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Division of Pulmonary Medicine, Allergy, and Clinical Immunology, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, OH 45229
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain,
IL-4R, and at least two other cell surface proteins, IL-13R1 and
IL-13R2, which specifically bind IL-13. IL-13 has been reported to
have very limited effects on mouse B cells. It was unclear whether this
was due to a lack of receptor expression, a disproportionate relative
expression of the receptor components, or an additional subunit
requirement in B cells. To determine the requirements for IL-13
signaling in murine B cells, we examined IL-13-dependent Stat6
activation and CD23 induction in the murine B cell line, A201.1. A201.1
cells responded to murine IL-4 via the type I IL-4R, but were
unresponsive to IL-13, and did not express IL-13 receptor.
B220+ splenocytes also failed to signal in response to
IL-13 and did not express IL-13 receptor. We transfected A201.1 cells
with human IL-4R, IL-13R1, or both. Transfectants expressing
either human IL-4R or human IL-13R1 alone were unable to respond
or signal to IL-13. Thus, human IL-13R1 could not combine with the
endogenous murine IL-4R to generate a functional IL-13R. However,
cells transfected with both human IL-4R and IL-13R1 responded to
IL-13. Thus, the relative lack of IL-13 responsiveness in murine B
cells is due to a lack of receptor expression. Furthermore, the
heterodimeric interaction between IL-4R and IL-13R1 is species
specific. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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helix superfamily, and their
respective genes are located on chromosome 5q31 only 12 kb apart
(2). Although they share only 25% homology, IL-13 shares
many functional properties with IL-4, including the up-regulation of
MHC class II and CD23 Ags on monocytes (1, 2). IL-13
mediates its effects via a complex receptor system that includes
IL-4R (IL-4R -chain) and at least two other cell surface
proteins, IL-13R1 and IL-13R2, which specifically bind IL-13
(3, 4, 5, 6, 7, 8). IL-13R1 binds IL-13 with low affinity by
itself, but when paired with IL-4R, it binds IL-13 with high
affinity and forms a functional IL-13R that signals (6).
Consistent with the fact that IL-4 and IL-13 share a common receptor
component, IL-4R, they also share some common signaling
pathways. Studies in Stat6-deficient mice have revealed that IL-13
signaling utilizes the Janus kinase-Stat pathway and specifically Stat6
(9, 10). In contrast, IL-13R2 by itself binds IL-13
with high affinity, but does not signal (11). Thus, the
receptor complexes for IL-4 and IL-13 are intertwined systems that are
most likely regulated at multiple levels, including by differential
levels of expression of the various components and/or by preferential
association of certain components. Although IL-4 and IL-13 have many overlapping functions, they also have distinct roles. In parasitic infection models, IL-13, but not IL-4, was necessary for the Th2-dependent expulsion of Nippostrongyloides brasiliensis (12). Furthermore, IL-13 has recently been shown to be a key mediator of allergic asthma independent of IL-4 in mouse models whereby IL-13 blockade prevented allergen-induced airway inflammation (13, 14). Tissue-specific overexpression of IL-13 in the lungs of transgenic mice resulted in several features found in an asthmatic airway, including airway inflammation, mucus hypersecretion, goblet cell hyperplasia, deposition of Charcot-Leyden crystals, increased nonspecific airways hyperreponsiveness, and subepithelial fibrosis and airway remodeling (15).
In human B cells, human IL-13 and IL-4 have similar effects, including
modulating surface Ag expression and inducing class switching to IgG4
and IgE in combination with CD40:CD40 ligand costimulation (16, 17). In contrast, mouse IL-13 has been reported to have no
effects on mouse B cells (2). However, several lines of
indirect evidence exist for IL-13 actions on mouse B cells.
IL-13-deficient mice had depressed levels of serum IgE
(18), and IL-13 transgenic mice on the IL-4 null
background had elevated levels of serum IgE (19).
Furthermore, administration of rIL-13 to mice resulted in enhanced Ab
production, although IgE was not enhanced (20). Thus, both
overexpression and the absence of IL-13 had an impact on Ig levels,
supporting a role for IL-13 on B cell function. However, the effects of
IL-13 on the regulation of IgE production in murine in vivo systems may
be indirect. These observations led us to investigate IL-13
responsiveness in murine B cells. Mouse B cells express IL-4R and
readily respond to murine IL-4, and since IL-13 utilizes the same
signaling pathways as IL-4, IL-13 responsiveness in mouse B cells is
most likely regulated at the level of IL-13R expression. Several
possibilities existed for the relative unresponsiveness of mouse B
cells to IL-13 (2, 21): 1) a relative overexpression of
IL-13R2 compared with IL-13R1 may result in a cell being
unresponsive to IL-13 since the nonsignaling, high affinity IL-13R2
would bind the available IL-13 and prevent its association with
IL-13R1; 2) mouse B cells may express little or no IL-13R1; and
3) a functional IL-13R in B cells may require an additional yet
undefined component(s). In this manuscript, we addressed each of these
possibilities, and provide evidence for the mechanism of relative
unresponsiveness in mouse B cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A201.1 murine B cells, a gift from Gregg Milligan (Children’s
Hospital Medical Center, Cincinnati, OH), are derived from the parent
line A20. The cells are B220+,
IgG+, Ia+,
IgA-, IgM-, and
IgD- and were originally derived from a BALB/c
mouse. Cells were maintained in complete RPMI 1640
(cRPMI),3 consisting
of RPMI 1640 (Life Technologies, Grand Island, NY) supplemented with
10% FBS (Life Technologies), 2 mM L-glutamine
(BioWhittaker, Walkersville, MD), 100 U/ml penicillin and 100 µg/ml
streptomycin (BioWhittaker), and 50 µM 2-ME (Sigma, St. Louis, MO).
Recombinant human and mouse IL-4 and human IL-13 were purchased from
R&D Systems (Minneapolis, MN). Murine IL-13, rabbit anti-murine
IL-13R2 IgG, and Ba/F3.mIL-13R2 cells (Ba/F3 cells stably
expressing mouse IL-13R2) were kindly provided by Debra Donaldson
(Genetics Institute, Cambridge, MA). Anti-Stat6 rabbit polyclonal Ab
was a generous gift from Ulrike Schindler (Tularik, San Francisco, CA).
Anti-CD40, anti-µ, and anti-I-Ad (MKD6)
were gifts from Fred Finkelman (University of Cincinnati, Cincinnati,
OH). FITC-coupled anti-murine CD23 Ab was purchased from PharMingen
(San Diego, CA). Biotinylated anti-human IL-13R1 was purchased
from Diaclone Research (Besancon, France). Anti-murine IL-4R (code
1688-01) and anti-human IL-4R (code 80-3285-01) were purchased
from Genzyme Diagnostics (Cambridge, MA); both Abs are blocking Abs.
[
-32P]ATP was purchased from NEN (Boston,
MA). FITC-conjugated goat anti-rabbit IgG was purchased from
Southern Biotechnology Associates (Birmingham, AL).
cDNA constructs and expression vectors
Human IL-13R1 cDNA, kindly provided by Debra Donaldson
(Genetics Institute), was subcloned into the mammalian expression
vector pCEP4 (Invitrogen, Carlsbad, CA). Human IL-4R cDNA, obtained
from John Ryan (Virginia Commonwealth University, Richmond, VA), was
subcloned into the mammalian expression vector pREP9 (Invitrogen).
Transfection
A total of 5 x 106 A201.1 cells was
washed, resuspended in RPMI 1640 containing 20 µg of uncut
pREP9.human IL-4R and/or pCEP4.humanIL-13R1, and pulsed with a
Genepulser II electroporation device (Bio-Rad, Melville, NY) set at 960
µF and 200 V. After electroporation, cells were grown for 24 h
in 10 ml cRPMI and then selected for resistance to neomycin (G418
sulfate; BioWhittaker) at 1000 µg/ml and/or hygromycin at 400 µg/ml
for 12–21 days, respectively. Cell populations were screened by flow
cytometry for CD23 surface expression in response to stimulation with
human IL-4 (10 ng/ml) for 48 h and/or by staining with
anti-IL-13R1-FITC Ab. Positive transfectant pools were cloned by
limiting dilution.
EMSA
A201.1 cells (2.5 x 106) were stimulated with murine or human IL-4 (10 ng/ml), or murine IL-13 (50 ng/ml) in cRPMI for 15 min, pelleted by centrifugation at 10,000 x g, and reconstituted in lysis buffer (10 mM HEPES, pH 7.9, 10 mM KCl, 0.1 mM EDTA, 1.5 mM MgCl2, 0.2% Nonidet P-40, 1 mM DTT, and 0.5 mM PMSF). Lysates were centrifuged at 10,000 x g for 5 min at 4°C, and supernatants containing the cytoplasmic extracts were removed. Pelleted nuclei were reconstituted in nuclear extract buffer (20 mM HEPES, pH 7.9, 420 mM NaCl, 0.1 mM EDTA, 1.5 mM MgCl2, 25% glycerol, 1 mM DTT, and 0.5 mM PMSF). Nuclei were lysed for 15 min at 4°C and centrifuged at 20,000 x g for 15 min at 4°C, and supernatants were removed as nuclear extracts.
After quantitation of protein by CoomassiePlus (Pierce, Rockford, IL),
5 µg of nuclear extracts was reconstituted in TE buffer (10 mM
Tris-Cl, pH 7.4, and 1 mM EDTA). Equal volumes of 2x EMSA reaction
buffer (24 mM HEPES, pH 7.9, 8 mM Tris, 50 mM KCl, 10 mM
MgCl2, 24% glycerol, 0.08 µg/ml poly(dI-dC), 2
mM EDTA, and 2 mM DTT) were added, and the reaction mixtures were
incubated for 10 min on ice. Reactions were incubated with 0.2 ng of
Stat6 probe (Santa Cruz Biotechnology, Santa Cruz, CA) end labeled with
[-32P]ATP for an additional 10 min on ice. A
100-fold excess of unlabeled nucleotide (20 ng) was used in cold
competition samples, and 1 µl of anti-Stat6 polyclonal Ab was
added to supershift samples. Extracts were incubated on ice for an
additional hour and then electrophoresed on 5% polyacrylamide gels in
0.5x TBE. Bands were visualized by autoradiography.
Flow cytometry and cell sorting
A201.1 cells (5 x 105) were washed
in cold PBS with 1% FBS and stained with FITC-conjugated
anti-mouse CD23 Ab (PharMingen) or biotinylated anti-human
IL-13R1 Ab in the presence of anti-FcR Ab 2.4G2 (PharMingen) for
30 min on ice. In the case of IL-13R1 staining, cells were then
washed and incubated in the presence of streptavidin-PE (Southern
Biotechnology Associates). Cells were washed in cold PBS with 1% FBS
and analyzed on a FACScan instrument (Becton Dickinson, San Jose,
CA).
Spleen cell suspensions were prepared from BALB/c mice, reconstituted in cold PBS with 2% FBS, and stained with FITC-conjugated RA3-6B2 anti-mouse B220 Ab (PharMingen) in the presence of anti-FcR Ab 2.4G2 (PharMingen) for 30 min on ice. Cells were then washed in cold PBS with 2% FBS and sorted into B220+ and B220- populations using a FACSvantage instrument (Becton Dickinson).
For double staining of splenocytes for B220 and IL-13R2 expression,
3.5 x 106 splenocytes prepared from BALB/c
mice were washed with PBS, and then incubated in the presence of 0.2
µg of anti-murine IL-13R2 and anti-FcR Ab 2.4G2
(PharMingen) for 30 min on ice. Cells were then washed with PBS and
incubated in the presence of PE-conjugated DNL-1.9 anti-mouse B220
Ab (PharMingen) and goat F(ab')2 anti-rabbit
IgG FITC (Southern Biotechnology Associates) for an additional 30 min
on ice. Then cells were washed and analyzed on a FACScalibur
instrument.
Immunoprecipitation and immunoblotting
A201.1 cells (2 x 107) were pelleted by centrifugation at 20,000 x g at 4°C and reconstituted in IP-lysis buffer (50 mM Tris, pH 8, 150 mM NaCl, 1% Nonidet P-40, 1 mM PMSF, 10 µg/ml leupeptin, 10 µg/ml aprotinin, 5 mM iodoacetamide, 1 mM sodium orthovanadate, 20 mM NaF, and 1 mM EDTA). Cells were incubated on ice for 30 min, and lysates were clarified by centrifugation at 20,000 x g for 20 min at 4°C. Soluble Stat6 was immunoprecipitated with anti-Stat6 polyclonal Ab, followed by protein A/G PLUS agarose (Santa Cruz Biotechnology), as previously described (22). Briefly, precipitates were washed three times in IP-lysis buffer, reconstituted in Laemmli buffer, and resolved by electrophoresis on 10% SDS-polyacrylamide gels.
Proteins were transferred to nitrocellulose membranes and blocked overnight in block solution (20 mM Tris, pH 7.4, 150 mM NaCl, 3.1% BSA, and 0.1% polyethylene glycol 20,000). Membranes were probed with anti-phosphotyrosine mAb PY20 (Transduction Laboratories, Lexington, KY) or anti-Stat6 polyclonal Ab. Bound Abs were detected by incubation with anti-mouse or anti-rabbit IgG Abs conjugated to HRP (Transduction Laboratories), followed by ECL using ECL substrate (Amersham, Arlington Heights, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A201.1 is a mouse B cell line, which expresses IL-2Rc (data not
shown) and readily responds to murine IL-4, as evidenced by the
induction of CD23 and class II MHC surface expression after 48 h
(Fig. 1
). However, the cells did not
respond to murine IL-13 at any dose (Fig. 1A) even after
prolonged treatment with IL-13 up to 96 h (Fig. 1B).
The cells also did not respond to IL-13 at superphysiologic (10
µg/ml) doses (data not shown). To determine whether IL-13 was capable
of transducing a signal in A201.1 cells, we examined Stat6 activation.
Murine IL-4 induced Stat6 activation, but murine IL-13 treatment did
not result in Stat6 phosphorylation (Fig. 1C).
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2 is not expressed on A201.1 cells
IL-13R2 binds IL-13 with high affinity, but does not transduce
a signal (11), thus a relative abundance of this receptor
compared with the signaling IL-13R1 would lead to a cell being
unresponsive to IL-13. We analyzed A201.1 cells for IL-13R2
expression and found that A201.1 cells do not express detectable
IL-13R2 (Fig. 2). Ba/F3 cells
transfected with IL-13R2 demonstrated staining with an
anti-IL-13R2 Ab, but the A201.1 cells did not stain above
background. Thus, the absence of an IL-13 signal or response in A201.1
cells is most likely due to only negligible or absent expression of
IL-13R1.
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Our data demonstrate that A201.1 cells are unresponsive to IL-13.
We next wanted to determine whether primary mouse B lymphocytes behaved
in a similar fashion. We isolated splenocytes from a BALB/c mouse,
sorted the cells into B220+ and
B220- populations, and then tested the cells for
the ability to respond to IL-13 (Fig. 3A). As expected, both the
B220+ and B220- cells
responded to IL-4. In contrast, IL-13-induced Stat6 activation was
detected only in the B220- population. The
B220+ population was unresponsive to IL-13.
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2 expression to
determine whether IL-13R2 expression might be responsible for the
lack of IL-13 response. However, like the A201.1 cells, the
B220+ cells did not express detectable levels of
IL-13R2. In contrast, the B220- cells did
express IL-13R2 (Fig. 3
B).
IL-13 signaling is not apparent in the presence of transfected
human IL-4R in A201.1
Unlike IL-13, which is not species specific, IL-4 is species
specific and does not cross-react between human and mouse. A201.1 cells
respond to murine IL-4, but not human IL-4. They gain the ability to
respond to human IL-4 only after they are successfully transfected with
the human IL-4R (Fig. 4). Since IL-13
is not species specific, it remained possible that the endogenous
IL-4R-chain preferentially binds IL-2Rc, and thus is not
available to associate with IL-13R1 and form a functional IL-13R. We
investigated whether overexpressing human IL-4R, which associates
with the endogenous murine IL-2Rc to form a functional human IL-4R,
would render the cells responsive to IL-13 by enabling more endogenous
murine IL-4R to be available for association with IL-13R1. A201.1
cells transfected with human IL-4R expressed 
1800 receptors/cell
by Scatchard analysis (data not shown) and gained the ability to
respond to human IL-4. However, even in the presence of excess
IL-4R, IL-13, either human or mouse, did not induce Stat6 activation
in transfectants (Fig. 4). In addition, IL-13 had no effect on the IL-4
response in the transfectants.
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and IL-13R1,
but neither one alone, renders them responsive to IL-13
We next examined whether transfection of A201.1 cells with human
IL-13R1 would render them responsive to IL-13. Untransfected A201.1
or cells stably expressing human IL-4R were stably transfected with
human IL-13R1, and surface expression was confirmed by flow
cytometry using a biotinylated anti-human IL-13R1 Ab (Fig. 5A). The single transfectants
expressing human IL-13R1 and the double transfectants expressing
both human IL-13R1 and human IL-4R both expressed human
IL-13R1 on the cell surface. We then analyzed the transfectants for
the ability to signal in response to IL-13 (Fig. 5B). No
appreciable Stat6 activation was detected after IL-13 stimulation in
cells transfected with either human IL-13R1 or human IL-4R. Thus,
human IL-13R1 is incapable of associating with the endogenous murine
IL-4R to generate a functional IL-13R. In Fig. 5, mouse IL-13 was
used, but identical results were obtained with human IL-13 as expected
since IL-13 is not species specific (data not shown). In contrast,
cells transfected with both human IL-13R1 and IL-4R were capable
of transducing a signal in response to IL-13, as evidenced by Stat6
activation. Densitometric analysis revealed that Stat6 activation was
1.8-fold stronger with either human or murine IL-4, than with murine or
human IL-13. This was not surprising since human IL-13R1 expression
was relatively low in the double transfectants (Fig. 5A).
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). Untransfected
A201.1, or transfectants expressing either IL-13R1 or IL-4R
remained unresponsive to IL-13. However, in cells expressing both human
IL-13R1 and human IL-4R, IL-13 treatment resulted in the
induction of CD23 expression.
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1 associates with human IL-4R, but not murine
IL-4R to form a functional IL-13R
Since A201.1 cells expressing human IL-13R1 were not responsive
to IL-13, our data supported that the interaction between IL-13R1
and IL-4R to generate a functional receptor complex was species
specific. To test this directly, we pretreated A201.1 cells stably
transfected with both human IL-13R1 and IL-4R with either
anti-human IL-4R or anti-murine IL-4R to block either the
transfected human IL-4R or the endogenous murine IL-4R. Both Abs
recognize their cognate IL-4R and block IL-4 binding. We then
treated the cells with IL-13 and analyzed them for Stat6 activation by
EMSA (Fig. 7). Blockade of the endogenous
mouse IL-4R completely inhibited the cellular response to murine
IL-4, but had no effect on IL-13-dependent Stat6 activation. In
contrast, blockade of the human IL-4R inhibited signaling to both
human IL-4 and IL-13. Since the anti-IL-4R Abs do not recognize
IL-13R1, the inhibition of IL-13 signaling by anti-human
IL-4R is due to steric hinderance, preventing the formation of a
functional receptor complex. Thus, the interaction between IL-4R and
IL-13R1 is completely species specific.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-13 has two cognate receptors, IL-13R1 and IL-132
(3, 4, 5, 6, 7, 8). IL-13R1 associates with IL-4R to form a high
affinity signaling receptor complex. In contrast, IL-13R2 binds
IL-13 with high affinity, but does not signal (11).
Sharing of a common receptor chain, and consequently overlapping
signaling intermediates, is the basis of the multiple overlapping
functions between IL-13 and IL-4. However, IL-4 and IL-13 also have
some distinct functions (12, 25). The distinction between
IL-4 and IL-13 is perhaps most evident in mouse B cells, in which IL-4
has many functions, but IL-13 has limited effects (2).
We now provide evidence that unresponsiveness in mouse B cells is due
to a lack of receptor expression, rather than a relative abundance of a
decoy receptor, IL-13R2, or the presence of an inhibitor. We
demonstrated that A201.1 cells and B220+
lymphocytes do not respond to IL-13. Neither A201.1 cells nor
B220+ splenocytes express IL-13R2; therefore,
this was not the mechanism responsible for the absence of IL-13
responsiveness. The absence of an IL-13 response provides evidence that
IL-13R1 is absent or negligibly expressed on A201.1 mouse B cells.
However, IL-13-deficient mice had depressed levels of serum IgE
(18), and IL-13 transgenic mice on the IL-4 null
background had elevated levels of serum IgE (19),
supporting a role for IL-13 on mouse B cells in vivo. Based on our
data, we propose that mouse B cells do not express functional IL-13R at
baseline, but that receptor expression can be induced at certain stages
of B cell development or in specific B cell subsets. Alternatively,
since B220- splenocytes do express IL-13R and
signal in response to IL-13, the role for IL-13 in regulating IgE
production may be indirect. Studies to define which factors may
regulate IL-13R expression are currently underway.
A201.1 cells transfected with human IL-13R1 alone remained
unresponsive to IL-13. Thus, human IL-13R1 cannot associate with the
endogenous murine IL-4R. Transfection with both human IL-4R and
IL-13R1 rendered cells responsive to IL-13 (Fig. 8). Thus, the interaction between
IL-4R and IL-13R1 is completely species specific. We went on to
confirm the species specificity by demonstrating that Ab blockade of
human IL-4R, but not mouse IL-4R inhibited IL-13 signaling in the
double transfectants. The open reading frame of human IL-13R1 has
81% nucleotide and 76% amino acid identity with murine IL-13R1
(3, 5). Thus, the epitopes on IL-13R1 for binding
IL-4R must not be conserved between human and mouse. This is
surprising since the epitope on mouse IL-2Rc for associating with
human or mouse IL-4R to generate a signaling type I IL-4R is
conserved (26). Murine IL-2Rc can complex with either
human or murine IL-4R to create a functional type I IL-4R. In
contrast, our data establish that this is not the case for IL-13R1,
and provide novel insights into the possible contact residues that must
not be conserved between human and mouse. Exploitation of this species
specificity will aid in the identification of the epitope required for
the IL-13R1/IL-4R interaction. Studies to identify these key
epitopes are underway. Pharmaceuticals targeted specifically to the
target residues would allow specific inhibition of IL-13 function while
leaving IL-4 signaling intact, and may prove beneficial in the
treatment of atopic disorders.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Gurjit K. Khurana Hershey, Division of Pulmonary Medicine, Allergy, and Clinical Immunology, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229.
3 Abbreviation used in this paper: cRPMI, complete RPMI 1640.
Received for publication April 6, 2000. Accepted for publication November 2, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain. J. Biol. Chem. 271:29265. chain. J. Biol. Chem. 271:16921.l chain and reconstitution with the IL-4R of a functional IL-4/IL-13 receptor complex. FEBS Lett. 401:163.[Medline]
2: molecular cloning, characterization, and comparison with murine IL-13 receptor 1. J. Immunol. 161:2317., and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8:255.[Medline]
receptor: identification of glycosylation intermediates. J. Biol. Chem. 264:11981.-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr. Biol. 8:669.[Medline]
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