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2: Molecular Cloning, Characterization, and Comparison with Murine IL-13 Receptor 11
*
Genetics Institute, Immunology Department, Cambridge, MA 02140; and
Brigham and Women’s Hospital, Division of Genetics, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1, have been cloned in mice and
humans. An additional high affinity binding chain for IL-13,
IL-13R2, has been described in humans. We isolated a cDNA from the
thymus that encodes the murine orthologue of the human IL-13R2. The
predicted protein sequence of murine IL-13R2 (mIL-13R2)
has 59% overall identity to human IL-13R2 and is closely related to
the murine low affinity IL-13-binding subunit, IL-13R1. The genes
for both mIL-13-binding chains map to the X chromosome. A specific
interaction between mIL-13R2.Fc protein and IL-13 was demonstrated
by surface plasmon resonance using a BIACORE instrument. Ba/F3
cells that were transfected with mIL-13R2 expressed 5000 molecules
per cell and bound IL-13 with a single Kd of
0.5 to 1.2 nM. However, these cells did not proliferate in response to
IL-13, and the IL-4 dose response was unaffected by high concentrations
of IL-13. In contrast, the expression of mIL-13R1 by Ba/F3 cells
resulted in a sensitive proliferative response to IL-13. Consistent
with its lower affinity for IL-13, IL-13R1.Fc was 100-fold less
effective than IL-13R2.Fc in neutralizing IL-13 in vitro. These
results show that mIL-13R2 and mIL-13R1 are not functionally
equivalent and predict distinct roles for each polypeptide in IL-13R
complex formation and in the modulation of IL-13 signal
transduction. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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13
(mIL-13R1),4 a murine
hematopoietin receptor chain that binds IL-13 with low affinity
(kDa = 2–10 nM). Human IL-13R1 (hIL-13R1) has also
been isolated; this component binds IL-13 with low affinity
(7, 8, 9). Caput et al. (10) have identified a different human
hemopoietin receptor chain, hIL-13R2, that binds IL-13 with higher
affinity (kDa = 0.25 nM). In the present work, we describe the
identification of mIL-13R2 cDNA and the genetic mapping of the
mIL-13R1 and mIL-13R2 loci. Furthermore, we have functionally
compared the two distinct IL-13-binding polypeptides.
We have found that many characteristics of the hIL-13R2 are
conserved in the mouse; however, there are some interesting
differences. This observation is of particular importance given the
known differences between responses in humans and mice to IL-13. A
detailed understanding of the mechanisms by which IL-13 regulates
immune responses in the mouse may enhance the usefulness of mouse
models of human diseases such as asthma and allergy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mIL-3 and mIL-6 were obtained from titered COS-1 and Chinese hamster ovary (CHO) cell supernatant. All other cytokines were purchased from R&D Systems (Minneapolis, MN). The Ba/F3 cell line (11) was maintained in RPMI 1640, 10% (v/v) FBS, and 0.05% (v/v) CHO mIL-3-conditioned medium. The B9 cell line was cultured in RPMI 1640, 10% (v/v) FBS, 20 nM of ß-mercaptoethanol, and 0.01% (v/v) COS-1 mIL-6-conditioned medium (12).
Isolation of mIL-13R2
Poly(A)+ RNA was prepared from the thymii of 6- to 8-wk-old C3H/HeJ mice, and a cDNA library of 1.5 x 106 primary recombinant phage was prepared according to the manufacturer’s instructions using the Zap Express Kit from Stratagene (La Jolla, CA). A total of 200,000 plaques were screened with a degenerate 17-base oligonucleotide probe of the sequence 5'-dKSRCTCCABK CRCTCCA-3' (K = G or T; S = C or G; R = A or G; and B = C or G or T) using standard tetramethylammonium chloride hybridization conditions (13).
Isolation of hIL-13R2
A partial fragment of the human homologue of this receptor was isolated by PCR using oligonucleotides that had been derived from the mouse sequence. cDNA was prepared from human testis poly(A)+ RNA that had been obtained from Clontech (Palo Alto, CA). A DNA fragment of 274 base pairs (bp) was amplified from this cDNA by PCR with the oligonucleotides 5'-dATAGTTAAACCATTGCCACC-3' and 5'-CTCCATTCGCTCCAAATTCC-3' using Taq polymerase in 1x Taq buffer containing 1.5 mM MgCl2 for 30 cycles (94°C for 1 min, 42°C for 1 min, and 72°C for 1 min). The DNA sequence of this fragment was determined, and two oligonucleotides were prepared from an internal portion of this fragment with the following sequence: 5'-dAGTCTATCTTACTTTTACTCG-3' and 5'-dCATCTGAGCAATAAATATTCAC-3'. These oligonucleotides were used as probes to screen a human testis cDNA library that had been purchased from Clontech (catalog no. HL1161). Filters were hybridized at 52°C using standard 5x SSC hybridization conditions and washed in 2x SSC at 52°C. A total of 22 clones were isolated that hybridized to both oligonucleotides in a screen of 400,000 clones. The DNA sequence was determined from four of the cDNA clones.
Mapping of mIL-13R1 and mIL-13R2 genetic loci
Primers were designed to amplify a region corresponding to the
3' untranslated region of either IL-13R2 (A25) or IL-13R1 (NR4)
to test for single-strand conformation polymorphisms (SSCPs) between
mouse strains. These SSCPs were analyzed as described previously
(14). Briefly, oligonucleotides were radiolabeled with
[32P]ATP using polynucleotide kinase, and genomic DNA
from a series of mouse strains was amplified using standard protocols
(anneal at 55°C for 1 min, extend at 72°C for 2 min, and denature
at 94°C for 1 min for 40 cycles, with a final extension at 72°C). A
volume of 2 µl of the amplified reaction was added to 8.5 µl of
stop solution (United States Biochemical, Cleveland, OH),
denatured at 94°C for 5 min, and immediately placed onto ice. An
aliquot of 2 µl of each reaction was loaded on a nondenaturing 6%
acrylamide-sequencing gel and electrophoresed in 0.5x Tris-borate/EDTA
buffer for 2 to 3 h at 40 watts in a 4°C cold room. A
primer pair with the sequence 5'-dCCACCAATTTCTTGACATAGAGC-3'
(forward) and 5'-dACTTTAGTCAAAAACCCAACACT-3' (reverse) identified a
polymorphism between C57BL/6J and Mus spretus for
IL-13R2, and a primer pair with the sequence
5'-dGCATTCTCCATTTGTTATCTG-3' (forward) and
5'-dTCCCCTTGTCTTTGTCCTCTA-3' (reverse) identified a polymorphism
between C57BL/6J and M. spretus for IL-13R1. These
primers were used to analyze DNA prepared from the BSS
backcross (15). The strain distribution patterns were analyzed using
the Map Manager Program (16).
Expression of mIL-13R2 and hIL-13R2 RNA in tissues
Northern blots of poly(A)+ RNA from various tissues
(Clontech) were performed as recommended by the manufacturer. An RT-PCR
analysis of mIL-13R2 RNA expression in murine tissues was performed
as follows: Poly(A)+ RNAs were purchased from Clontech, and
2 µg of each RNA was treated with RQ1 RNase-free DNase (Promega,
Madison, WI) according to the manufacturer’s instructions. Following
DNase inactivation, each sample was divided into two tubes; random
hexamer-primed first strand cDNA synthesis (Superscript II
Preamplification System; Life Technologies, Gaithersburg, MD) was
conducted according to the manufacturer’s instructions, except that
the reverse transcriptase was omitted from one tube in each sample
pair. Reaction products were purified using the QIAquick PCR
Purification Kit (Qiagen, Hilden, Germany) as described by the
manufacturer and recovered in 50 µl of double-distilled
H2O. We conducted 50-µl PCRs using 5 µl of the
recovered material and Advantage cDNA Polymerase Mix (Clontech)
according to the manufacturer’s instructions. A total of 25 reaction
cycles were performed at 94°C for 1 min, at 64°C for 1 min, and at
72°C for 1 min for actin and at 96°C for 1 min, at 56°C for 1 min
and at 72°C for 1 min for IL-13R2 in a Perkin-Elmer Cetus Thermal
Cycler (Branchburg, NJ). The oligonucleotide primers that were used for
the amplification of mIL-13R2 were
5'-dATGGCTTTTGTGCATATCAGATGCT-3' (forward) and
5'-dCAGGTGTGCTCCATTTCATTCTAAT-3' (reverse), which generate an
800-bp fragment; the primers used for 
-actin were
5'-dCAGAGCAAGAGGGGTATCCTGA (forward) and 5'-dTGATCCACATCTGCTGGAAGGT-3'
(reverse), which generate a 900-bp fragment. An aliquot of each
reaction was electrophoresed on a 0.8% agarose (w/v) gel and
transferred to nitrocellulose. The membranes were hybridized at 55°C
for 18 h to end-labeled oligonucleotides that were specific for
mIL-13R2 5'dTGCCACCAGAATTCCTTCATATTAG-3' (internal) and
-actin 5'dTGAAGATCCTGACTGAACGGGGCTACAGCTTT-3' (internal)
followed by autoradiography.
Transfection of Ba/F3 cells
Expression vectors for mIL-13R1 (6) and IL-13R2 were
constructed in pLNCX (17). Ba/F3 cells were transfected with 20 µg of
either mIL-13R2 or mIL-13R1 linearized expression plasmids by
electroporation using the Gene Pulsar (Bio-Rad, Richmond, CA) at 270 V
and 960 µF. Pools of stable transfectants (Ba/F3.IL-13R2 or
Ba/F3.IL-13R1) were isolated by selection in 1.0 mg/ml of G418 (Life
Technologies).
SDS-PAGE analysis of mIL-13R2.T7 and mIL-13R1.HA protein
Expression vectors were also constructed that encode either
full-length mIL-13R2 or mIL-13R1 fused in frame at the C terminus
to sequences encoding either T7 or hemagglutinin (HA) epitope
tags and inserted into the COS-1 expression vector, pED. COS monolayers
that had been transiently transfected with mIL-13R2.T7 or
mIL-13R1.HA expression plasmids or mock transfected were
radiolabeled with L-[35S]methionine and
L-[35S]cysteine (Amersham, Arlington Heights,
IL). Proteins containing the T7 epitope tag were precipitated from
detergent-solubilized cell extracts by incubation with a murine T7.Tag
mAb that had been conjugated to agarose (Novagen, Madison, WI).
Proteins containing the HA epitope tag were precipitated by incubation
with a murine mAb against the HA peptide epitope (Boehringer Mannheim,
Indianapolis, IN) and with goat anti-mIgG that had been conjugated
to Sepharose 4B (Zymed, San Francisco, CA). Immunoprecipitated
material was examined by reducing SDS-PAGE that was followed by
treatment with Amplify (Amersham) and fluorography.
Production of mIL-13R2.Fc or mIL-13R1.Fc protein
Expression vectors encoding either the extracellular domain of
IL-13R2 (amino acids (aa) 1–332) or IL-13R1 fused to a
Gly-Ser-Gly spacer and the sequence encoding the hinge-CH2-CH3 regions
of hIg-1 were also constructed in pED. The mIL-13R2.Fc or
mIL-13R1.Fc protein was produced from stably transfected CHO cells
and purified via protein A Sepharose chromatography (Pharmacia,
Uppsala, Sweden) (18).
BIACORE binding assay
A BIACORE 2000 instrument (Biacore AB, Uppsala, Sweden) was used
to show IL-13 binding to IL-13R2.Fc (19). Purified IL-13R2.Fc,
IL-11R.Fc, or hIgG1 (The Binding Site, Birmingham, U.K.) in 10 mM
sodium acetate (pH 4) were each coupled to the carboxymethyl dextran
layer of a CM5 research-grade chip using standard amine-coupling
procedures. Typically, 
10,000 to 17,000 resonance units (RUs) were
immobilized by this procedure. The running buffer used for screening
cytokine binding was 10 mM sodium acetate (pH 7.4), 300 mM sodium
chloride, 3.4 mM EDTA, and 0.005% (v/v) Tween 20. Purified IL-13,
IL-4, IL-7, and IL-15 (R&D Systems) were separately injected at 10
µg/ml in series over the immobilized IL-13R2.Fc, IL-11R.Fc, and
IgG1 for 10 min at 2 µl/min. Binding was quantified as the increase
in RUs at 60 s after the end of injection compared with a baseline
established at 20 s before injection.
Affinity measurements
Carrier-free mrIL-13 was purchased from R&D Systems and
radioiodinated with 125I-labeled N-succinimidyl
p-iodobenzoate (New England Nuclear, Boston, MA)
according to the manufacturer’s instructions. 125I-labeled
mIL-13 (125I-mIL-13) was purified by fractionation over a
PD-10 column (Pharmacia) followed by ultrafiltration on a Centricon 3
microconcentrator (Amicon, Beverly, MA). 125I-mIL-13
was >99% TCA precipitable and displayed a specific activity of 10,000
cpm/ng by bioassay on B9 cells; >90% 125I-mIL-13 could be
bound by Ba/F3.IL-13R2 cells. For binding assays, 2.5 x
105 to 1 x 106 Ba/F3.IL-13R2 or Ba/F3
cells were incubated with 0 to 10 nM 125I-mIL-13 in 100
µl of media with or without 100x excess unlabeled IL-13 at 4°C for
4 h. Cell-bound 125I-mIL-13 was separated from free
125I-mIL-13 by centrifugation over serum, and radioactivity
was determined for each pellet and supernatant. Curve fitting of the
binding data was performed using the Ligand program and plotted
in the Scatchard format (20).
Proliferation assays
The stimulation of proliferation of B9, Ba/F3, Ba/F3.IL-13R2,
and Ba/F3.IL-13R1 cells in response to IL-13 or IL-4 was measured by
[3H]thymidine (New England Nuclear) incorporation into
DNA. Cells (0.5–1 x 104/well) were seeded into
96-well plates in 200 µl of media with and without growth factors.
After incubation for 3 days, 1 µCi/well of
[3H]thymidine was added, and the cells were incubated for
an additional 4 h. The incorporated radioactivity was determined
using an LKB 1205 plate reader (LKB Pharmacia, Gaithersburg, MD).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 cDNAThe hemopoietin receptor superfamily is characterized by a conserved aa motif, WSXWS, in the extracellular domain (21). We screened an adult murine thymus cDNA library using a degenerate 17-base oligonucleotide that encodes a subset of sequences containing this motif. Clone A25 was identified as a positive that did not hybridize to probes derived from known cytokine receptors.
Sequencing of the 1.5-kilobase (kb) murine A25 cDNA revealed a 1149-bp
open reading frame that was predicted to encode a 383-aa protein. The
predicted sequence contains a putative signal peptide, an extracellular
domain with four potential N-linked glycosylation sites, a
transmembrane domain, and a short cytoplasmic domain (Fig. 1
). The extracellular domain contains an
N-terminal fibronectin type III domain followed by a typical cytokine
receptor module at residues 139 to 321. This cytokine receptor
module includes a WSEWS motif and the four cysteine residues that are
the most conserved features of the hemopoietin receptor superfamily.
The A25 domain structure is shared with the murine receptors for
granulocyte-macrophage CSF, IL-3, IL-5, and mIL-13R1 (NR4). The
extracellular region of A25 is most closely related to mIL-13R1,
with 29% identical aa residues (Fig. 1). However, in contrast to
mIL-13R1, the short cytoplasmic tail of A25 contains no box 1 or box
2 signaling motifs (22). A25 shows 59% overall aa identity with
hIL-13R2 (10), suggesting that it is the murine orthologue (Fig. 1).
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2 and mIL-13R1
The genes encoding both mIL-13R2 and mIL-13R1 were mapped by
SSCP analysis (14). IL-13R2 and IL-13R1 were both found to map to
chromosome X, with log of the odds likelihood scores of 26.8 and 18.5,
respectively. No recombinants were found between IL-13R2 and DXMit34
in the 89 progeny that were scored. The position of IL-13R2 with
respect to flanking microsatellite markers is: DXMit4 - 6.4
± 2.5 cM - (IL-13R2, DXMit34) - 7.9 ± 2.9 cM -
DXMit120. No recombinants were found between IL-13R1 and
angiotensin receptor-2 (Agtr2) in the 80 progeny that were scored. The
position of IL-13R1 with respect to flanking markers is:
DXMit85 - 3.8 ± 2.1 cM - (IL-13R1, Agtr2) -
3.8 ± 2.1 cM - DXMit49.
Expression of mIL-13R2 and hIL-13R2 RNA in tissues
We also examined the expression of murine and human IL-13R2 RNA
by Northern blotting and RT-PCR (Fig. 2).
Two transcripts of 1.5 and 2.1 kb were detected in the murine spleen,
brain, and 7-day-old embryo. The presence of mIL-13R2 RNA was
further confirmed in the spleen and brain by RT-PCR. A single
transcript of 2.1 kb was seen in the human liver, lung, and thymus, and
a smaller 1.5-kb transcript was observed in the placenta, brain, and
heart. An intensely labeled transcript in human testis was detected and
was shown to be a single band of 2.1 kb upon shorter exposure. Testis
RNA from a second pooled source showed the same intensity of signal.
Apparent differences in transcript size in the RNA preparations of
different human tissues did not correlate with changes in actin
transcript mobility. The sequence comparisons of four independent cDNA
clones from human testis were identical in the coding region and ranged
in size from 1.1 to 1.3 kb.
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2 and mIL-13R1 protein by SDS-PAGE
Results from cross-linking studies of hIL-13 and hIL-13R have
shown specific binding proteins of similar molecular masses from
a variety of tissue sources. Therefore, we wished to directly compare
the observed molecular masses of noncross-linked mIL-13R1 and
mIL-13R2. The mIL-13R2 and mIL-13R1 cDNA were modified to
encode epitope tags at the carboxyl terminus of each protein and
inserted into a COS expression vector. COS cells that had been
transiently transfected with these plasmids were biosynthetically
labeled with L-[35S]methionine and
L-[35S]cysteine and examined by
immunoprecipitation with mAb specific for the T7 (for IL-13R2) or HA
(for IL-13R1) epitopes. SDS-PAGE and fluorography resulted in the
detection of both polypeptides; each polypeptide had a similar apparent
molecular mass of 56 kDa (Fig. 3).
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The specificity of the interaction between IL-13 and mIL-13R2
was investigated by surface plasmon resonance using a BIACORE 2000
instrument. IL-4, IL-5, IL-7, IL-9, IL-15, and IL-13 were screened for
binding to immobilized mIL-13R2.Fc, and only IL-13 binding was
detected. None of these cytokines were found to interact with
IL-11R.Fc or human IgG1 (Fig. 4).
Similar results were obtained for hIL-13R2.Fc protein; these results
were consistent with results reported previously (10).
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2, we used Ba/F3 cells
that had been stably transfected with the mIL-13R2 expression
plasmid. IL-13 was iodinated and bound to the transfected cells. A
Scatchard analysis of the binding data from three separate experiments
revealed that these cells expressed 5000 IL-13-binding sites of a
single Kd of 0.5 to 1.2 nM (Fig. 5). No binding was detected on
untransfected Ba/F3 cells.
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Hilton and colleagues have reported that the expression of
mIL-13R1 (NR4) by their Ba/F3 subline was not sufficient to allow a
proliferative or survival response to IL-13 (6). In contrast, the
expression of mIL-13R1 in CTLL cells did confer a proliferative
response to IL-13 (6). The potential signaling functions of hIL-13R2
have not yet been investigated. Therefore, we examined the
proliferative responses of IL-3-dependent Ba/F3 cells that had been
transfected with mIL-13R2 or mIL-13R1 to assess the relative
contributions of each protein to receptor function. Ba/F3 cells
expressing mIL-13R2 were unable to proliferate in response to IL-13,
even though they expressed high numbers of receptors per cell (Figs. 5
and 6). Surprisingly, Ba/F3 cells that
had been transfected with mIL-13R1 responded to IL-13 and
proliferated with a half-maximal response of 200 pg/ml. The
half-maximal proliferation to IL-4 occurred at 1.2 ng/ml and was
unchanged from untransfected Ba/F3 cells even in the presence of high
levels of IL-13.
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2 is a potent inhibitor of IL-13 in vitro
The effect of a dimeric form of mIL-13R2, the IL-13R2.Fc
fusion protein, on the proliferative response of Ba/F3.IL-13R1 cells
to IL-13 was examined. mIL-13R2.Fc was added at various
concentrations to cultures of Ba/F3.IL-13R1 cells that contained a
saturating concentration (3 ng/ml) of mIL-13. Figure 7 shows that the concentration of fusion
protein giving a 50% level of inhibition of IL-13-stimulated
proliferation is 8 ng/ml. Similar results were obtained using B9 cells
(data not shown). In contrast, mIL-13R1.Fc was at least 100-fold
less effective in neutralizing the proliferative effect of IL-13 than
mIL-13R2.Fc (Fig. 7). This difference in potency is consistent with
the lower affinity (Kd = 2–10 nM) of IL-13
for mIL-13R1 (6) when compared with the higher affinity of IL-13 for
mIL-13R2 (Kd = 0.5 nM).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1, has been shown to participate in the
formation of an IL-13R complex in combination with the IL-4R (6, 7, 8, 9). A
higher affinity subunit, which had only been described previously in
humans, is designated hIL13-R2 (9). However, the contribution of
this IL-13-binding chain to receptor function has not been elucidated.
We have used motif-based cloning to identify a novel member of the
hemopoietin receptor family, designated mIL-13R2, which encodes the
murine orthologue of hIL-13R2. Comparisons of the human and murine
receptors show that they are structurally conserved, share 59% aa
identity, and specifically bind IL-13 with high affinity. Within the
hemopoietin receptor family, we show that the extracellular region of
mIL-13R2 is most closely related to mIL-13R1. In contrast, the
cytoplasmic domains of mIL-13R2 and mIL-13R1 are dissimilar.
Importantly, the cytoplasmic domains of both the murine and human
IL-13R2 are short and devoid of box 1 or box 2 signaling motifs.
However, hIL-13R2 does contain a putative consensus phosphorylation
site, Y369PKM (23), which is potentially suitable as a
docking site for an SH2-containing signaling molecule.
We also show that two IL-13R2 mRNA transcripts of 1.5 and 2.1 kb are
expressed in the murine brain, spleen, and day 7 embryo,
although lower levels were detected in the liver, lung, and testis with
longer exposure (data not shown). Isolation of IL-13R2 from a thymus
cDNA library also indicated that this gene is expressed in the murine
thymus at a low level (1/200,000 cDNA clones). Interestingly, the
transcript is also expressed in RNA isolated from mouse embryos, with
strong expression at day 7. This observation suggests that IL-13 may
have an important role in embryogenesis.
An hIL-13R2 mRNA transcript of either 1.5 or 2.1 kb was detected and
was found to have a broad range of expression in primary tissues. A
particularly high level of expression was observed in human testis. The
cDNA clones that were isolated by us from the testis were identical in
sequence to the cDNA that was isolated by Caput et al. (10) from human
renal carcinoma cells as well as to several partial cDNA clones that
were isolated from human brain RNA (data not shown). The difference in
tissue-specific transcript expression between mice and humans may be
related to differences in IL-13 function between the two species. For
example, IL-13 has been shown to induce IgE class switching in human
but not in murine B cells. Another observation is that this receptor is
also expressed in tissues that are not typically associated with immune
function, such as the testis and brain. It will be interesting to
determine which cells in these tissues are expressing IL-13R2, and
whether they are cells that might be associated with immune
surveillance.
The full-length murine and human cDNAs isolated by us correspond to the
smaller 1.5-kb transcripts. Zhang et al. have determined the partial
sequence of a soluble form of IL-13-binding protein in mouse serum and
urine that matches that of the predicted N terminus of mIL-13R2
(2A). This soluble form may be generated by proteolytic
processing. Alternatively, the larger 2.1-kb mIL-13R2 transcript may
encode this form.
Using SSCP analysis, we localized the genes for mIL-13R1 and
IL-13R2 to the murine X chromosome. This finding is consistent with
the reported chromosomal locations of hIL-13R1 and
hIL-13R2 on the X chromosome (7, 25). Although the
hIL-13R2 gene has been precisely mapped to Xq24
(25), the precise location of the hIL-13R1 on the X
chromosome has not been determined. We have found that
mIL-13R1 is nonrecombinant with mAgtr2. Since
linkage relationships in this subchromosomal region are highly
conserved between mice and humans, our data predict that the
hIL-13R1 would also be tightly linked to
hAgtr2, which maps to human chromosome Xq22–23 (26). The
presence of these two genes on the X chromosome suggests that they
should be considered as candidate genes in X-linked immune disease.
Our BIACORE data demonstrate that mIL-13R2 specifically binds IL-13.
In particular, we were unable to detect the binding of IL-4 at high
concentrations to mIL-13R2. Our affinity measurements for the
mIL-13R2 that is expressed in Ba/F3 cells ranged from 0.5 nM to 1.2
nM and are similar but not identical with the 0.25 and 0.44 nM affinity
that was determined for the hIL-13R2 in COS and Caki cells,
respectively (10). This discrepancy may reflect a true difference
between the human and murine proteins or may reflect experimental
variation (e.g., differences due to methods of iodination). These
affinities are in contrast to the lower affinity that was measured for
cells expressing either mIL-13R1 (2–10 nM) (6) or hIL-13R1,
which could not be detected unless both IL-13R1 and IL-4R were
coexpressed (7).
The structural differences between the cytoplasmic domains of the high
and low affinity IL-13-binding chains suggest that these chains are
functionally distinct. To test this possibility, we examined the
proliferative responses to IL-13 in Ba/F3 cells that had been
transfected with either the low affinity mIL-13R1 chain or the high
affinity mIL-13R2 chain. These cells express the IL-4R, and the
mitogenic response to IL-4 was unchanged by the heterologous expression
of these IL-13-binding proteins. We found that the expression of the
IL-13R1 chain led to a proliferative response to IL-13, presumably
by the formation of an IL-13R1/IL-4R complex. In contrast,
expression of the IL-13R2 was not sufficient to generate a mitogenic
response to IL-13.
The extracellular region of mIL-13R2 has been fused to the Fc
portion of hIgG1 to generate a soluble form of this IL-13-binding
protein. We have demonstrated that this molecule is a specific
inhibitor of IL-13 in vitro and can block the IL-13-stimulated
proliferation of Ba/F3 cells that have been transfected with the
IL-13R1. We have also made an IL-13R1.Fc fusion protein and
examined the ability of this fusion protein to inhibit the
proliferation of an IL-13-dependent cell line. This inhibition requires
100-fold more IL-13R1.Fc fusion protein than IL-13R2.Fc, which is
consistent with its lower affinity for IL-13. We have found that
soluble IL-13R2.Fc fusion protein can inhibit the action of IL-13 in
murine models in vivo (27).
The effects of the IL-13R2.Fc fusion protein and the relative
affinities of the two IL-13-binding proteins raise the possibility that
the IL-13R2 is a dominant negative inhibitor of or a decoy for
IL-13. This function would be paralleled by IL-1, the IL-1 type II
receptor (28), and the recently described decoy receptor for TRAIL (29, 30). However, our observations are insufficient to conclude
that the IL-13R2 performs such a role in physiologic
circumstances.
It is also possible that an undiscovered molecule acts with the
IL-13R2 to form a second IL-13-signaling complex. In addition, the
IL-13R2 may have a complementary role with the mIL-13R1 to
facilitate the formation of a high affinity signaling complex that has
not yet been detected in our work (7).
IL-13 has been shown to have various effects on APCs in vitro,
including the modulation of cell surface molecules, the inhibition of
inducible nitric oxide synthase and cyclooxygenase-2 expression, the
stimulation of intracellular Ca2+ flux, and the induction
of IgE class switching in human B cells (31, 32, 33, 34, 35). The role of the high
affinity IL-13-binding protein, IL-13R2, in these processes is
unclear. Additional functional studies are required to understand the
relative roles of the two IL-13-binding proteins.
The demonstration in the present work of two X chromosome-linked genes for both a high and a low affinity IL-13-binding protein that are structurally conserved between humans and mice suggests that the regulation of IL-13 responses may be more complex than previously appreciated. The conservation of an additional chain that could specifically enhance IL-13 binding, contribute to an additional IL-13R complex, or block IL-13 response raises the possibility that IL-13, rather than IL-4, may be a more important mediator in vivo on cells expressing an IL-13R.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mary Collins, Immunology Department, Genetics Institute, Inc., 87 Cambridge Park Dr., Cambridge, MA 02140. E-mail address:
3 The GenBank accession no. for murine IL-13R2 is U65747.
4 Abbreviations used in this paper: m, murine; h, human; CHO, Chinese hamster ovary; SSCP, single-strand conformation polymorphism; RU, resonance unit; Agtr2, angiotensin receptor-2; 125I-mIL-13; 125I-labeled mIL-13; HA, hemagglutinin.
Received for publication September 8, 1997. Accepted for publication May 6, 1998.
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V. Ling, P. W. Wu, H. F. Finnerty, K. M. Bean, V. Spaulding, L. A. Fouser, J. P. Leonard, S. E. Hunter, R. Zollner, J. L. Thomas, et al. Cutting Edge: Identification of GL50, a Novel B7-Like Protein That Functionally Binds to ICOS Receptor J. Immunol., February 15, 2000; 164(4): 1653 - 1657. [Abstract] [Full Text] [PDF]
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W. R. Henderson Jr., E. Y. Chi, and C. R. Maliszewski Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma J. Immunol., January 15, 2000; 164(2): 1086 - 1095. [Abstract] [Full Text] [PDF]
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D. Ford, C. Sheehan, C. Girasole, R. Priester, N. Kouttab, J. Tigges, T. C. King, A. Luciani, J. W. Morgan, and A. L. Maizel The Human B Cell Response to IL-13 Is Dependent on Cellular Phenotype as Well as Mode of Activation J. Immunol., September 15, 1999; 163(6): 3185 - 3193. [Abstract] [Full Text] [PDF]
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J. Poudrier, P. Graber, S. Herren, D. Gretener, G. Elson, C. Berney, J.-F. Gauchat, and M. H. Kosco-Vilbois A Soluble Form of IL-13 Receptor {alpha}1 Promotes IgG2a and IgG2b Production by Murine Germinal Center B Cells J. Immunol., August 1, 1999; 163(3): 1153 - 1161. [Abstract] [Full Text] [PDF]
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P. L. Orchansky, R. Kwan, F. Lee, and J. W. Schrader Characterization of the Cytoplasmic Domain of Interleukin-13 Receptor-alpha J. Biol. Chem., July 23, 1999; 274(30): 20818 - 20825. [Abstract] [Full Text] [PDF]
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N. Noben-Trauth, W. E. Paul, and D. L. Sacks IL-4- and IL-4 Receptor-Deficient BALB/c Mice Reveal Differences in Susceptibility to Leishmania major Parasite Substrains J. Immunol., May 15, 1999; 162(10): 6132 - 6140. [Abstract] [Full Text] [PDF]
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M. G. Chiaramonte, L. R. Schopf, T. Y. Neben, A. W. Cheever, D. D. Donaldson, and T. A. Wynn IL-13 Is a Key Regulatory Cytokine for Th2 Cell-Mediated Pulmonary Granuloma Formation and IgE Responses Induced by Schistosoma mansoni Eggs J. Immunol., January 15, 1999; 162(2): 920 - 930. [Abstract] [Full Text] [PDF]
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 M. Wills-Karp, J. Luyimbazi, X. Xu, B. Schofield, T. Y. Neben, C. L. Karp, and D. D. Donaldson Interleukin-13: Central Mediator of Allergic Asthma Science, December 18, 1998; 282(5397): 2258 - 2261. [Abstract] [Full Text]
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G. Grünig, M. Warnock, A. E. Wakil, R. Venkayya, F. Brombacher, D. M. Rennick, D. Sheppard, M. Mohrs, D. D. Donaldson, R. M. Locksley, et al. Requirement for IL-13 Independently of IL-4 in Experimental Asthma Science, December 18, 1998; 282(5397): 2261 - 2263. [Abstract] [Full Text]
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