Miyajima
A.
, Mee
P. J.
, Tybulewicz
V. L.
, Murray
R.
(1996
). Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions.
Blood
88
, 2458
–2464
Ogawa
M.
(1993
). Differentiation and proliferation of hematopoietic stem cells.
Blood
81
, 2844
–2853
Sakamaki
K.
, Miyajima
I.
, Kitamura
T.
, Miyajima
A.
(1992
). Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation.
EMBO J
11
, 3541
–3549
Sanderson
C. J.
(1992
). Interleukin-5, eosinophils, and disease.
Blood
79
, 3101
–3109
Smith
A.
, Metcalf
D.
, Nicola
N. A.
(1997
). Cytoplasmic domains of the common beta-chain of the GM-CSF/IL-3/IL-5 receptors that are required for inducing differentiation or clonal suppression in myeloid leukaemic cell lines.
EMBO J
16
, 451
–464
Spooncer
E.
, Heyworth
C. M.
, Dunn
A.
, Dexter
T. M.
(1986
). Self-renewal and differentiation of interleukin-3-dependent multipotent stem cells are modulated by stromal cells and serum factors.
Differentiation
31
, 111
–118
Stanley
E.
, Lieschke
G. J.
, Grail
D.
, Metcalf
D.
, Hodgson
G.
, Gall
J. A.
, Maher
D. W.
, Cebon
J.
, Sinickas
V.
, Dunn
A. R.
(1994
). Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology.
Proc. Nat. Acad. Sci. USA
91
, 5592
–5596
Suda
T.
, Suda
J.
, Ogawa
M.
, Ihle
J. N.
(1985
). Permissive role of interleukin 3 (IL-3) in proliferation and differentiation of multipotential hemopoietic progenitors in culture.
J. Cell Physiol
124
, 182
–190
Takagi
M.
, Hara
T.
, Ichihara
M.
, Takatsu
K.
, Miyajima
A.
(1995
). Multi-colony stimulating activity of interleukin 5 (IL-5) on hematopoietic progenitors from transgenic mice that express IL-5 receptor alpha subunit constitutively.
J. Exp. Med
181
, 889
–899
Takaki
S.
, Kanazawa
H.
, Shiiba
M.
, Takatsu
K.
(1994
). A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction.
Mol. Cell Biol
14
, 7404
–7413
Tavernier
J.
, Devos
R.
, Cornelis
S.
, Tuypens
T.
, van der Heyden
J.
, Fiers
W.
, Plaetinck
G.
(1991
). A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF.
Cell
66
, 1175
–1184
van der Heyden
J.
, Devos
R.
, Plaetinck
G.
, Fache
I.
, Fiers
W.
, Tavernier
J.
(1991
). Characterization of the murine IL-5 receptor complex with the use of a panel of monoclonal antibodies. Relationship to the murine IL-3 receptor.
J. Immunol
147
, 3413
–3418
Whetton
A. D.
, Heyworth
C. M.
, Nicholls
S. E.
, Evans
C. A.
, Lord
J. M.
, Dexter
T. M.
, Owen-Lynch
P. J.
(1994
). Cytokine-mediated protein kinase C activation is a signal for lineage determination in bipotential granulocyte macrophage colony-forming cells.
J. Cell Biol
125
, 651
–659
Woodcock
J. M.
, McClure
B. J.
, Stomski
F. C.
, Elliott
M. J.
, Bagley
C. J.
, Lopez
A. F.
(1997
). The human GM-CSF receptor exists as a preformed complex that can be activated by GM-CSF, IL-3 or IL-5.
Blood
90
, 3005
–3017
Wu
H.
, Liu
X.
, Jaenisch
R.
, Lodish
H. F.
(1995
). Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor.
Cell
83
, 59
–67
Yamaguchi
Y.
, Suda
T.
, Suda
J.
, Eguchi
M.
, Miura
Y.
, Harada
N.
, Tominaga
A.
, Takatsu
K.
(1988
). Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors.
J. Exp. Med
167
, 43
–56
Yoder
M. C.
, Williams
D. A.
(1995
). Matrix molecule interactions with hematopoietic stem cells.
Exp. Hematol
23
, 961
–967
Ziltener
H. J.
, de St. Groth
B. F.
, Leslie
K. B.
, Schrader
J. W.
(1988
). Multiple glycosylated forms of T cell-derived interleukin 3 (IL-3). Heterogeneity of IL-3 from physiological and nonphysiological sources.
J. Biol. Chem
263
, 14511
–14517
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1998
