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(Received for publication, July 8, 1994; and in revised form, November 8,
1994) From the
We have investigated tyrosine phosphorylation of cellular
proteins induced by interleukin (IL) 4 and compared it with the effects
of three related cytokines, IL-2, IL-7, and IL-13. We show here that
both IL-4 and IL-13 stimulate tyrosine phosphorylation of the 140-kDa
IL-4 receptor subunit, which suggests that this receptor protein is
used by both cytokines. Receptor phosphorylation induced by IL-13 was
both weaker and slower than with IL-4. Stimulation of cells with IL-2
and IL-7 induced identical phosphorylation patterns to each other but
not phosphorylation of the 140-kDa IL-4 receptor subunit. The only
signal appearing upon stimulation with any of the four cytokines was
the weak phosphorylation of an unidentified protein of 160 kDa. SH2
domains of p56 Sharing of receptor subunits is an increasingly recognized
property of cytokines(1, 2) . One family of growth
factors, comprising leukemia inhibiting factor, oncostatin M, ciliary
neurotrophic growth factor, IL( IL-4 is a pleiotropic
immunoregulatory cytokine(12) . Its receptor has at least two
subunits, an IL-4 binding receptor protein of 140 kDa (IL-4R Transfection of cells with
truncated versions of
Peripheral blood lymphocytes were obtained from lymphocyte
concentrates of healthy blood donors by Ficoll centrifugation. Cells
(10 The human pre-myeloid
erythroleukemic cell line TF-1 was cultured in RFP containing 100 ng/ml
GM-CSF. The human monocyte-like histiocytic lymphoma U937 was grown
in RFP without additions. The IL-3-dependent murine hematopoietic
cell line FDCP-2 (a gift of J. Pierce, Bethesda, MD) was cultured in
RFP with 5% of X63 Ag 8-653 BPV-mIL-3-conditioned
medium(23) .
Anti-phosphotyrosine antibodies used were 4G10 (UBI, Lake Placid,
NY) for immunoprecipitation and horseradish peroxidase-coupled RC20
(Affiniti, Nottingham, UK) for detection on Western blots. RC20
consists of the bacterially expressed variable regions of the
anti-phosphotyrosine antibody PY20, which were mutated for higher
affinity(26) . The monoclonal anti-IL-4 receptor antibody A3/10 (27) was a gift from P. Reusch. The recombinant
extracellular domain of the IL-4R
The proteins were expressed
in E. coli. Cultures of 800 ml with an absorbance of
0.8-1.0 (550 nm) were induced for 3 h with 1 mM isopropyl-1-thio-
IL-4, like most other cytokines, induces changes of protein
tyrosine phosphorylation in responsive
cells(29, 30, 31) . We have compared tyrosine
phosphorylation patterns in three human cell types: PHA-stimulated
peripheral blood lymphocytes, the erythroleukemic cell line TF-1, and
the histiocytic lymphoma U937. The murine myeloid precursor cell line
FDCP-2 was used for comparison. When any of the human cell types was
stimulated with IL-4, changes in tyrosine phosphorylation were observed (Fig. 1). There was consistently strong phosphorylation of a
protein at 140 kDa and, at least in peripheral blood lymphocytes and
TF-1 cells, also a weak signal from a protein at 160 kDa. Other changes
observed were less reproducible. Stimulation of mouse cells with murine
IL-4 induced phosphorylation of several bands, most prominently at 160,
130, 100, and 65 kDa (Fig. 1).
Figure 1:
Tyrosine
phosphorylation in different cell types after stimulation with IL-4.
Human peripheral blood lymphocytes and the human cell lines TF-1 and
U937 were stimulated with 100 ng/ml IL-4 for 10 min or left untreated
as indicated. The murine cell line FDCP-2 was stimulated with 5% of
mIL-4 containing cell supernatant. Cells were lysed, the cleared cell
lysates were immunoprecipitated with anti-phosphotyrosine antibody
4G10, and the immune complexes were analyzed by immunoblotting with
anti-phosphotyrosine antibody RC20. Lines to the left in this and all other figures indicate positions of marker
proteins in kDa, while arrows indicate positions of bands discussed in the text.
When PHA-prestimulated
peripheral blood lymphocytes were treated with IL-2 or IL-7, changes in
tyrosine phosphorylation were similar but clearly different to the
response upon IL-4 (Fig. 2). Both cytokines induced strong
phosphorylation of bands at 160 and 85 kDa along with some weaker
signals. The kinetics of IL-2- and IL-7-induced phosphorylation were
also identical with maximal signals 10 min after stimulation (not
shown). The only band appearing with IL-2, IL-4, and IL-7 was the one
at 160 kDa, which was weakly phosphorylated in response to all three
cytokines.
Figure 2:
Tyrosine phosphoproteins after stimulation
with IL-2, IL-4, and IL-7 in peripheral blood lymphocytes. Cells were
stimulated with 100 ng/ml IL-2, IL-4, or IL-7 for 10 min and lysed;
phosphoproteins were analyzed as in Fig. 1.
The cell line TF-1 is dependent on GM-CSF but can also
respond to IL-4 and IL-13 with transient
proliferation(10, 32) . We used this line to compare
the effects of IL-4 and IL-13. Tyrosine phosphorylation after different
stimulation times is shown in Fig. 3. IL-4 and IL-13 induced
tyrosine phosphorylation of proteins at 160 and 140 kDa. With IL-4,
both bands were seen after only 30 s of stimulation. Phosphorylation
was maximal after 5-10 min and declined afterwards. Signals
obtained with IL-13 were consistently weaker and slower than with IL-4.
Both the 160- and the 140-kDa band were detectable after 1-5 min
and were maximal after 15 min. The band at 180-190 kDa was
sometimes already present in unstimulated cells.
Figure 3:
Time course of tyrosine phosphorylation
during treatment with IL-4 (A) or IL-13 (B). TF-1
cells were stimulated with 100 ng/ml of IL-4 (A) or IL-13 (B) for the indicated time. Cells were lysed, and
phosphoproteins were analyzed as in Fig. 1. In the IL-13
experiment (B), the blot had to be exposed for a longer time
during ECL development to obtain acceptable signal
strength.
A protein of
approximately 140 kDa that has been previously identified as
IL-4-dependent phosphorylation substrate in murine cells is IL-4R
Figure 4:
Both IL-4 and IL-13 induce tyrosine
phosphorylation of the IL-4R
The identity of the
tyrosine kinase phosphorylating IL-4R
Figure 5:
Binding of cellular phosphoproteins to
fusion proteins of glutathione S-transferase (GST)
and fyn-SH2 (A) or lck-SH2 (B).
Lysates from unstimulated peripheral blood lymphocytes or cells
stimulated for 10 min with 100 ng/ml of IL-2, IL-4, or IL-7 were
incubated with fyn-SH2 (A) or lck-SH2 fusion
proteins (B) bound to glutathione-Sepharose beads. The immune
complexes were analyzed by immunoblotting with anti-phosphotyrosine
antibody RC20.
The pleiotropic and redundant effects displayed by an ever
increasing number of identified cytokines make the assignment of
specific functions to individual members of the cytokine network a
difficult enterprise. Promiscuous receptor subunits may account for
some of this complexity. Both cross-competition between cytokines for a
receptor and initiation of common signal transduction pathways have to
be considered. IL-4 and IL-13 have very similar functions and share
at least one receptor subunit(10, 20) . Data presented
in this paper show that IL-4R Available data
therefore prove sharing of IL-4R IL-4 belongs to the family of cytokines sharing the Only one band, at 160 kDa, appeared
to be common to all four cytokines studied here. In mouse cells, a
protein of 170 kDa, named 4PS, is strongly phosphorylated in response
to IL-4(30, 39) . This protein is related to IRS-1,
the major phosphorylation substrate of the insulin receptor, because it
cross-reacts weakly with some anti-IRS-1 antibodies(40) , and a
cell line deficient in responses to insulin and IL-4 could be
reconstituted in both aspects by transfection with IRS-1 (41) .
A binding motif for IRS-1 was identified in receptors for insulin,
insulin-like growth factor, and the IL-4R In human cells (29) and in murine cells
transfected with the human IL-4R It is unclear
which tyrosine kinases participate in IL-4-dependent signal
transduction. Jak3 is activated by IL-4(45) . A Jak-type kinase
probably mediates IL-4-stimulated tyrosine phosphorylation of a
transcription factor that binds to sequences resembling the
interferon- Another candidate
kinase is a 92-kDa protein found associated with the IL-4 receptor that
was recognized by an anti-Fes antibody, which shows that either c-Fes
or a closely related protein may be involved in the IL-4 signal
transduction pathway(49) . The protein is tyrosine
phosphorylated after IL-4 stimulation(50) . Kinases of the src family could well be involved in IL-4 signaling because
p56
Volume 270,
Number 2,
Issue of January 13, 1995 pp. 966-970
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
and p59
precipitated the same proteins as anti-phosphotyrosine
antibodies after IL-4 stimulation, which suggests that a src-type kinase may be involved in signal transduction through
the IL-4 receptor.
)-6, and IL-11, uses the
gp130 molecule as receptor subunit, while IL-3, IL-5, and GM-CSF share
the KH97 receptor protein, also designated 
c. A third family of
cytokines has emerged with the discovery that
IL-4(3, 4) , IL-7(5, 6) , and IL-15 (7) all bind to receptor complexes that contain the
subunit of the IL-2 receptor(8) . The IL-2R
, a member of
the cytokine-type receptor superfamily(8) , has been named
c(4, 5) , in analogy to the
c protein of the
IL-3/IL-5/GM-CSF group. The same component may also be a part of the
receptor for IL-13. Two findings suggest that the receptor for IL-13
shares at least one subunit with the IL-4 receptor: the IL-4 mutant
protein Y124D, which inhibits IL-4-dependent reactions(9) ,
also inhibits effects of IL-13(10, 11) , and IL-13
competes with radiolabeled IL-4 for binding to intact TF-1
cells(10) . It is not clear whether these cytokines share the
subunit or the subunit or both.
) and
the c chain(13) . Specific functions of IL-4 include
induction of a T
2 phenotype in peripheral T-helper cells (14, 15) and stimulation of IgE synthesis by activated
B-cells(16) . Based on size, gene organization, and sequence
homologies, IL-13 has been classified as member of a cytokine subgroup
designated the IL-4 family(17) . IL-4 and IL-13 have very
similar effects on B-cells and monocytes, but in contrast to IL-4,
IL-13 cannot stimulate T-cells (18, 19, 20) .
It is particularly interesting that IL-13, like IL-4, can induce IgE
synthesis by B-cells (18, 21) because this suggests a
role for IL-13 in the allergic response.c has shown that its cytoplasmic domain is
involved in two different IL-2-induced signaling pathways, one leading
to expression of c-fos and c-jun and the other
leading to activation of a tyrosine kinase and expression of
c-myc(22) . We have compared tyrosine phosphorylation
induced by cytokines that have been shown or suggested to use the
c subunit. Our results demonstrate that IL-2 and IL-7 have
identical effects, while IL-4 and IL-13 induce a second type of
phosphorylation pattern. In the course of these studies, we have
identified IL-4R
as a substrate of IL-13-dependent tyrosine
phosphorylation.
Cells
Cells were cultured in RFP
(RPMI 1640 plus 8% fetal bovine serum, 100 units/ml penicillin, 100
µg/ml streptomycin) at 37 °C and 5% CO
. 
/ml) were prestimulated with 9 µg/ml PHA (Wellcome
Diagnostics, Dartford, UK) for 5 days. The cells were washed twice and
incubated two days without PHA before use.Antibodies and Growth Factors
Human IL-2,
IL-4, IL-7, and GM-CSF were expressed in Escherichia coli and
purified as described(24, 25) . Murine IL-4 was
applied as cell supernatant of 3T3-mIL4, a transfected cell line
derived from NIH 3T3 (a gift from W. Müller,
Köln, Germany). Human IL-13 was obtained from IC
Chemicals (München, Germany). was expressed in Chinese hamster
ovary cells (9) and was a gift from S. Arnold.Generation of SH2 Fusion Proteins
Fusion
proteins consisted of the 27-kDa C-terminal fragment of Schistosoma
japonicum glutathione S-transferase linked to the SH2
domains of p56 (amino acids 115-240) or p59
(amino acids 137-231). The cDNAs of the SH2 domains were
amplified from cDNA derived from PHA-stimulated T-cells by polymerase
chain reaction with specific primers that incorporated a
5`-BamHI and a 3`-EcoRI site. Using these sites, the
amplified cDNA was cloned into a pGEX-2T vector (Pharmacia LKB
Biotechnology Inc., Freiburg, Germany).
-D-galactopyranoside. Bacteria were
lysed, and the fusion proteins were purified as described by Lavan et al.(28) .Immunoprecipitation and Western
Blotting
Cells were incubated for the indicated times with
growth factors at 37 °C and 5% CO, pelleted, and
suspended in ice-cold lysis buffer (50 mM Hepes, pH 7.1, 1.5%
Triton X-100, 150 mM NaCl, 1 mM MgCl, 10%
glycerol, 10 mM Na
PO
, 100
mM NaF, 1 mM Na
VO, 100
µM Pefabloc, 1 µg/ml aprotinin, 2.5 µg/ml
leupeptin, 100 µM antipain, 10 µM pepstatin).
Cell lysates were centrifuged at 10.000 
g for 10 min.
Cleared supernatants were incubated for 1 h at 4 °C with the
anti-IL-4 receptor antibody A3/10 or the anti-phosphotyrosine antibody
4G10, and the immune complexes were collected on protein G-Sepharose
for 1 h at 4 °C. In other experiments, the clarified lysates were
incubated for 2 h at 4 °C with SH2 fusion proteins bound to
glutathione-Sepharose. The immunoprecipitates were washed twice with
lysis buffer, twice with 0.5 M LiCl in 100 mM Tris-HCl, pH 8.0, and boiled for 1 min in SDS sample buffer (50
mM Tris-HCl, pH 6.8, 2% SDS, 26 mM dithiothreitol,
10% glycerol). The samples were subjected to SDS-gel electrophoresis on
7.5% gels followed by Western blot analysis with horseradish
peroxidase-coupled RC20 (0.1 µg/ml) using an enhanced
chemiluminescence detection system (Amersham, Braunschweig).
(29, 30) . We used the monoclonal antibody A3/10,
which was raised against the recombinant extracellular domain of the
human IL-4R (27) to precipitate IL-4R from stimulated
cell lysate. The precipitate was probed with an anti-phosphotyrosine
antibody. We found that both in IL-4- and IL-13-stimulated lysates from
TF-1 cells the IL-4R was tyrosine phosphorylated, while no band
was obtained from unstimulated cell lysate (Fig. 4A).
Competition experiments with the recombinant extracellular domain
confirmed that the precipitated protein was the subunit of the
IL-4R. These results proved that human IL-4R is phosphorylated on
tyrosine residues in response to both IL-4 and IL-13. The IL-4R
was identified as phosphorylation substrate in peripheral blood
lymphocytes as well (Fig. 4B). Tyrosine phosphorylation
induced by IL-13 was weaker than with IL-4, regardless whether
precipitation was with anti-phosphotyrosine (Fig. 3) or with
anti-IL-4R (Fig. 4A).
. A, TF-1 cells were
stimulated with 100 ng/ml IL-4 or IL-13 for 10 min or left
unstimulated. B, peripheral blood lymphocytes (PBL)
were stimulated in the same way with IL-4. Both cell types were lysed,
and the lysates were immunoprecipitated with antibodies against the
IL-4R in the absence (A, lanes1-3; B, lanes1-2)
or presence (A, lanes4-6, B, lanes3 and 4) of the recombinant
extracellular domain of the IL-4R. The precipitates were blotted
and probed with the anti-phosphotyrosine antibody
RC20.
is not known. A src-type kinase would be a likely candidate because the IL-2R
-subunit and the IL-7 receptor complex are associated with
p56(33, 34) and
p59
(35) , respectively. We expressed the SH2
domains of these two kinases as fusion proteins with glutathione S-transferase and used them to precipitate phosphorylated
proteins from lysates of IL-2-, IL-4-, and IL-7-stimulated peripheral
blood lymphocytes (Fig. 5). The protein patterns precipitated
were identical to the ones observed when using the anti-phosphotyrosine
antibody 4G10 (Fig. 2). Both lck-SH2 and fyn-SH2 domains precipitated the same proteins.
is phosphorylated on tyrosine
residues following stimulation with either IL-4 or IL-13, which argues
for direct participitation of IL-4R in the IL-13 receptor complex.
It has indeed been shown that a monoclonal antibody raised against the
extracellular domain of the IL-4R inhibits IL-4- and
IL-13-dependent responses of TF-1 and B-cells(27) . The slower
and weaker response observed with IL-13 compared with IL-4 could be due
to the unknown specific subunit of the IL-13 receptor, which may result
in a lower and limiting number of functional receptors. Another
possible explanation could be the use of different src-type
kinases by the receptors for IL-4 and IL-13. between IL-4 and IL-13, but it is
not clear whether c is shared as well. Receptors for IL-4 and
IL-13 cannot be identical because some IL-4 responsive cells
(peripheral T-cells and the SP-B21 cell line) fail to respond to IL-13,
presumably because they lack an IL-13-specific receptor subunit (10) . IL-13 does not bind to COS cells transfected with the
human IL-4R
, apparently for lack of another receptor
component(10) . The molecule lacking is not c because
SP-B21 cells fail to bind IL-13, despite the fact that they are IL-4
responsive and must therefore have
c(10) . So far, it is
not clear whether the IL-13 receptor uses both IL-4R
and c.
c chain,
and IL-13 is a candidate to this club. To compare signaling pathways
within this family, we stimulated peripheral blood lymphocytes with two
other interleukins known to use
c, IL-2 (8) and
IL-7(5, 6) . IL-2 and IL-7 induced tyrosine
phosphorylation of the same proteins with identical kinetics. These
cytokines seem to be equivalent stimuli for T-cells because extent and
kinetics of cell proliferation induced by IL-2 and IL-7 are also very
similar to each other but clearly distinct to effects of
IL-4(37, 38) .
(42) . A highly
tyrosine-phosphorylated IRS-1-like protein can therefore be involved in
IL-4-induced signal transduction, but it seems to be absent in some
IL-4-responsive cell types(13) . The 4PS protein has not yet
been further characterized, and neither sequence nor antibodies are
available.(44) , no phosphorylation
in the range of 150-170 kDa has been found. In our hands, murine
FDCP-2 cells showed IL-4 induced tyrosine phosphorylation patterns
similar to those reported in the literature (30) , including a
prominent band at 160 kDa, but the pattern was quite different to those
found in human cells (see Fig. 1). The 160-kDa band from human
cells appeared at the same molecular weight as the putative 4PS band
from FDCP-2 cells, but we hesitate to identify this band as the human
homologue of 4PS because the tyrosine phosphorylation observed was much
weaker than found in mouse cells and, more importantly, because it also
appeared after stimulation with IL-2 and IL-7, which have so far not
been suspected to use IRS-1 or 4PS for signal transduction. The 160-kDa
band may well represent a signaling element common to the members of
the c family, but its identity remains unclear.
activation site and increases transcriptional activity
in reporter gene assays(46, 47, 48) . IL-13
activates the same transcription factor as IL-4(49) , which may
be a consequence of the shared IL-4R
subunit. binds to IL-2R
and is activated by IL-2
stimulation(33, 34) . Similarly, IL-7 stimulation
induces activation of p59 and its binding to the IL-7
receptor complex(35) . We have precipitated phosphorylated
proteins from IL-4-stimulated cells with SH2 domains from p56
and p59
. Both SH2 domains precipitated similar
bands from stimulated cell lysate. A possible explanation is that the
precipitated proteins are substrates for src-type kinases,
which after phosphorylation can bind to the SH2 domain of the kinase.
SH2 domains from different proteins have pronounced specificities, but
the binding affinities of SH2 domains from src-type kinases to
phosphotyrosine-containing peptides are very
similar(51, 52) , so the equivalence of fyn-SH2 and lck-SH2 in our assay is not surprising.
Furthermore, it is known that different src-type kinases can
be recruited for IL-2 signaling, like p53/56
and
p59
in pro-B-cells lacking p56
(53, 54) and p59
in cells
transfected with an IL-2R
mutant lacking the p56 binding site(55) . Three src-type kinases are
expressed in peripheral T-cells, p56
, p59
,
and to a low level p62
(43) . We have
recently found that yes-SH2 does not bind proteins from PHA
blasts after stimulation with IL-2, IL-4, or IL-7. (
)This
suggests that p56 or p59
(or both) may be
activated by stimulation of peripheral blood lymphocytes with IL-4,
just as in the case of IL-2 and IL-7. Because all three cytokines share
the
c subunit, activation of src-type kinases could be
linked to this common chain.
)c, common subunit of IL-3, IL-5, and GM-CSF; c, common
subunit of receptors for IL-2, IL-4, IL-7, and IL-15; IRS-1,
insulin receptor substrate 1; PHA, phytohemagglutinin; GM-CSF,
granulocyte-macrophage colony-stimulating factor.
)
We thank Drs. W. Sebald and K. Friedrich
(Theodor-Boveri-Institut (TBI)) for stimulating discussions. We are
also grateful to Drs. J. Pierce (National Institutes of Health) and W.
Müller (Institute for Genetics,
Köln, Germany) for providing cell lines, P. Reusch
(TBI) for anti-IL-4R antibodies, and S. Arnold (TBI) for the
extracellular domain of the IL-4R. We are indebted to B. Schnarr
(TBI) for help with some experiments, to H. Spengler for cell culture
work, and to W. Hädelt for oligonucleotide
synthesis and DNA sequencing.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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 K. M. DeFIFE, C. R. JENNEY, E. COLTON, and J. M. ANDERSON Disruption of filamentous actin inhibits human macrophage fusion FASEB J, May 1, 1999; 13(8): 823 - 832. [Abstract] [Full Text]
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Y. H. Lai and T. R. Mosmann Mouse IL-13 Enhances Antibody Production In Vivo and Acts Directly on B Cells In Vitro to Increase Survival and Hence Antibody Production J. Immunol., January 1, 1999; 162(1): 78 - 87. [Abstract] [Full Text] [PDF]
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B. Roy and M. K. Cathcart Induction of 15-Lipoxygenase Expression by IL-13 Requires Tyrosine Phosphorylation of Jak2 and Tyk2 in Human Monocytes J. Biol. Chem., November 27, 1998; 273(48): 32023 - 32029. [Abstract] [Full Text] [PDF]
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C.-R. Yu, R. A. Kirken, M. G. Malabarba, H. A. Young, and J. R. Ortaldo Differential Regulation of the Janus Kinase-STAT Pathway and Biologic Function of IL-13 in Primary Human NK and T Cells: A Comparative Study with IL-4 J. Immunol., July 1, 1998; 161(1): 218 - 227. [Abstract] [Full Text] [PDF]
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S. M. Grunewald, A. Werthmann, B. Schnarr, C. E. Klein, E. B. Brocker, M. Mohrs, F. Brombacher, W. Sebald, and A. Duschl An Antagonistic IL-4 Mutant Prevents Type I Allergy in the Mouse: Inhibition of the IL-4/IL-13 Receptor System Completely Abrogates Humoral Immune Response to Allergen and Development of Allergic Symptoms In Vivo J. Immunol., April 15, 1998; 160(8): 4004 - 4009. [Abstract] [Full Text] [PDF]
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P. L. Orchansky, S. D. Ayres, D. J. Hilton, and J. W. Schrader An Interleukin (IL)-13 Receptor Lacking the Cytoplasmic Domain Fails to Transduce IL-13-Induced Signals and Inhibits Responses to IL-4 J. Biol. Chem., September 5, 1997; 272(36): 22940 - 22947. [Abstract] [Full Text] [PDF]
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H. Fujiwara, S. H. Hanissian, A. Tsytsykova, and R. S. Geha Homodimerization of the human interleukin 4 receptor alpha chain induces Cvarepsilon germline transcripts in B cells in the absence of the interleukin 2 receptor gamma chain PNAS, May 27, 1997; 94(11): 5866 - 5871. [Abstract] [Full Text] [PDF]
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K. Wright, S. G. Ward, G. Kolios, and J. Westwick Activation of Phosphatidylinositol 3-Kinase by Interleukin-13. AN INHIBITORY SIGNAL FOR INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION IN EPITHELIAL CELL LINE HT-29 J. Biol. Chem., May 9, 1997; 272(19): 12626 - 12633. [Abstract] [Full Text] [PDF]
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J.-G. Zhang, D. J. Hilton, T. A. Willson, C. McFarlane, B. A. Roberts, R. L. Moritz, R. J. Simpson, W. S. Alexander, D. Metcalf, and N. A. Nicola Identification, Purification, and Characterization of a Soluble Interleukin (IL)-13-binding Protein. EVIDENCE THAT IT IS DISTINCT FROM THE CLONED IL-13 RECEPTOR AND IL-4 RECEPTOR alpha -CHAINS J. Biol. Chem., April 4, 1997; 272(14): 9474 - 9480. [Abstract] [Full Text] [PDF]
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N. Taylor, F. Candotti, S. Smith, S. A. Oakes, T. Jahn, J. Isakov, J. M. Puck, J. J. O'Shea, K. Weinberg, and J. A. Johnston Interleukin-4 Signaling in B Lymphocytes from Patients with X-linked Severe Combined Immunodeficiency J. Biol. Chem., March 14, 1997; 272(11): 7314 - 7319. [Abstract] [Full Text] [PDF]
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S. M. Grunewald, S. Kunzmann, B. Schnarr, J. Ezernieks, W. Sebald, and A. Duschl A Murine Interleukin-4 Antagonistic Mutant Protein Completely Inhibits Interleukin-4-induced Cell Proliferation, Differentiation, and Signal Transduction J. Biol. Chem., January 17, 1997; 272(3): 1480 - 1483. [Abstract] [Full Text] [PDF]
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M. J. Aman, N. Tayebi, N. I. Obiri, R. K. Puri, W. S. Modi, and W. J. Leonard cDNA Cloning and Characterization of the Human Interleukin 13Receptor alpha Chain J. Biol. Chem., November 15, 1996; 271(46): 29265 - 29270. [Abstract] [Full Text] [PDF]
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W. Kammer, A. Lischke, R. Moriggl, B. Groner, A. Ziemiecki, C. B. Gurniak, L. J. Berg, and K. Friedrich Homodimerization of Interleukin-4 Receptor alpha Chain Can Induce Intracellular Signaling J. Biol. Chem., September 27, 1996; 271(39): 23634 - 23637. [Abstract] [Full Text] [PDF]
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K. Izuhara, T. Heike, T. Otsuka, K. Yamaoka, M. Mayumi, T. Imamura, Y. Niho, and N. Harada Signal Transduction Pathway of Interleukin-4 and Interleukin-13 in Human B Cells Derived from X-linked Severe Combined Immunodeficiency Patients J. Biol. Chem., January 12, 1996; 271(2): 619 - 622. [Abstract] [Full Text] [PDF]
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Y. Oshima and R. K. Puri Characterization of a Powerful High Affinity Antagonist That Inhibits Biological Activities of Human Interleukin-13 J. Biol. Chem., April 27, 2001; 276(18): 15185 - 15191. [Abstract] [Full Text] [PDF]
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