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CUTTING EDGE |
-Chain in IgE Synthesis1
*
Department of Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan;
Clinical Research Center for Allergy, National Sagamihara Hospital, Sagamihara, Japan;
Department of Experimental Medicine, University of Wales, Swansea, United Kingdom;
§
Department of Pediatrics, Faculty of Medicine, Kyushu University, Fukuoka, Japan;
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Department of Otolaryngology, Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan;
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Department of Pediatrics, Osaka College of Medicine, Takatsuki, Japan; and
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Kyoto Preventive Medical Center, Kyoto, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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-chain (IL-4R) gene have
been recently identified in association with different atopic
disorders. To clarify the etiological relationship between the two
variants, we analyzed responsiveness to IL-4 of transfectants with four
kinds of IL-4R carrying either Val or Ile at 50 and either Gln or
Arg at 551. The substitution of Ile for Val augmented STAT6 activation,
proliferation, and transcription activity of the I
promoter by IL-4,
whereas that of Arg for Gln did not change these IL-4 signals.
Arg551 was not associated with atopic asthma in the
Japanese population. CD23 expression and IgE synthesis by IL-4 were
augmented in Ile50-bearing PBMC, compared with those
bearing Val50. Taken together, substitution of
Arg551 does not enhance the IL-4 signal for generation of
germline transcript, whereas the substitution of Ile50
contributes to enhancement of IgE synthesis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-chain
(IL-4R3); Ref. (3, 4).
IL-4 is a pleiotropic cytokine, essential for IgE synthesis in B cells
and differentiation to Th2 phenotype in T cells (5). IL-4 exerts its
biological activity by binding to the target cell receptor, which is
composed of a heterodimer of IL-4R and the common 
-chain (6).
IL-4R is a critical component for the binding to IL-4 and signal
transduction of IL-4 (7, 8, 9, 10, 11). Upon stimulation of IL-4, Janus tyrosine
kinase-1 and 3 are activated, followed by activation of STAT6, which
has a central role in IgE synthesis (12, 13, 14, 15).
We have recently demonstrated that the substitution of valine (Val) at
amino acid 50 of human IL-4 (hIL-4)R for isoleucine (Ile) augments
hIL-4 signals in B cell lines, and patients with atopic asthma show
high incidence of the substitution (16), indicating that the
Ile50 variant of hIL-4R causes atopy. In contrast,
another variant of hIL-4R carrying arginine (Arg) at 551 (numbering
from the start of mature protein) instead of glutamine (Gln) has also
been shown to be correlated with hyper IgE syndrome and severe atopic
eczema and to cause up-regulation of CD23 expression and dissociation
with a tyrosine-phosphatase, SHP-1 (17). Based on these two studies,
two possibilities arise. One is that these two substitutions act
independently to cause atopy. In this case, an individual bearing both
variants would belong to a higher risk group than one who carries each
single variant. The other possibility is that these two polymorphisms
are linkage disequilibrium. In this case, either of these variants
simply represents a marker of the other variant. It is important to
address this point, to estimate the quantity of risk of contracting
atopic asthma.
In this study, we generated transfectants on which four kinds of
hIL-4R, carrying either Val or Ile at 50 and either Gln or Arg at
551, are expressed, and we analyzed responsiveness to hIL-4. We further
assessed the genetic association of the substitution Arg551Gln
with atopic asthma, and CD23 expression and IgE synthesis induced by
hIL-4 in Ile50Val-bearing PBMC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Site-directed mutagenesis of either Val at 50 amino acid with
Ile, or Gln at 551 with Arg in the hIL-4R, was accomplished using
oligonucleotide-mediated mutagenesis by selection using the uracil
technique against template strands, as previously described (18).
Oligonucleotides used for mutagenesis to generate mutations of the
223th and 1727th nucleic acid from the first ATG codon were
5'-CTCAGGGATACACCG-3' and
5'-CAAACTCCCGATAGCCA-3', whose mutated nucleic acids are
underlined. Plasmids of these hIL-4Rs were inserted into pME18S, and
these plasmids were denoted Val50Gln551,
Val50Arg551,
Ile50Gln551, and
Ile50Arg551, respectively.
Construction of transfected B cell line
Four kinds of plasmids (Val50Gln551, Val50Arg551, Ile50Gln551, and Ile50Arg551) were transfected by electroporation to a mouse pro-B cell line, Ba/F3, and drug-resistant and hIL-4-responsive clones were selected, which were denoted BF-Val50Gln551, BF-Val50Arg551, BF-Ile50Gln551, and BF-Ile50Arg551, respectively. These transfectants were maintained in the presence of mouse IL-3 (mIL-3) kindly provided by Dr. T. Hara, (Tokyo University, Tokyo, Japan), as described previously (16).
Extraction of nuclear proteins and electrophoretic mobility-shift assay (EMSA)
Procedures of extraction of nuclear proteins and EMSA were
conducted as previously described (19). Briefly, the cells were
stimulated with 10 ng/ml of either hIL-4 or mIL-4 for 15 min, and then
lysed to extract nuclear proteins. The amounts of loaded nuclear
extracts were normalized before mixing. The oligonucleotide probe used
was I (5'-GTCAACTTCCCAAGAACAGAA-3').
Luciferase activity assay
The plasmid used for the luciferase activity assay was
constructed by pGL3-enhancer vector (Promega, Madison, WI) into which
the promoter region from -187 to +6 of human I was inserted. After
the plasmid was electroporated into each transfectant, followed by
incubation for 24 h, the cells were further incubated with 2 ng/ml
of either hIL-4 or mIL-4 for 24 h in the presence of mIL-3. The
cells were washed once by PBS, and then lysed with reporter lysis
buffer (Toyoink, Tokyo, Japan) and centrifuged to remove debris. Cell
lysates were mixed with luciferse assay reagent (Toyoink).
Binding assay
Binding of [125I]-labeled hIL-4 (NEN, Boston, MA) to the cells was assayed as described before (20). After the cells were incubated with various concentrations of [125I]-labeled hIL-4 for 3 h at 4°C, bound and free ligands were separated by centrifugation through an oil gradient. Nonspecific binding was measured by adding a 150-fold molar excess of nonradiolabeled hIL-4.
Immunoprecipitation and Western blotting
Procedures of immunoprecipitation and Western blotting were
conducted, as previously described (21). The cells lysed in the
lysis buffer containing 1% Triton X-100 were immunoprecipitated with
anti-hIL-4R mAb that was provided by Schering-France (Dardilly,
France). Proteins eluted by boiling with SDS-PAGE sample buffer were
applied to SDS-PAGE and transferred electrophoretically to a
polyvinylidene fluoride membrane (Amersham, Arlington Heights, IL).
Proteins were probed with anti-hIL-4R mAb (Genzyme, Cambridge,
MA) and visualized by enhanced chemiluminescence (Amersham).
Genetic analysis
All the asthmatic subjects had been diagnosed by physicians specializing in asthma, with 1) recurrent breathlessness and chest tightness requiring on-going treatment, 2) physician-documented wheeze, and 3) documented labile airflow obstruction with variability in serial peak expiratory flow rates >30%. Specific IgE was detected by MAST (Hitachi, Tokyo, Japan), as previously described (22). Atopy was diagnosed as the presence of high concentration of total serum IgE, a positive specific IgE titer against one or more of 15 highly purified aeroallergens or a combination of these two features.
DNA samples were extracted using a commercial kit (IsoQuick, Microprobe, Garden Grove, WA). The PCR reaction was performed with 100 ng of genomic DNA as template after an initial 5 min denaturation at 94°C, followed by 40 cycles of 94°C for 30 s, 60°C for 30 s, and 72°C for 15 s. The primers to detect Ile50Val were 5'-GAAGCCCACACGTGTA for Ile50, 5'-GAAGCCCACACGTGTG for Val50, and 5'-TCGCTGGGCTTGAAGGAG. The primers for Arg551Gln were 5'-GTCTCGGCCCCCACCACCGGCTATC and 5'-ACCCAAGCCCACCACCGCACT. Underlined nucleotides were exchanged to incorporate the polymorphic site into a BslI recognition site. All three genotypes for each substitution were confirmed by sequencing randomly selected from each genotype. The whole data set was scored blind.
Measurement of CD23 expression and IgE synthesis
Heparinized blood samples were collected from 10 adult volunteers, all of who were ascertained not to have any allergic history, to show normal serum IgE level, and to be negative in a radioallergosorbent test for airborn allergens. PBMC was isolated by Ficoll-sodium metrizoate sedimentation (Organon Teknika, Durham, NC). Genotype of Ile50Val was confirmed by sequencing.
Measurement of CD23 expression on CD20+ B cells was analyzed, as described before (23). PBMC incubated in the presence or absence of 2.5 ng/ml hIL-4 for 48 h were incubated with biotinylated anti-CD23 mAb, followed by incubation with phycoerythrin-conjugated streptavidin and FITC-conjugated anti-CD20 mAb (Becton Dickinson, San Jose, CA). Isotype-matched control mAbs were used for a negative staining. Stained cells were analyzed by flow cytometry on a FACScan using a gate for CD20+ B cells.
Measurement of IgE synthesis was conducted as described before (24). After PBMC were incubated in the presence or absence of 5 ng/ml hIL-4 for 14 days, IgE in culture supernatants was measured by a solid-phase RIA, and net IgE synthesis was calculated by subtracting the value of preformed IgE. To estimate preformed IgE, both 50 µg/ml of cycloheximide and 10 µg/ml of puromycin were added.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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It has been shown that STAT6 has a central role for germline
transcript induced by IL-4, based on studies of the promoter region of
I, and STAT6-disruption mice (12, 13, 14, 15). We have also shown that the
Ile50 variant augmented STAT6 activation induced by IL-4
(16). For this reason, we analyzed STAT6 activation induced by hIL-4 in
the variants to investigate whether activation of a signal-transducing
molecule for generation of germline transcript is enhanced by the
Arg551Gln variant. The STAT6 activities in
BF-Ile50Gln551 and
BF-Ile50Arg551 were up-regulated compared with
those of BF-Val50Gln551 and
BF-Val50Arg551, as judged by image analyzer
(Fig. 1
A; 1.6- and 1.8-fold,
the averages of three experiments, respectively), whereas those of
BF-Val50Arg551 and
BF-Ile50Arg551 were invariable with those of
BF-Val50Gln551 and
BF-Ile50Gln551 (Fig. 1A; 0.8- and
0.9-fold, the averages of three experiments, respectively). There was
no difference of the STAT6 activities induced by mIL-4 (Fig. 1B). These results confirmed our previous finding that STAT6
activation by hIL-4 is increased by Ile50 variant (16). As
Khurana Hershey et al. stated, it is unlikely that the substitution
Arg551Gln influences STAT6 activation (17).
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promoter of the variants
In our previous study, it was demonstrated that the
Ile50 variant up-regulates the transcription activity of
the I promoter by hIL-4 (16). Although Arg551Gln does not influence
STAT6 activation, it would be still possible that this substitution
augments the transcription activity of the I promoter, through
another pathway independent of that of Jak/STAT. To address this point,
we next measured luciferase activity induced by hIL-4 and mIL-4 in the
variants. We first analyzed the proliferation activity of the variants
by hIL-4. The proliferations by hIL-4 in
BF-Ile50Gln551 and
BF-Ile50Arg551 were up-regulated compared with
BF-Val50Gln551 and
BF-Val50Arg551 (Fig. 2A; 1.5- and 1.9-fold,
respectively). The proliferations of
BF-Val50Gln551 and
BF-Val50Arg551, or of
BF-Ile50Gln551 and
BF-Ile50Arg551, were almost the same (Fig. 2A), and the proliferations by mIL-4 in the variants were
invariable (data not shown). Based on these results, we performed the
luciferase assay in the presence of mIL-3 to normalize the analyzed
cells. The relative transcription activities in
BF-Ile50Gln551 and
BF-Ile50Arg551 induced by hIL-4 were higher
than those of BF-Val50Gln551 and
BF-Val50Arg551 (Fig. 2B; 1.5- and
1.6-fold, respectively), whereas those of
BF-Val50Arg551 and
BF-Ile50Arg551 were invariable with those of
BF-Val50Gln551 and
BF-Ile50Gln551 (Fig. 2B; 1.1- and
1.1-fold, respectively). The relative transcription activities in the
variants induced by mIL-4 were invariable (Fig. 2B). The
proliferations of the variants in this condition were the same (data
not shown). These results revealed that although it was reproducible
that the Ile50 variant augmented the transcription activity
of I promoter induced by hIL-4, the Arg551Gln variant did not elicit
a clear change. It has been unclear how Arg551Gln is involved in the
pathogenesis of hyper IgE syndrome and severe eczema. Because it has
been shown that IL-4 induces tyrosine phosphorylation
of various intracellular proteins (21), further studies focused on
identifying the target of SHP-1, whose association with IL-4R is
less in Arg551 type than in Gln551 type, would
be useful.
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expression of the variants
In our previous study, we demonstrated that the Ile50Val variant
does not influence the binding affinity of hIL-4R with hIL-4 (16).
We next performed the binding assay using the variants. The values of
Kd were not varied by the substitution Ile50Val,
as described previously, whereas the substitution Arg551Gln slightly
increased the values of Kd (Fig. 3A;
BF-Val50Gln551,
BF-Val50Arg551,
BF-Ile50Gln551, and
BF-Ile50Arg551: 1.3 x 10, 2.3 x 10,
1.5 x 10, and 2.1 x 10 pM, respectively). These results
suggest that higher responsiveness to hIL-4 in the Ile50
type is not explained by higher affinity of the receptor with hIL-4 in
that type. The receptors expressed on the surfaces of these four clones
were invariable, as estimated by the binding assay (Fig. 3A;
3100–4200/cell) and by Western blotting (Fig. 3B),
indicating that higher responsiveness to hIL-4 in the Ile50
type is not due to the high expression of the receptor on the surface.
To date, the mechanism by which the Ile50 variant
up-regulates the hIL-4 signals remains unresolved. As for mIL-4R,
the substitution of threonine (Thr) at amino acid 49 to Ile enhances
dissociation of mIL-4 from mIL-4R, probably by abrogating one
N-glycosylation site (25). Although Ile50Val is not involved
in glycosylation of hIL-4R, it would be possible that Thr49Ile of
mIL-4R and Ile50Val of hIL-4R cause up-regulation of the IL-4
signals by similar mechanisms, as both amino acids are adjacent to one
cysteine positionally conserved in the cytokine receptor family.
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To address the genetic correlation of Arg551Gln with atopic
asthma, we next conducted a genetic association study in a Japanese
population (Table I). As previously
described, the frequency of Ile50 was significantly higher
than Val50 in atopic asthma patients and correlated with
total IgE and mite-specific IgE. In contrast, Arg551Gln genotype
frequency was invariable in all three kinds of classification. These
results indicate that the incidence of Ile50Val, but not Arg551Gln, is
correlated with atopic asthma and that there is no linkage
disequilibrium between these substitutions. Arg551Gln may be
specifically associated with hyper IgE syndrome and severe atopic
eczema or may be specific to Caucasians, although there has been a
conflicting result (26).
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Our previous (16) and present studies have verified that the
Ile50 variant amplifies the IL-4 signals concerned with
generation of germline transcript, and have shown high incidence in
patients with atopic asthma. To elucidate whether
Ile50-bearing PBMCs respond strongly to exogenous hIL-4
compared with Val50-bearing cells, we assessed expression
of CD23 and production of IgE induced by IL-4, using PBMCs whose
genotypes were confirmed as homozygotes of either Ile50 or
Val50. The genotype of amino acid at 551 was a homozygote
of Gln in all of the investigated donors. When either
Ile50- or Val50-bearing PBMCs from each of five
donors were stimulated by hIL-4, CD23 expression induced by hIL-4 on
CD20+ B cells was slightly higher in the Ile50
type than the Val50 type (Fig. 4A; the mean 
MFI 957 vs
616, respectively), and IgE production induced by hIL-4 in the
Ile50 type was three times as high as the Val50
type (Fig. 4B; 8.5 vs 2.8 ng/ml, respectively). These
results were compatible with our previous and present results using B
cell lines and based on genetic study, indicating that
Ile50 variant enhanced the transducing signal for IgE
synthesis, in not only in vitro, but also in intact B cells.
Furthermore, it would also be possible that Ile50 variant
augments Th2 differentiation induced by IL-4, in synergy with the
variant’s effect on B cells, increasing IgE synthesis in PBMC by IL-4.
Elucidation of this point is awaited.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprints requests to Dr. Kenji Izuhara, Department of Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail address:
3 Abbreviations used in this paper: IL-4R, IL-4R -chain; hIL-4, human IL-4; mIL-3, mouse IL-3; EMSA, electrophoretic mobility-shift assay.
Received for publication July 20, 1998. Accepted for publication November 23, 1998.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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L. Stephenson, M. H. Johns, E. Woodward, A. L. Mora, and M. Boothby An IL-4R{alpha} Allelic Variant, I50, Acts as a Gain-of-Function Variant Relative to V50 for Stat6, But Not Th2 Differentiation J. Immunol., October 1, 2004; 173(7): 4523 - 4528. [Abstract] [Full Text] [PDF]
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D. C. Webb, K. I. Matthaei, Y. Cai, A. N. J. McKenzie, and P. S. Foster Polymorphisms in IL-4R{alpha} Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13-/- Mice J. Immunol., January 15, 2004; 172(2): 1092 - 1098. [Abstract] [Full Text] [PDF]
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