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J Biol Chem, Vol. 274, Issue 20, 13733-13736, May 14, 1999
From the TR6 (decoy receptor 3 (DcR3)) is a new member of
the tumor necrosis factor receptor (TNFR) family. TR6 mRNA is
expressed in lung tissues and colon adenocarcinoma, SW480. In addition,
the expression of TR6 mRNA was shown in the endothelial cell line and induced by phorbol 12-myristate 13-acetate/ionomycin in Jurkat T
leukemia cells. The open reading frame of TR6 encodes 300 amino acids
with a 29-residue signal sequence but no transmembrane region. Using
histidine-tagged recombinant TR6, we screened soluble forms of
TNF-ligand proteins with immunoprecipitation. Here, we demonstrate that
TR6 specifically binds two cellular ligands, LIGHT (herpes virus entry
mediator (HVEM)-L) and Fas ligand (FasL/CD95L). These bindings were
confirmed with HEK 293 EBNA cells transfected with LIGHT cDNA by
flow cytometry. TR6 inhibited LIGHT-induced cytotoxicity in HT29 cells.
It has been shown that LIGHT triggers apoptosis of various tumor cells
including HT29 cells that express both lymphotoxin The members of the tumor necrosis factor
(TNF)1 family are involved in
regulating diverse biological activities such as regulation of cell
proliferation, differentiation, cell survival, cell death, cytokine
production, lymphocyte co-stimulation, and isotype switching (1, 2).
Receptors in this family share a common structural motif in their
extracellular domains consisting of multiple cysteine-rich repeats of
approximately 30-40 amino acids (3). While TNFR1, CD95/Fas/APO-1,
DR3/TRAMP/APO-3, DR4/TRAIL-R1/APO-2, DR5/TRAIL-R2, and DR6 receptors
contain a conserved intracellular motif of ~80 amino acids called
death domain, associated with the activation of apoptotic signaling
pathways, other members, which contain a low sequence identity in the
cytoplasmic domains, stimulate the transcription factors NF- Most TNF receptors contain a functional cytoplasmic domain. However,
some members of the TNFR superfamily do not have cytoplasmic domains
and are secreted, such as osteoprotegerin (OPG) (4), or linked to the
membrane through a glycophospholipid tail, such as TRID/DcR1/TRAIL-R3
(5, 6). Viral open reading frames encoding soluble TNFRs have also been
identified, such as SFV-T2 (7), Va53 (8), G4RG (9), and crmB
(3).
By searching an expressed sequence tag (EST) data base, a new member of
the TNFR superfamily was identified, named TR6, and was characterized
as a soluble cognate receptor for LIGHT and FasL/CD95L. LIGHT and FasL
mediate the apoptosis, which is the most common physiological form
of cell death and occurs during embryonic development, tissue
remodeling, immune regulation, and tumor regression.
LIGHT is highly induced in activated T lymphocytes and macrophages.
LIGHT was characterized as a cellular ligand for HVEM/TR2 and LT FasL is one of the major effectors of cytotoxic T lymphocytes and
natural killer cells. It is also involved in the establishment of
peripheral tolerance in the activation-induced cell death of lymphocytes. Moreover, expression of FasL in nonlymphoid and tumor cells contributes to the maintenance of immune privilege of tissues by
preventing the infiltration of Fas-sensitive lymphocytes (16). FasL is
also processed and shed from the surface of human cells (17).
Here we demonstrate that TR6 (DcR3), a new member of the TNFR
superfamily, binds LIGHT and FasL. Therefore TR6 may act as an
inhibitor in LIGHT-induced tumor cell death by blocking LIGHT interaction with its receptors.
Identification and Cloning of New Members of the TNFR
Superfamily--
An EST cDNA data base, obtained from more than
600 different cDNA libraries, was screened for sequence homology
with the cysteine-rich motif of the TNFR superfamily, using the blastn
and tblastn algorithms. Three EST clones containing an identical open
reading frame, the amino acid sequence of which showed significant
homology to TNFR-II, were identified from cDNA libraries of human
normal prostate and pancreas tumor. A full-length TR6 cDNA clone
encoding an intact N-terminal signal peptide was obtained from a human
normal prostate library.
RT-PCR Analysis--
For RT-PCR analysis, total RNA was isolated
using TriZOL (Life Technologies, Inc.) from various human cell lines
before and after stimulation with phorbol 12-myristate
13-acetate/ionomycin or lipopolysaccharide. RNA was converted to
cDNA by reverse transcription and amplified for 35 cycles by PCR.
Primers used for amplification of the TR6 fragment are according to the
sequence of TR6. Recombinant Protein Production and Purification--
The
recombinant TR6 protein was produced with hexahistidine at the C
terminus. TR6-(His) encoding the entire TR6 protein was amplified by
PCR. For correctly oriented cloning, a HindIII site on the 5' end of the forward primer
(5'-AGACCCAAGCTTCCTGCTCCAGCAAGGACCATG-3') and a
BamHI site on the 5' end of the reverse primer
(5'-AGACGGGATCCTTAGTGGTGGTGGTGGTGGTGCACAGGGAGGAAGCGCTC-3') were created. The amplified fragment was cut with
HindIII/BamHI and cloned into a mammalian
expression vector, pCEP4 (Invitrogen). The TR6-(His)/pCEP4 plasmid was
stably transfected into HEK 293 EBNA cells to generate recombinant
TR6-(His). Serum-free culture media from cells transfected
TR6-(His)/pCEP4 were passed through Ni-column (Novagen). The column
eluents were fractionated by SDS-PAGE, and TR6-(His) was detected by
Western blot analysis using the anti-poly(His)6 antibody (Sigma).
Production of HVEM/TR2-Fc, LT Immunoprecipitation--
TR6-(His) was incubated overnight with
various FLAG-tagged ligands of the TNF superfamily and anti-FLAG
agarose in binding buffer (150 mM NaCl, 0.1% Nonidet P-40,
0.25% gelatin, 50 mM HEPES, pH 7.4) at 4 °C and then
precipitated. The bound proteins were resolved by 12.5% SDS-PAGE and
detected by Western blot with HRP-conjugated anti-poly(His)6 or anti-human IgG1 antibodies.
Cell-binding Assay--
For cell-binding assays, HEK 293 EBNA
cells were stably transfected using the calcium phosphate method with
pCEP4/full sequence of LIGHT cDNA or pCEP4 vector alone. After
selection with hygromycin B, cells were harvested with 1 mM
EDTA in phosphate-buffered saline and incubated with TR6-(His),
HVEM/TR2-Fc, or LT Cytotoxicity Assay--
Cytotoxicity assays using HT29 cells
were carried out as described previously (13). Briefly, 5000 HT29 cells
were seeded in 96-well plates with 1% fetal bovine serum, Dulbecco's
modified Eagle's medium, and treated with sLIGHT (10 ng/ml) and 10 units/ml human recombinant interferon- TR6 Is a New Member of the TNFR Superfamily--
TR6 was
identified by searching an EST data base. Three clones containing an
identical open reading frame were identified from cDNA libraries of
human normal prostate and pancreas tumor. A full-length TR6 cDNA
encoding an intact N-terminal signal peptide was obtained from a human
normal prostate library. The open reading frame of TR6 encodes 300 amino acids. To determine the N-terminal amino acid sequence of mature
TR6, hexahistidine-tagged TR6 was expressed in the mammalian cell
expression system, and the N-terminal amino acid sequences were
determined by peptide sequencing. The N-terminal sequence of the
processed mature TR6-(His) started from amino acid 30, indicating that
the first 29 amino acids constituted the signal sequence (Fig.
1A). Therefore, the mature
protein of TR6 was composed of 271 amino acids with no transmembrane
region. There was one potential N-linked glycosylation site
(Asn-173) in TR6. Like OPG (4), the predicted protein was a soluble, secreted protein, and the recombinant TR6 expressed in mammalian cells
was ~40 kDa as estimated on polyacrylamide gel. Fig. 1B shows the potential cysteine-rich motif aligned among TNFR-I, TNFR-II,
4-1BB, TR2/HVEM, LT mRNA Expression--
We analyzed expression of TR6 mRNA in
human multiple tissue blots by Northern hybridization. Northern blot
analyses indicated that TR6 mRNA was ~1.3 kilobases in length and
was expressed predominantly in lung tissue and the colorectal
adenocarcinoma cell line SW480 (data not shown). RT-PCR analyses were
performed to determine the expression patterns of TR6 in various cell
lines. TR6 transcript was detected weakly in most hematopoietic cell
lines. The expression of TR6 was induced upon activation in Jurkat T
leukemia cells. Interestingly, TR6 mRNA was constitutively
expressed in endothelial cell line, HUVEC, at high level (Fig.
2).
Identification of the Ligand for TR6--
To identify the ligand
for TR6, several FLAG-tagged soluble proteins of TNF ligand family
members were screened for binding to recombinant TR6-(His) protein by
immunoprecipitation. TR6-(His) selectively bound LIGHT-FLAG and
FasL-FLAG among FLAG-tagged soluble TNF ligand members tested (Fig.
3). This result indicates that TR6 binds
at least two ligands, LIGHT and FasL. LIGHT exhibits significant
sequence homology with the C-terminal receptor-binding domain of FasL
(31%), but sLIGHT is unable to bind to Fas (10, 14). They may have a
similar binding epitope for TR6 binding.
Previously, Zhai et al. (14) and Harrop et al.
(15) reported the biological functions of LIGHT and its possible
mechanisms of action as a ligand for HVEM/TR2 and/or LT
To determine whether TR6 might act as an inhibitor to LIGHT
interactions with HVEM/TR2 or LT Binding of TR6-(His) to LIGHT-transfected Cells--
To determine
whether TR6 binds to LIGHT expressed on the cell surface, we performed
a binding assay using LIGHT-transfected HEK 293 EBNA cells by flow
cytometry. LIGHT-transfected HEK 293 EBNA cells were stained
significantly by TR6-(His) as well as by HVEM/TR2-Fc and LT TR6 Inhibits LIGHT-induced Cytotoxicity in HT29
Cells--
Browning et al. (13) have shown that Fas
activation leads to rapid cell death (12-24 h) whereas LT
To determine whether binding of TR6 inhibits LIGHT-mediated
cytotoxicity, HT29 cells were incubated with 10 ng/ml sLIGHT and IFN-
LIGHT interaction with HVEM/TR2 and/or LT
TR6 may function as a cytokine to trigger membrane-bound FasL or LIGHT
and transduce signals through FasL or LIGHT. Recently the Desbarats and
Suzuki groups (19, 20) reported that FasL could itself transduce
signals, leading to cell cycle arrest and cell death in
CD4+ T cells but cell proliferation in CD8+ T
cells. Therefore, TR6 may be involved in signaling through FasL and LIGHT.
HUVEC cells constitutively expressed TR6 in RT-PCR analysis. LIGHT and
FasL have been known to be expressed in activated T cells. Therefore it
is speculated that TR6 and its ligands are important for interactions
between activated T lymphocytes and endothelium. TR6 may be involved in
activated T cell trafficking as well as endothelial cell survival.
In this paper we have identified a novel soluble member of the TNFR
superfamily, TR6, which is constitutively expressed in lung tissue,
tumor cells, and in endothelial cells. We have also identified the
ligands for TR6, LIGHT, and FasL, which are involved in the cell death
pathway. TR6 bound specifically to LIGHT and FasL and inhibited their
activities. Like DcR1, DcR2, and another soluble member of the TNFR
superfamily, OPG, TR6 may act as an inhibitor of signaling through TNF
family members, FasL and LIGHT. Hence, TR6 may have important roles in
the inhibition of apoptosis and tumor modulation.
We thank Sister Mary Etta Kiefer, Dr.
Byung-S. Youn, and Dr. Ihn-K. Jang for editing the manuscript and Dr.
Young-J. Kim for comments.
During the preparation of this manuscript, Pitti
et al. (18) published the DcR3 that is identical to TR6. Our
finding that TR6 interacts with FasL is in line with their observation.
*
This work was supported by National Institutes of Health
Grants AI28125 and DE12156 (to B. S. K.), research funds from the University of Ulsan, and Molecular Medicine Program 98-MM-02-01-A-04 from the Ministry of Science and Technology, Korea.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF134240.
The abbreviations used are:
TNF, tumor necrosis
factor;
TNFR, TNF receptor;
LT
COMMUNICATION
A Newly Identified Member of Tumor Necrosis Factor Receptor
Superfamily (TR6) Suppresses LIGHT-mediated Apoptosis*
,,¶
Department of Microbiology and Immunology
and Walther Oncology Center, Indiana University School of Medicine and
the Walther Cancer Institute, Indianapolis, Indiana 46202, § Human Genome Sciences, Rockville, Maryland 20850, and the
¶ Department of Biological Sciences and the Immunomodulation
Research Center, University of Ulsan, Ulsan 680-749, Korea
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
receptor
(LTR) and HVEM/TR2 receptors. Our data suggest that TR6 inhibits the
interactions of LIGHT with HVEM/TR2 and LTR, thereby suppressing
LIGHT- mediated HT29 cell death. Thus, TR6 may play a regulatory role
for suppressing in FasL- and LIGHT-mediated cell death.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
B and
AP-1 (1-3).
R
(10). HVEM/TR2 is a receptor for herpes simplex virus type 1 (HSV-1)
entry into human T lymphoblasts. The soluble form of HVEM/TR2-Fc and
antibodies to HVEM/TR2 were shown to inhibit a mixed lymphocyte
reaction, suggesting a role for this receptor or its ligand in T
lymphocyte proliferation (10-12). The level of LTR expression is
prominent on epithelial cells but is absent in T and B lymphocytes.
Signaling via LTR triggers cell death in some adenocarcinomas (13).
LIGHT produced by activated lymphocytes could evoke immune modulation
from hematopoietic cells expressing only HVEM/TR2 and induce apoptosis
of tumor cells, which express both LTR and HVEM/TR2 receptors (14,
15).
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
-Actin was used as an internal control for RNA
integrity. PCR products were run on 2% agarose gel, stained with
ethidium bromide, and visualized by UV illumination.
R-Fc, and FLAG-tagged soluble LIGHT
(sLIGHT) fusion proteins were previously described (14). Fc fusion
protein-containing supernatants were filtered and trapped onto protein
G-Sepharose beads. FLAG-tagged sLIGHT proteins were purified with
anti-FLAG mAb affinity column.
R-Fc for 20 min on ice. For detecting Fc-fusion
protein, cells were stained with FITC-conjugated goat anti-human IgG.
To detect TR6 binding, cells were stained with
anti-poly(His)6 and FITC-conjugated goat anti-mouse IgG
consecutively. The cells were analyzed by FACScan (Becton Dickinson).
(IFN-) (supplied
from NIAID, NIH Repository). Serial dilutions of TR6-(His)
were added in quadruplicate to microtiter wells. Cells treated with
IFN- and sLIGHT were incubated with various amounts of TR6-(His) for
4 days before the addition of [3H]thymidine for the last
6 h of culture. Cells were harvested, and thymidine incorporation
was determined using a liquid scintillation counter.
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
R, TR1/OPG, and TR6. TR6 contained two perfect
and two imperfect cysteine-rich motifs, and its amino acid sequence was
remarkably similar to the TR1/OPG amino acid sequence. TR6 shares
~30% sequence homology with OPG and TNFR-II.
View larger version (70K):
[in a new window]
Fig. 1.
Sequence of TR6 and aligned amino acid
sequence of cysteine-rich motif. A, a deduced amino
acid sequence of TR6. The signal sequence is underlined. The
potential N-glycosylation site is underlined with
shadow. The N-terminal amino acid sequence of recombinant
TR6-(His) reads as VAETPT ... , which indicates that the first 29 amino acids constitute a signal sequence. B, aligned amino
acid sequence of the cysteine-rich motif of TR6 with other TNF receptor
family members. The amino acid sequence of TR6 was aligned with those
of TNFR-I, TNFR-II, 4-1BB, TR2 (HVEM), LT R, and TR1 (OPG) on the
basis of sequence homology and conserved cysteines.
View larger version (40K):
[in a new window]
Fig. 2.
mRNA expression of TR6 in various human
cell lines. TR6 mRNA expression was detected with TR6-specific
RT-PCR. A low level of TR6 expression was detected in most hemopoietic
cells, and high level expression was found in stimulated Jurkat T
cells, monocytic THP-1 cells, and endothelial HUVEC cells.
Amplification of -actin was used as an internal control.
View larger version (28K):
[in a new window]
Fig. 3.
Biochemical identification of TR6
ligand. A, LIGHT and FasL are ligands for TR6.
Flag-tagged soluble members of the TNF ligand superfamily, TRANCE,
LIGHT, FasL, 4-1BBL and unpublished novel protein, TL3, TL6, and TL7,
in 1 ml of 150 mM NaCl, 0.1% Nonidet P-40, 0.25% gelatin,
50 mM HEPES (pH 7.4) buffer was mixed with poly(His)-tagged
TR6, incubated, and then precipitated with anti-FLAG agarose. The bound
TR6-(His) was resolved by SDS-PAGE (12.5%) and detected by immunoblot
with anti-poly(His) antibody. B, TR6 competitively inhibits
the HVEM/TR2-Fc-LIGHT-Flag interaction. The same concentrations of
HVEM-Fc (20 nM) and TR6-(His) (20 nM) were
incubated with cultured supernatant containing LIGHT-FLAG protein and
then precipitated with anti-FLAG agarose. The bound protein was
resolved by SDS-PAGE and detected HVEM-Fc with HRP-conjugated
anti-human IgG antibody (top), and stripped membrane was
reused to detect TR6-(His) with HRP-conjugated anti-poly(His) antibody.
C, TR6 inhibits the HVEM/TR2-Fc-LIGHT-FLAG binding and
LT R-Fc-LIGHT-FLAG binding. HVEM/TR2-Fc (6 nM) and
LTR-Fc (6 nM) with or without TR6-(His) (20 nM) were mixed with LIGHT-FLAG and then precipitated with
anti-FLAG antibody and resolved on 12.5% SDS-PAGE. The bound
HVEM/TR2-Fc and LTR-Fc were detected with anti-human IgG
antibody.
R. LIGHT is
expressed in activated T cells. LIGHT, in conjunction with serum
starvation or addition of IFN-, inhibits the cell proliferation in
tumor cells, MDA-MB-231 and HT29.
R, TR6-(His) was used as a
competitive inhibitor in LIGHT-HVEM/TR2 interaction. When LIGHT was
immunoprecipitated with HVEM/TR2-Fc in the presence of TR6-(His),
HVEM/TR2-Fc binding to LIGHT was decreased competitively by TR6-(His),
but TR6-(His) binding to LIGHT was not changed by HVEM/TR2-Fc (Fig.
3B). Furthermore, the binding of HVEM/TR2-Fc (6 nM) or LTR (6 nM) was completely inhibited
by 20 nM TR6-(His) protein in immunoprecipitation assays (Fig. 3C). These results support the notion that TR6 may act
as a strong inhibitor of LIGHT function through HVEM/TR2 and
LTR.
R-Fc. No
binding was detected by HVEM/TR2-Fc or LTR-Fc on pCEP4
vector-transfected HEK 293 EBNA cells. (Fig. 4). Furthermore, control isotype did not
bind to LIGHT-transfected HEK 293 EBNA cells, and none of the above
fusion proteins bound to vector-transfected cells, confirming the
specificity of these bindings. These bindings indicate that TR6 can
bind to both soluble and membrane-bound forms of LIGHT.
View larger version (14K):
[in a new window]
Fig. 4.
Identification of the membrane-bound TR6
ligand. HEK293 EBNA cells were transfected with pCEP4 control
vector (shaded area) or with pCEP4/encoding full-length
LIGHT cDNA (solid line). Cells were incubated with
HVEM/TR2-Fc (0.34 µg) (A), LT R-Fc (0.34 µg)
(B), TR6-(His) (0.34 µg) or buffer control (same as
vector) (C). Cells were stained with anti-hIgG-FITC for
detecting HVEM/TR2 and LTR binding. For detecting TR6 binding, cells
were stained with anti-poly(His) and anti-mIgG-FITC. They were analyzed
for binding by FACS.
R takes
2-3 days in induction of apoptosis for the colorectal adenocarcinoma
cell line, HT29. Zhai et al. (14) also reported that LIGHT
leads to the death of the cells expressing both LTR and HVEM/TR2 but
not the cells expressing only the LTR or HVEM/TR2 receptor. Both
HVEM/TR2 and LTR are involved cooperatively in LIGHT-mediated
killing of HT29 cells (14).
(10 units/ml) in the presence of 200 ng/ml LTR-Fc or
TR6-(His). As shown in Fig.
5A, TR6-(His) blocked
significantly the LIGHT-mediated cell killing. Cells were also
incubated with sLIGHT and/or IFN- in the presence of varying
concentrations of TR6-(His). TR6-(His) blocked sLIGHT-induced cell
death in a dose-dependent manner (Fig. 5B).
Taken together, TR6 appears to act as a natural inhibitor of
LIGHT-induced tumor cell killing. The data also suggest that TR6
contributes to immune evasion of tumors.
View larger version (27K):
[in a new window]
Fig. 5.
TR6 inhibits LIGHT-induced cell death in HT29
cells. A, HT29 cells were incubated in 96-well plates
with control medium, 10 units/ml IFN- alone, purified sLIGHT protein
(10 ng/ml) in the absence or presence of IFN- (10 units/ml),
purified sLTR-Fc (200 ng/ml), or TR6-(His) (200 ng/ml) in the
presence of IFN- (10 units/ml) and sLIGHT (10 ng/ml). B,
cells were incubated with various doses of TR6-(His) and IFN- (10 units/ml) with (open circle) or without (filled
circle) sLIGHT (10 ng/ml). In all assays, cells were cultured for
4 days, and proliferation was detected during the last 6 h of
culture by the addition of 1 µCi of [3H]thymidine.
Cells were harvested, and thymidine incorporation was determined using
a liquid scintillation counter.
R may trigger the distinct
biological events, such as T cell proliferation, blocking of
HVEM-dependent HSV1 infection, and anti-tumor activity (10, 14, 15). TR6 may act as an inhibitor of LIGHT interaction and may play
diverse roles in different cell types. Indeed, while this paper was in
preparation, another group reported an identical cDNA to TR6, which
they called decoy receptor (DcR) 3 and showed that it bound to FasL and
might contribute to immune evasion by certain tumor (18). TR6 may act
as a decoy receptor and contribute to immune evasion both in slow and
rapid tumor cell death, which is mediated by LIGHT or the FasL-mediated
apoptosis pathway.
ACKNOWLEDGEMENTS
Addendum
FOOTNOTES
To whom correspondence should be addressed: Dept. of
Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202. Tel.: 317-274-3950; Fax: 317-274-4090; E-mail: kkwon{at}sunflower.bio.indiana.edu.
ABBREVIATIONS
R, lymphotoxin receptor;
DcR3, decoy receptor 3;
HVEM, herpes virus entry mediator;
HUVEC, human
umbilical vein endothelial cell;
OPG, osteoprotegerin;
TR6-(His), C-terminal hexahistidine-tagged TR6;
EST, expressed sequence tag;
RT-PCR, reverse transcription-polymerase chain reaction;
HRP, horseradish peroxidase;
FITC, fluorescein isothiocyanate;
IFN, interferon.
REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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T.-L. Hsu, Y.-Y. Wu, Y.-C. Chang, C.-Y. Yang, M.-Z. Lai, W. B. Su, and S.-L. Hsieh Attenuation of Th1 Response in Decoy Receptor 3 Transgenic Mice J. Immunol., October 15, 2005; 175(8): 5135 - 5145. [Abstract] [Full Text] [PDF]
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G. Shi, J. Mao, G. Yu, J. Zhang, and J. Wu Tumor Vaccine Based on Cell Surface Expression of DcR3/TR6 J. Immunol., April 15, 2005; 174(8): 4727 - 4735. [Abstract] [Full Text] [PDF]
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C.-R. Yang, S.-L. Hsieh, F.-M. Ho, and W.-W. Lin Decoy Receptor 3 Increases Monocyte Adhesion to Endothelial Cells via NF-{kappa}B-Dependent Up-Regulation of Intercellular Adhesion Molecule-1, VCAM-1, and IL-8 Expression J. Immunol., February 1, 2005; 174(3): 1647 - 1656. [Abstract] [Full Text] [PDF]
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O. Cohavy, J. Zhou, C. F. Ware, and S. R. Targan LIGHT Is Constitutively Expressed on T and NK Cells in the Human Gut and Can Be Induced by CD2-Mediated Signaling J. Immunol., January 15, 2005; 174(2): 646 - 653. [Abstract] [Full Text] [PDF]
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S. J. Levine Mechanisms of Soluble Cytokine Receptor Generation J. Immunol., November 1, 2004; 173(9): 5343 - 5348. [Abstract] [Full Text] [PDF]
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Y.-Y. Wu, Y.-C. Chang, T.-L. Hsu, S.-L. Hsieh, and M.-Z. Lai Sensitization of Cells to TRAIL-induced Apoptosis by Decoy Receptor 3 J. Biol. Chem., October 15, 2004; 279(42): 44211 - 44218. [Abstract] [Full Text] [PDF]
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O. Cohavy, J. Zhou, S. W. Granger, C. F. Ware, and S. R. Targan LIGHT Expression by Mucosal T Cells May Regulate IFN-{gamma} Expression in the Intestine J. Immunol., July 1, 2004; 173(1): 251 - 258. [Abstract] [Full Text] [PDF]
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 R. M. Gill and J. S. Hunt Soluble Receptor (DcR3) and Cellular Inhibitor of Apoptosis-2 (cIAP-2) Protect Human Cytotrophoblast Cells Against LIGHT-Mediated Apoptosis Am. J. Pathol., July 1, 2004; 165(1): 309 - 317. [Abstract] [Full Text] [PDF]
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A. Mantovani, M. Locati, N. Polentarutti, A. Vecchi, and C. Garlanda Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR J. Leukoc. Biol., May 1, 2004; 75(5): 738 - 742. [Abstract] [Full Text] [PDF]
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 H.-H. Sung, J.-H. Juang, Y.-C. Lin, C.-H. Kuo, J.-T. Hung, A. Chen, D.-M. Chang, S.-Y. Chang, S.-L. Hsieh, and H.-K. Sytwu Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice J. Exp. Med., April 19, 2004; 199(8): 1143 - 1151. [Abstract] [Full Text] [PDF]
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 J.T. Bridgham and A.L. Johnson Alternatively Spliced Variants of Gallus gallus TNFRSF23 Are Expressed in the Ovary and Differentially Regulated by Cell Signaling Pathways Biol Reprod, April 1, 2004; 70(4): 972 - 979. [Abstract] [Full Text] [PDF]
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Y.-C. Chang, T.-L. Hsu, H.-H. Lin, C.-C. Chio, A. W. Chiu, N.-J. Chen, C.-H. Lin, and S.-L. Hsieh Modulation of macrophage differentiation and activation by decoy receptor 3 J. Leukoc. Biol., March 1, 2004; 75(3): 486 - 494. [Abstract] [Full Text] [PDF]
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C.-R. Yang, S.-L. Hsieh, C.-M. Teng, F.-M. Ho, W.-L. Su, and W.-W. Lin Soluble Decoy Receptor 3 Induces Angiogenesis by Neutralization of TL1A, a Cytokine Belonging to Tumor Necrosis Factor Superfamily and Exhibiting Angiostatic Action Cancer Res., February 1, 2004; 64(3): 1122 - 1129. [Abstract] [Full Text] [PDF]
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S.-F. Wu, T.-M. Liu, Y.-C. Lin, H.-K. Sytwu, H.-F. Juan, S.-T. Chen, K.-L. Shen, S.-C. Hsi, and S.-L. Hsieh Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication J. Leukoc. Biol., February 1, 2004; 75(2): 293 - 306. [Abstract] [Full Text] [PDF]
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 S. Kim, W. J. McAuliffe, L. S. Zaritskaya, P. A. Moore, L. Zhang, and B. Nardelli Selective Induction of Tumor Necrosis Receptor Factor 6/Decoy Receptor 3 Release by Bacterial Antigens in Human Monocytes and Myeloid Dendritic Cells Infect. Immun., January 1, 2004; 72(1): 89 - 93. [Abstract] [Full Text] [PDF]
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G. Shi, Y. Wu, J. Zhang, and J. Wu Death Decoy Receptor TR6/DcR3 Inhibits T Cell Chemotaxis In Vitro and In Vivo J. Immunol., October 1, 2003; 171(7): 3407 - 3414. [Abstract] [Full Text] [PDF]
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 Y. Wu, B. Han, H. Luo, R. Roduit, T. W. Salcedo, P. A. Moore, J. Zhang, and J. Wu DcR3/TR6 Effectively Prevents Islet Primary Nonfunction After Transplantation Diabetes, September 1, 2003; 52(9): 2279 - 2286. [Abstract] [Full Text] [PDF]
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J. Liu, C. S. Schmidt, F. Zhao, A. J. Okragly, A. Glasebrook, N. Fox, E. Galbreath, Q. Zhang, H. Y. Song, S. Na, et al. LIGHT-deficiency impairs CD8+ T cell expansion, but not effector function Int. Immunol., July 1, 2003; 15(7): 861 - 870. [Abstract] [Full Text] [PDF]
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L. Benetti, J. Munger, and B. Roizman The Herpes Simplex Virus 1 US3 Protein Kinase Blocks Caspase-Dependent Double Cleavage and Activation of the Proapoptotic Protein BAD J. Virol., June 1, 2003; 77(11): 6567 - 6573. [Abstract] [Full Text] [PDF]
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 J. C. Reed, K. Doctor, A. Rojas, J. M. Zapata, C. Stehlik, L. Fiorentino, J. Damiano, W. Roth, S.-i. Matsuzawa, R. Newman, et al. Comparative Analysis of Apoptosis and Inflammation Genes of Mice and Humans Genome Res., June 1, 2003; 13(6): 1376 - 1388. [Abstract] [Full Text] [PDF]
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J. Wang and Y.-X. Fu LIGHT (a Cellular Ligand for Herpes Virus Entry Mediator and Lymphotoxin Receptor)-Mediated Thymocyte Deletion Is Dependent on the Interaction Between TCR and MHC/Self-Peptide J. Immunol., April 15, 2003; 170(8): 3986 - 3993. [Abstract] [Full Text] [PDF]
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 V. J. Wroblewski, C. McCloud, K. Davis, J. Manetta, R. Micanovic, and D. R. Witcher Pharmacokinetics, Metabolic Stability, and Subcutaneous Bioavailability of a Genetically Engineered Analog of DcR3, FLINT [DcR3(R218Q)], in Cynomolgus Monkeys and Mice Drug Metab. Dispos., April 1, 2003; 31(4): 502 - 507. [Abstract] [Full Text] [PDF]
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X. Wan, J. Zhang, H. Luo, G. Shi, E. Kapnik, S. Kim, P. Kanakaraj, and J. Wu A TNF Family Member LIGHT Transduces Costimulatory Signals into Human T Cells J. Immunol., December 15, 2002; 169(12): 6813 - 6821. [Abstract] [Full Text] [PDF]
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R. M. Gill, J. Ni, and J. S. Hunt Differential Expression of LIGHT and Its Receptors in Human Placental Villi and Amniochorion Membranes Am. J. Pathol., December 1, 2002; 161(6): 2011 - 2017. [Abstract] [Full Text] [PDF]
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R. Castellano, C. Van Lint, V. Peri, E. Veithen, Y. Morel, R. Costello, D. Olive, and Y. Collette Mechanisms Regulating Expression of the Tumor Necrosis Factor-related light Gene. ROLE OF CALCIUM-SIGNALING PATHWAY IN THE TRANSCRIPTIONAL CONTROL J. Biol. Chem., November 1, 2002; 277(45): 42841 - 42851. [Abstract] [Full Text] [PDF]
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G. Shi, H. Luo, X. Wan, T. W. Salcedo, J. Zhang, and J. Wu Mouse T cells receive costimulatory signals from LIGHT, a TNF family member Blood, October 16, 2002; 100(9): 3279 - 3286. [Abstract] [Full Text] [PDF]
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S. Scheu, J. Alferink, T. Potzel, W. Barchet, U. Kalinke, and K. Pfeffer Targeted Disruption of LIGHT Causes Defects in Costimulatory T Cell Activation and Reveals Cooperation with Lymphotoxin {beta} in Mesenteric Lymph Node Genesis J. Exp. Med., June 17, 2002; 195(12): 1613 - 1624. [Abstract] [Full Text] [PDF]
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F. H. Igney and P. H. Krammer Immune escape of tumors: apoptosis resistance and tumor counterattack J. Leukoc. Biol., June 1, 2002; 71(6): 907 - 920. [Abstract] [Full Text] [PDF]
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K. Tamada, J. Ni, G. Zhu, M. Fiscella, B. Teng, J. M. A. van Deursen, and L. Chen Cutting Edge: Selective Impairment of CD8+ T Cell Function in Mice Lacking the TNF Superfamily Member LIGHT J. Immunol., May 15, 2002; 168(10): 4832 - 4835. [Abstract] [Full Text] [PDF]
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T.-L. Hsu, Y.-C. Chang, S.-J. Chen, Y.-J. Liu, A. W. Chiu, C.-C. Chio, L. Chen, and S.-L. Hsieh Modulation of Dendritic Cell Differentiation and Maturation by Decoy Receptor 3 J. Immunol., May 15, 2002; 168(10): 4846 - 4853. [Abstract] [Full Text] [PDF]
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Q. Ye, C. C. Fraser, W. Gao, L. Wang, S. J. Busfield, C. Wang, Y. Qiu, A. J. Coyle, J.-C. Gutierrez-Ramos, and W. W. Hancock Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival J. Exp. Med., March 18, 2002; 195(6): 795 - 800. [Abstract] [Full Text] [PDF]
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 A. Bobik and N. Kalinina Tumor Necrosis Factor Receptor and Ligand Superfamily Family Members TNFRSF14 and LIGHT: New Players in Human Atherogenesis Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1873 - 1875. [Full Text] [PDF]
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F. C. Kischkel, D. A. Lawrence, A. Tinel, H. LeBlanc, A. Virmani, P. Schow, A. Gazdar, J. Blenis, D. Arnott, and A. Ashkenazi Death Receptor Recruitment of Endogenous Caspase-10 and Apoptosis Initiation in the Absence of Caspase-8 J. Biol. Chem., November 30, 2001; 276(49): 46639 - 46646. [Abstract] [Full Text] [PDF]
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S. W. Granger, K. D. Butrovich, P. Houshmand, W. R. Edwards, and C. F. Ware Genomic Characterization of LIGHT Reveals Linkage to an Immune Response Locus on Chromosome 19p13.3 and Distinct Isoforms Generated by Alternate Splicing or Proteolysis J. Immunol., November 1, 2001; 167(9): 5122 - 5128. [Abstract] [Full Text] [PDF]
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Y. Morel, A. Truneh, R. W. Sweet, D. Olive, and R. T. Costello The TNF Superfamily Members LIGHT and CD154 (CD40 Ligand) Costimulate Induction of Dendritic Cell Maturation and Elicit Specific CTL Activity J. Immunol., September 1, 2001; 167(5): 2479 - 2486. [Abstract] [Full Text] [PDF]
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 G. Matute-Bello, W. C. Liles, C. W. Frevert, M. Nakamura, K. Ballman, C. Vathanaprida, P. A. Kiener, and T. R. Martin Recombinant human Fas ligand induces alveolar epithelial cell apoptosis and lung injury in rabbits Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L328 - L335. [Abstract] [Full Text] [PDF]
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 K. Connolly, Y. H. Cho, R. Duan, J. Fikes, T. Gregorio, D. W. LaFleur, Z. Okoye, T. W. Salcedo, G. Santiago, S. Ullrich, et al. In Vivo Inhibition of Fas Ligand-Mediated Killing by TR6, a Fas Ligand Decoy Receptor J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 25 - 33. [Abstract] [Full Text]
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G. L. Sica, G. Zhu, K. Tamada, D. Liu, J. Ni, and L. Chen RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-{kappa}B Blood, May 1, 2001; 97(9): 2702 - 2707. [Abstract] [Full Text] [PDF]
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W. Roth, S. Isenmann, M. Nakamura, M. Platten, W. Wick, P. Kleihues, M. Bähr, H. Ohgaki, A. Ashkenazi, and M. Weller Soluble Decoy Receptor 3 Is Expressed by Malignant Gliomas and Suppresses CD95 Ligand-induced Apoptosis and Chemotaxis Cancer Res., March 1, 2001; 61(6): 2759 - 2765. [Abstract] [Full Text]
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T. J. Yun, M. D. Tallquist, A. Aicher, K. L. Rafferty, A. J. Marshall, J. J. Moon, M. K. Ewings, M. Mohaupt, S. W. Herring, and E. A. Clark Osteoprotegerin, a Crucial Regulator of Bone Metabolism, Also Regulates B Cell Development and Function J. Immunol., February 1, 2001; 166(3): 1482 - 1491. [Abstract] [Full Text] [PDF]
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N.-J. Chen, M.-W. Huang, and S.-L. Hsieh Enhanced Secretion of IFN-{{gamma}} by Activated Th1 Cells Occurs Via Reverse Signaling Through TNF-Related Activation-Induced Cytokine J. Immunol., January 1, 2001; 166(1): 270 - 276. [Abstract] [Full Text] [PDF]
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Y. Morel, J.-M. Schiano de Colella, J. Harrop, K. C. Deen, S. D. Holmes, T. A. Wattam, S. S. Khandekar, A. Truneh, R. W. Sweet, J.-A. Gastaut, et al. Reciprocal Expression of the TNF Family Receptor Herpes Virus Entry Mediator and Its Ligand LIGHT on Activated T Cells: LIGHT Down-Regulates Its Own Receptor J. Immunol., October 15, 2000; 165(8): 4397 - 4404. [Abstract] [Full Text] [PDF]
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I. A. Rooney, K. D. Butrovich, A. A. Glass, S. Borboroglu, C. A. Benedict, J. C. Whitbeck, G. H. Cohen, R. J. Eisenberg, and C. F. Ware The Lymphotoxin-beta Receptor Is Necessary and Sufficient for LIGHT-mediated Apoptosis of Tumor Cells J. Biol. Chem., May 5, 2000; 275(19): 14307 - 14315. [Abstract] [Full Text] [PDF]
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K. Tamada, K. Shimozaki, A. I. Chapoval, Y. Zhai, J. Su, S.-F. Chen, S.-L. Hsieh, S. Nagata, J. Ni, and L. Chen LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response J. Immunol., April 15, 2000; 164(8): 4105 - 4110. [Abstract] [Full Text] [PDF]
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 C. Bai, B. Connolly, M. L. Metzker, C. A. Hilliard, X. Liu, V. Sandig, A. Soderman, S. M. Galloway, Q. Liu, C. P. Austin, et al. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster PNAS, February 1, 2000; 97(3): 1230 - 1235. [Abstract] [Full Text] [PDF]
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J. Bobe and F. W. Goetz A Tumor Necrosis Factor Decoy Receptor Homologue Is Up-Regulated in the Brook Trout (Salvelinus fontinalis) Ovary at the Completion of Ovulation Biol Reprod, February 1, 2000; 62(2): 420 - 426. [Abstract] [Full Text]
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M.-C. Chen, T.-L. Hsu, T.-Y. Luh, and S.-L. Hsieh Overexpression of Bcl-2 Enhances LIGHT- and Interferon-gamma -mediated Apoptosis in Hep3BT2 Cells J. Biol. Chem., December 1, 2000; 275(49): 38794 - 38801. [Abstract] [Full Text] [PDF]
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