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Is Essential for Binding IL-15 and Inhibiting Inflammatory and Allogenic Responses In Vitro and In Vivo1
*
Department of Immunology and Bacteriology and
Center of Rheumatic Disease, University of Glasgow, Glasgow, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain and the common IL-2R 
-
and 
-chains. Characterization of IL-15/IL-15R interactions may
facilitate the development of improved IL-15 antagonists for
therapeutic interventions. We previously constructed soluble murine
IL-15R (sIL-15R) by deleting the cytoplasmic and transmembrane
domains. To localize the functional domain of IL-15R, we have now
constructed various truncated versions of sIL-15R. The shortest
region retaining IL-15 binding activity is a 65-aa sequence spanning
the Sushi domain of IL-15R. Sushi domains, common motifs in
protein-protein interactions, contain four cysteines forming two
disulfide bonds in a 1-3 and 2-4 pattern. Amino acid substitution of
the first or fourth cysteine in sIL-15R completely abolished its
IL-15 binding activity. This also abrogated the ability of sIL-15R
to neutralize IL-15-induced proinflammatory cytokine production and
anti-apoptotic response in vitro. Furthermore, the mutant
sIL-15R lost its ability to inhibit carrageenan-induced local
inflammation and allogenic cell-induced T cell proliferation and
cytokine production in vivo. Thus, the Sushi domain is critical for the
functional activity of sIL-15R. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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knockout mice lack NK cells and activated
CD8+ T cells (6, 7). IL-15 also
provides survival signals to support mature lymphocytes
(8). Moreover, IL-15 is expressed by activated endothelial
cells and regulates the capacity of lymphocytes and neutrophils to
migrate across endothelial barriers into inflamed tissues
(9). We have demonstrated that IL-15 is present in the
synovium of patients with rheumatoid arthritis and may recruit and
activate synovial T cells in the relative absence of IL-2 (10, 11). Following IL-15-mediated activation, synovial T cells both
secrete TNF- directly and induce TNF- synthesis by macrophages
through cognate interactions (12, 13), indicating an
important role for IL-15 in the inflammatory cascade within the
synovium. Furthermore, IL-15 expression has been detected in several
diseases, including inflammatory bowel diseases, sarcoidosis, and
chronic active hepatitis (14, 15, 16), suggesting that such
proinflammatory pathways may be of general importance.
IL-15 functions through a trimeric receptor complex, which consists of
a unique high affinity -chain, the IL-2R -chain and the common
-chain for signal transduction (17, 18, 19). As part of our
investigation into the functional role of IL-15 in rheumatoid
arthritis, we have cloned and expressed a soluble fragment of IL-15R
and found that this protein profoundly suppressed the development of
collagen-induced arthritis in DBA/1 mice (20). More
recently, we demonstrated that soluble murine IL-15R
(sIL-15R)3
administered for a short period at the beginning of transplantation
markedly prolonged the survival of allogenic heart grafts
(21). These findings suggest that sIL-15R or its
analogs may have considerable therapeutic potential in a wide range of
diseases. We therefore conducted further investigation into the nature
and functional motif of sIL-15R to facilitate the potential
designing of therapeutic agents. The extracellular region of IL-15R
contains a Sushi domain, which is a common motif in protein-protein
interaction. Sushi domains are also known as short consensus repeats or
type 1 glycoprotein motifs. They have been identified on a number of
protein-binding molecules, including complement components C1r, C1s,
factor H, and C2m as well as the nonimmunologic molecules factor XIII
and 2-glycoprotein (22, 23). A
typical Sushi domain has approximately 60 aa residues and contains four
cysteines (24). The first cysteine forms a disulfide bond
with the third cysteine, and the second cysteine forms a disulfide
bridge with the fourth cysteine. The two disulfide bonds are essential
to maintain the tertiary structure of the protein. We report here that
the Sushi domain of IL-15R is critical for the binding and function
of this protein. Furthermore, substitution of any of the four cysteine
residues completely abrogated the ability of sIL-15R to inhibit
acute inflammation and T cell response to allogenic Ags in vivo. These
results not only established the critical role of the Sushi domain for
IL-15R activity, but revealed the therapeutic potential of truncated
sIL-15R in a range of diseases in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using PCR and restriction sites PstI and
RcaI, four truncated sIL-15R proteins were cloned from
previously synthesized cDNA of sIL-15R (T1). T1 consists of 182 aa
spanning the whole IL-15R extracellular domain, including the Sushi
domain, linker, and Pro/Thr-rich region (17) (see Fig. 1
). The other truncated proteins,
designated T2, T3, T4, and T5, are also shown in Fig. 1. T2 retains 85
residues of the N-terminal end of T1. T3, T4, and T5 have sequential 20
residues truncated off from the C-terminal end of T2. The PCR primers
for the constructs are as follows: T-P1, 5'-TTT CCT GCA GAA TTC ATT AAA
GAG GAG CCT GCA GAA TTC ATT AAA GAG GAG A-3'; T2P, 5'-TCA CTG TGG TTT
CCA CTG GAA GTA CTG TCT-3'; T3P, 5'-GGA GTT CAC GTA GTC TCT GGA GTA CTA
TCG-3'; T4P, 5'-GTG GGA CTA ACT CAC ACA CTA GTA CTT CTT-3'; and T5P,
5'-ACA CTT GAG GTC CCT CTC CAA GTA CTC ATT-3'. T2, T3, T4, and T5 were
amplified with T-P1/T2P, T-P1/T3P, T-P1/T4P, and T-P1/T5P primer pairs,
respectively. PCR products were digested with PstI and
RcaI, then inserted into pEGFP-1 (Clontech, Basingstoke,
U.K.). The recombinant six-histidine-tagged proteins were
expressed in Escherichia coli (XL-1 Blue, Stratagene, La
Jolla, CA) following isopropyl -D-thiogalactoside (Stratagene)
induction and purified by a nickel-agarose purification system (Qiagen,
Crawley, U.K.), according to the manufacturer’s
recommendations. Purified proteins were analyzed by SDS-PAGE. The
purity was >97% for all recombinant proteins. Two additional
truncated proteins, T6 and T7 (see Fig. 1), were cloned using T2 DNA as
template for PCR. PCR products were digested with NcoI and
BglII before insertion into pQE60 (Qiagen) to produce
C-terminal six-histidine-tagged proteins. The PCR primers for T6 and T7
clones were: T6P, 5'-ATC ACC ATG GCC TCC CTA GCT CAC TAC AGT CC-3';
T7P, 5'-GAG TCC ATG GTC AAC AAG AAC ACA AAT GTT GC-3'; and T-P2: CGC
TAG ATC TGT ACA GCT CGT CCA TGC CGA GA-3'. The primer pairs used for T6
and T7 were T6P/T-P2 and T6P/T-P2, respectively. T6 and T7 proteins
were expressed and purified as described above. LPS was not detected by
the Limulus amebocyte test (<0.01 ng/µg; E-Toxate; Sigma,
St. Louis, MO).
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Ninety-six-well plates (Immulon 4, Dynatech, Chantilly, VA) were
coated with 1 µg/ml sIL-15R (T1) in 0.1 M
NaH2CO3, pH 8.6, at 4°C
overnight. After blocking with 10% FCS (Life Technologies, Glasgow,
U.K.) in PBS, graded concentrations of the truncated IL-15R
proteins, previously incubated with 500 pg/ml rIL-15 (R&D Systems,
Oxon, U.K.), were added and incubated at 37°C for 1 h. IL-15
binding was detected by addition of biotin-conjugated anti-IL-15 Ab
(1/500 dilution; R&D Systems). This was followed by addition of
HRP-ExtrAvidin (Sigma; 1/1000 dilution) and was developed with 100
µl/well tetramethylbenzidine substrate (Kirkegaard & Perry,
Gaithersburg, MD). The OD was read at 630 nm.
Site-directed mutagenesis of the IL-15R Sushi domain
Site-directed mutants were generated based on the T1 construct.
Two pairs of primers were designed to replace the first and fourth
cysteines with arginine (R; protein M1) and aspartic acid (D; protein
M4), respectively (see Fig. 3A). After amplification of the
whole plasmid with pfu DNA polymerase (Stratagene), the DNA
was phosphorylated with T4 kinase (Roche, Lewes, U.K.), followed
by digestion with DpnI to remove template DNA plasmid. The
PCR fragments were purified for ligation and transformation into XL-1
Blue. M1 and M4 cDNA were sequenced to confirm the mutations. The
proteins were purified as before and analyzed by SDS-PAGE and Western
blot. LPS was not detectable by the amebocyte Limulus
test.
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Different concentrations of purified T1 and M4 were run on 12%
SDS-PAGE gel and transferred to nitrocellulose membranes (Bio-Rad,
Hemel Hempstead, U.K.). The membranes were blocked with 2% BSA
in PBS and incubated with sheep anti-sIL-15R Ab (Diagnostics
Scotland, Carluke, U.K.; 1/5000 dilution). After washing, this was
incubated with 10 ng/ml rIL-15 (R&D Systems, Abingdon, U.K.). For the
first blot, HRP-anti-sheep IgG was used; in the second blot,
biotin-conjugated anti-IL-15 (R&D Systems) and HRP-ExtrAvidin
(Sigma) were used. The bands were developed with the ECL system
(Amersham Pharmacia, Freiburg, Germany).
CTLL proliferation assay
The capacity of sIL-15R and the truncated proteins to
neutralize IL-15-driven proliferation was assessed using a CTLL cell
line (American Type Culture Collection, Manassas, VA). Following
several washes to remove IL-2 or IL-15 from the maintenance growth
medium, cells (5 x 103/well) were plated in
96-well plates. Cells were cultured for 48 h in the presence of
0.1 ng/ml IL-15 (Immunex, Seattle, WA) or with IL-15 that had been
previously incubated for 30 min at 37°C with graded concentrations of
the test proteins. Cells were pulsed during the last 6 h of
culture with 1 µCi [3H]thymidine, and
incorporated radioactivity was measured in a Packard Matrix 96 beta
counter (Pangbourne, U.K.).
Effect of sIL-15R on apoptosis
A variation of the standard apoptosis assay was performed using
the IL-2/IL-15-dependent human T cell line BDB2, previously called IDB
(25). These cells rapidly undergo apoptosis/necrosis in
the absence of IL-2 or IL-15. The cells were cultured in the presence
of IL-15 or with IL-15 previously incubated with sIL-15R or the
truncated proteins. Following culture for 24 h apoptosis was
assessed by the annexin V/propidium iodide system according to the
manufacturer’s protocol (BD PharMingen, San Diego, CA). Briefly, cells
were incubated with 5 µl (100 µg/ml) FITC-conjugated annexin V and
5 µl (50 µg/ml) propidium iodide for 15 min at 20°C in the dark.
Binding buffer (400 µl, pH 7.4, buffered HEPES/25 mM
CaCl2) was then added. Cells were analyzed within
30 min by flow cytometry (FACScan Becton Dickinson, Mountain View CA)
to reveal the three expected populations: live cells
(AN-/PI-), apoptotic
cells (AN+/PI-), and
necrotic cells
(AN+/PI+).
Carrageenin-induced footpad inflammation
Three groups of BALB/c female mice (6–8 wk old, obtained from
Harlan Olac, Bicester, Oxon, U.K.) were injected on the left footpad
with 300 µg -carrageenan (Sigma) mixed with 5 µg T1 or M4 or
with the diluent PBS alone. Footpad swelling was measured at 4, 8, 24,
and 32 h after injection using a dial caliper (Kroeplin, Munich,
Germany). The difference in thickness between the left footpad and the
uninjected right footpad was calculated to determine the degree of
inflammation (26).
Allogenic cellular activation in vivo
BALB/c female mice were injected in the left footpad with 106 mitomycin C-treated spleen cells from DBA/1 mice (males and females, 6–10 wk old; Harlan Olac) mixed with either 5 µg T1 or M4 or the diluent PBS alone. Recombinant proteins (40 µg) were then injected i.p. daily for 7 days. Mice were then sacrificed, and spleens were removed and weighted individually. Spleen cell populations were cocultured at (2 x 106) with mitomycin C-treated DBA/1 spleen cells (106/ml) for 48 h in medium (RPMI (Life Technologies/BRL, Glasgow, U.K.) supplemented with 2 mM L-glutamine, 100 IU/ml penicillin, 100 µg/ml streptomycin, 25 mM HEPES buffer, and 10% FCS (all from Life Technologies)) at 37°C in 5% CO2. Proliferation assays were performed in triplicate as described previously (20). Supernatants from parallel triplicate cultures were collected up to 72 h and stored at -70°C until estimation of cytokine content by ELISA.
Cytokine assays
Murine TNF-, IFN-, IL2, IL-4, IL-6, and IL-10 were assayed
by ELISA using paired Abs (BD PharMingen) according to the
manufacturer’s instructions. Lower limits of detection were as
follows: IL-4, IL-6, and TNF- were all at 10 pg/ml; IL-10 was at 40
pg/ml; and IFN- was at 80 pg/ml.
Statistical analysis
Statistics was performed using Minitab software for Macintosh. The analyses were performed using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is essential for IL-15 binding
Five sequential C-terminal truncated proteins of IL-15R were
constructed as T1, T2, T3, T4, and T5, which contain 182, 85, 65, 45,
and 25 aa residues, respectively (Fig. 1
). They were purified and
tested for their ability to bind IL-15 in vitro using a competitive
binding assay. As expected, T1 bound IL-15 strongly in a dose-dependent
manner. T2 bound IL-15 indistinguishably from T1. The binding of IL-15
by T3 was significantly weaker than that by T1 and T2. In contrast, T4
and T5 failed to bind (Fig. 2). We then
investigated whether the C-terminal end of IL-15R contributed to the
binding of IL-15. Two N-terminal truncated proteins, T6 and T7, were
constructed using the same approach as that for T2–T5. T6 and T7
contain 25 and 45 residues with a deleted or disrupted Sushi domain,
respectively (Fig. 1). T6 and T7 completely failed to bind IL-15 in a
standard binding assay (Fig. 2). These results therefore suggest that
the Sushi domain of IL-15R is essential for binding IL-15 with
contributions from the Pro/Thr-rich region.
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are critical
for binding IL-15
The Sushi domain has two overlapping disulfide bonds that
contribute to the maintenance of the unique tertiary structure of
IL-15R. The first cysteine forms a disulfide bond with the third
cysteine, and the second forms a bond with the fourth. To confirm the
functional importance of the disulfide bonds for sIL-15R,
site-directed mutation was conducted to replace the first cysteine with
arginine and the fourth cysteine with aspartic acid to form M1 and M4,
respectively (Fig. 3A). DNA
sequencing was conducted to confirm the single residue mutation. M1 and
M4 were then expressed in XL-1 blue as for T1. Competitive binding
ELISA showed that both M1 and M4 completely failed to bind IL-15 (Fig. 3B). Western blot analysis demonstrated that although both
M4 and T1 were equally recognized by an anti-IL-15R Ab, only T1
could bind IL-15, which was then recognized by an anti-IL-15 Ab
(Fig. 3C). These results therefore clearly demonstrate that
the disulfide bonds of the Sushi domain of sIL-15R are critical for
the binding of IL-15.
The Sushi domain of IL-15R is required for the neutralization of
IL-15-mediated T cell proliferation and rescue of apoptosis and
necrosis
CTLL cells proliferate in response to IL-15. Using this system,
the ability of truncated and mutated sIL-15R proteins to inhibit
IL-15 activity was analyzed. T1 and T2 were efficient in blocking the
ability of IL-15 to induce CTLL cells proliferation, T3 was only
partially so. In contrast, T4, T5, and M4 completely failed to inhibit
this proliferation (Fig. 4). IL-15 is
known to rescue T cells from apoptosis and necrosis (8, 27). A human T cell line, BDB2 (IBD in Ref. 25)
rapidly undergoes apoptosis and necrosis when cultured in medium alone.
This was almost completely prevented by the presence of IL-15. This
rescuing ability of IL-15 was totally reversed by the presence of T1 or
T2, but not by T5 or M4 (Fig. 5). Thus,
there is a direct correlation between the ability of sIL-15R and its
various derivatives to bind IL-15 and their ability to neutralize the
IL-15 functions in vitro.
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(T1), but not the mutant (M4), reduced acute
inflammation in vivo
Carrageenan is a potent inducer of acute local
inflammation in vivo. It leads to a rapid recruitment of neutrophils to
the site of administration and has been used extensively to investigate
the mechanism of local inflammation (26). Since IL-15 has
been shown to play a significant chemotactic role in cellular migration
and infiltration (3, 9, 13), we investigated the relative
abilities of T1 and M4 to influence carrageenan-induced local
inflammation. Carrageenan (300 µg) was mixed with T1, M4 (5 µg
each), or PBS alone and injected into the footpads of BALB/c mice. Mice
injected with carrageenan with PBS developed the expected local footpad
swelling, which started 4 h after injection and was sustained for
up to 48 h. This reaction was markedly reduced by the
coapplication of T1, but not by M4 (Fig. 6). These results therefore demonstrate
that IL-15 is a key mediator of carrageenan-induced local inflammation,
which was inhibited by T1, and that M4, with a disrupted Sushi domain,
was completely inactive.
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We have previously shown that sIL-15R (T1), administrated daily
for 10 days from the day of transplantation, markedly prolonged the
survival of allogenic heart graft in the mouse. This finding strongly
suggests that IL-15 may contribute to the rejection of the transplanted
allograft. However, the mechanism by which T1 suppressed the graft
rejection is unclear. Using the recombinant proteins T1 and M4, we
investigated the ability of sIL-15R to influence the proliferative
response and cytokine production by the recipient spleen cells
following administration of allogenic cells in vivo. BALB/c mice were
injected in the footpads with mitomycin C-treated allogenic (DBA/1)
spleen cells. The mice were treated with daily injections of 40 µg
T1, M4, or PBS alone for 7 days. Mice were sacrificed on day 8, and the
spleens were collected. Spleens from mice treated with T1 were
significantly smaller than those treated with M4 or PBS (Fig. 7A). Cells from T1-treated
mice also proliferated markedly less vigorously when cultured with
DBA/1 spleen cells in vitro compared with cells from M1 or PBS-treated
mice (Fig. 7B). Furthermore, cells from the T1-treated mice
produced significantly less IL-2, IFN-, TNF-, and IL-6 when
cultured with DBA/1 cells in vitro compared with spleen cells from the
M4- or PBS-treated mice (Fig. 7, C–F). However, there was
no significant difference in the percentages of
CD3+, CD4+, and
CD8+ T cells; B cells; or NK cells among the mice
injected with PBS alone and those treated with T1 or M4 (data not
shown). These results therefore demonstrate that sIL-15R is a potent
inhibitor of the allogenic Ag-induced T response in vivo, and that this
activity is completely abolished by disruption of the integrity of the
Sushi domain.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is critical for the binding of IL-15 and the biological
activity of sIL-15R. The Pro/Thr-rich region, immediately outside
the transmembrane domain, also contributes to this activity. The
minimum length required to retain the biological functions of
sIL-15R appears to be a sequence of 65 aa residues covering the
entire Sushi domain, of which the integrity of the two disulfide
bridges is absolutely essential. The Sushi domains may have a broad
general role in the protein-protein interaction essential for a range
of ligand-receptor interactions and biological functions. IL-2R has
two such Sushi domains, which are also required for the binding to IL-2
(28). However, IL15R binds IL-15 with an affinity
1000-fold higher than that of IL-2 to IL-2R (17).
Therefore, the Sushi domain of IL-15R is likely to be more important
than that of IL-2 for the biological activities of their respective
ligands. The unique and high affinity of the IL-15R -chain for
binding IL-15 strongly suggests that it, particularly its Sushi domain,
would be an important potential target for therapeutic interventions in
diseases where overexpression of IL-15 is clearly implicated.
Using the truncated sIL-15 (T1) and the single cysteine-substituted
mutant (M4), we have explored further the therapeutic potential of T1
in vitro and in vivo. The results reported here extend our earlier
findings on the anti-inflammatory role of sIL-15 in
collagen-induced arthritis (20) and the prolongation of
allograft survival (21) in the murine models by providing
insight into the mechanisms involved. It was previously shown that
IL-15 is a growth factor capable of rescuing cells from apoptosis and
necrosis, which occur through specific activation or neglect (8, 27). This was confirmed and extended in experiments reported
here using a defined human T cell line (BDB2) that rapidly undergoes
apoptosis/necrosis in the absence of IL-15 or IL-2. T1, but not M4, was
able to reverse the rescuing effect of IL-15 of BDB2 cells. These
results are the first demonstration of the role of sIL-15R in
cellular survival and strongly suggest the potential of T1 as an
anti-proliferative reagent in vivo.
We have investigated the effect of T1 in carrageenan-induced acute local inflammation in the mouse. T1, but not M4, markedly inhibited the footpad swelling that resulted from rapid infiltration of neutrophils and later the arrival of mononuclear cells (26). The effect of T1 was evident as early as 4 h after carrageenan administration. This probably reflects the inhibition of the chemotactic activity of locally induced IL-15, which is a known to attract the migration of neutrophils across endothelial membrane into inflamed tissues (9). IL-15 is also a chemoattractant for activated T cells (3), and this could account for the sustained inhibition of chronic inflammation by T1.
The finding that a short course of sIL-15R treatment can markedly
prolong the survival of allogenic heart graft opens up the possibility
that T1 could have a potential therapeutic value in preventing
transplantation rejections (21). This finding also
suggests that IL-15 is associated with the initiation of chronic
allograft rejection process, including the amplification of acquired
immunity. This is consistent with our observation that hosts accepting
the heart graft, as the results of T1 treatment, were able to mount a
normal rejection of a third-party skin graft (21). IL-15
is therefore required as an accessory signal for the full expansion of
activated T cells, or alternatively, it acts as a paracrine growth
factor for activated T cells. The results reported here demonstrate
clearly that T1, but not M4, profoundly inhibited the specific
proliferative response of spleen cells activated with allogenic cells
in vivo. Furthermore, this is associated with the inhibition of the
production of a number of proinflammatory cytokines, including IL-2,
IFN-, TNF-, and IL-6. These results thus provide a rational
explanation to the strong suppressive effect of sIL-15R in allograft
rejection.
In conclusion, we report here the potential therapeutic role of
sIL-15R in a number of experimental diseases. We have also defined
the critical role of the Sushi domain in the functional activity of
sIL-15Ra. The importance of the structural integrity of the Sushi
domain through the maintenance of the disulfide bridges implies that it
may be of interest to examine polymorphisms within the Sushi domain and
their possible association with disease. Additionally, any protein
competitor for IL-15 should contain an intact Sushi domain. However,
the general application of this principle to other receptor-ligand
interactions and the mechanism(s) by which the Sushi domain of a
receptor interacts with its ligand remain unclear, but is now amenable
to further experimentation.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Xiao-quing Wei or Dr. Foo Y. Liew, Department of Immunology and Bacteriology, University of Glasgow, Glasgow, U.K. G11 6NT. E-mail address: F.Y.Liew@clinmed.gla.ac.uk or xqw1r{at}clinmed.gla.ac.uk
3 Abbreviation used in this paper: sIL-15R, soluble murine IL-15R.
Received for publication January 19, 2001. Accepted for publication April 23, 2001.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-chain of the interleukin-2 receptor. Science 264:965.
B activation and IL-8 production in human neutrophils. Blood 92:4828. production in rheumatoid arthritis. Nat. Med. 3:189.[Medline]
, but not interleukin-10: possible relevance to pathophysiology of rheumatoid arthritis. Eur. J. Immunol. 27:624.[Medline]
(TNF-) receptors in type C chronic liver disease. Clin. Exp. Immunol. 109:458.[Medline]
chain of the IL-2 receptor. EMBO J. 14:3654.[Medline]
and IL2R genes. J. Biol. Chem. 270:29862.-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J. Immunol. 160:5654.-chain enhances cardiac allograft survival. J. Immunol. 165:3444.2 glycoprotein I: the presence of five Sushi domains. Biochemistry 30:11687.[Medline]
subunit of human factor XIII. Biochemistry 29:11195.[Medline]
from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J. Leukocyte Biol. 66:981.[Abstract]
in attenuated Salmonella typhimurium: oral administration leads to the reduction of inflammation, IL-2 and IFN-, but enhancement of IL-10, in carrageenan-induced oedema in mice. Immunology 84:8.[Medline]
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 N. Tejman-Yarden, M. Zlotnik, E. Lewis, O. Etzion, C. Chaimovitz, and A. Douvdevani Renal cells express a functional interleukin-15 receptor Nephrol. Dial. Transplant., March 1, 2005; 20(3): 516 - 523. [Abstract] [Full Text] [PDF]
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 M. Iwasaki, T. Kuwata, Y. Yamazaki, N. A. Jenkins, N. G. Copeland, M. Osato, Y. Ito, E. Kroon, G. Sauvageau, and T. Nakamura Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model Blood, January 15, 2005; 105(2): 784 - 793. [Abstract] [Full Text] [PDF]
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V. Budagian, E. Bulanova, Z. Orinska, A. Ludwig, S. Rose-John, P. Saftig, E. C. Borden, and S. Bulfone-Paus Natural Soluble Interleukin-15R{alpha} Is Generated by Cleavage That Involves the Tumor Necrosis Factor-{alpha}-converting Enzyme (TACE/ADAM17) J. Biol. Chem., September 24, 2004; 279(39): 40368 - 40375. [Abstract] [Full Text] [PDF]
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 J. A. Toomey, F. Gays, D. Foster, and C. G. Brooks Cytokine requirements for the growth and development of mouse NK cells in vitro J. Leukoc. Biol., August 1, 2003; 74(2): 233 - 242. [Abstract] [Full Text] [PDF]
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K. B. Nguyen, T. P. Salazar-Mather, M. Y. Dalod, J. B. Van Deusen, X.-q. Wei, F. Y. Liew, M. A. Caligiuri, J. E. Durbin, and C. A. Biron Coordinated and Distinct Roles for IFN-{alpha}{beta}, IL-12, and IL-15 Regulation of NK Cell Responses to Viral Infection J. Immunol., October 15, 2002; 169(8): 4279 - 4287. [Abstract] [Full Text] [PDF]
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 G. Gri, C. Chiodoni, E. Gallo, A. Stoppacciaro, F. Y. Liew, and M. P. Colombo Antitumor Effect of Interleukin (IL)-12 in the Absence of Endogenous IFN-{gamma}: A Role for Intrinsic Tumor Immunogenicity and IL-15 Cancer Res., August 1, 2002; 62(15): 4390 - 4397. [Abstract] [Full Text] [PDF]
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 I. A. Khan, M. Moretto, X.-q. Wei, M. Williams, J. D. Schwartzman, and F. Y. Liew Treatment with Soluble Interleukin-15R{alpha} Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response J. Exp. Med., June 3, 2002; 195(11): 1463 - 1470. [Abstract] [Full Text] [PDF]
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