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B Ligand (RANKL), TNF-Related Apoptosis-Inducing Ligand (TRAIL), and TNF-
During T Cell Activation1 ,2
Departments of
*
Immunology and
Tissue Biology, Jerome H. Holland Laboratory, American Red Cross, Rockville, MD 20855
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B
ligand (RANKL), TNF-
, CD95L, and TNF-related apoptosis inducing
ligand (TRAIL) in T cell hybridoma A1.1 cells, thus allowing us to
examine the expression pattern of these molecules under precisely the
same conditions. We have previously reported that CD95L expression
requires both protein kinase C (PKC) translocation and Ca2+
mobilization and is inhibited by cyclosporin A, and dexamethasone. We
demonstrate now that activation-induced expression of RANKL is mediated
by Ca2+ mobilization. PKC activation does not induce RANKL
expression nor does it synergize with the Ca2+ signal.
Activation-induced RANKL expression is blocked by cyclosporin A, but
not by dexamethasone. The expression of TNF, in contrast, is mediated
by PKC, but not by Ca2+. TNF- expression is not
inhibited by cyclosporin A, but is sensitive to dexamethasone. A1.1
cells constitutively express TRAIL at low levels. Stimulation with
anti-CD3 leads to an initial reduction and subsequent increase in
TRAIL expression. TRAIL induction is not inhibited by cyclosporin A,
but highly sensitive to dexamethasone. Therefore, expression of the TNF
superfamily genes is regulated by distinct signals. Detailed
understanding of the regulatory mechanisms could provide crucial
information concerning the role of these molecules in the modulation of
the immune system. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Concomitantly, the ligands for these receptors, now referred to
as the members of the TNF superfamily, have been identified as a series
of type II transmembrane glycoproteins that bind to and signal through
their cognate receptors (5). Although the biological role
of some of these ligand-receptor pairs remains obscure, a number of
studies have revealed insights into the mechanisms by which the
expression of the TNF superfamily genes is regulated. TNF- is
produced by a variety of cell types in response to diverse stimuli. The
regulation of TNF- is best appreciated in response to signals from
the TCR ligation. It has been reported that the production of TNF-
in T cell clones depends on Ca2+ mobilization
induced by TCR stimulation (6). This
Ca2+-dependent induction of TNF- is blocked by
cyclosporin A (6). In B cells, activation through Ag
receptor or via the CD40 pathway also induces NF-AT-dependent
expression of TNF- that is blocked by cyclosporin A/FK506, although
the promoter binding site of NF-AT may be different from that in T
cells (7, 8, 9). Moreover, transfection of a cDNA encoding a
constitutively active form of calcineurin is sufficient to activate the
TNF- promoter (10). Therefore, the induction of TNF-
expression by the TCR activation signals in lymphocytes is dependent on
Ca2+ mobilization and the activation of NF-AT. On
the other hand, it has been shown that the TNF- promoter can be
activated by phorbol esters (PMA) or LPS in human mononuclear cells, a
process dependent on NF-B (11, 12, 13). Interestingly, the
existence of elements in the promoter of TNF- gene is not
responsible for PMA- and LPS-induced TNF- production
(14). TNF- promoter analysis revealed that the
PMA-responsive element is activated by AP-1 (15, 16).
Our previous studies have demonstrated that activation-induced
expression of CD95 ligand
(CD95L)4 requires both
protein kinase C (PKC) translocation and Ca2+
mobilization (17). The expression of CD95L can be blocked
by either PKC inhibitors or blockers of Ca2+
mobilization (17). The same finding has also been reported
by others (18). A recent study has demonstrated that the
expression of CD95L is mediated by PKC
(19). In
addition, it has also been shown that CD95L expression is sensitive to
cyclosporin A, retinoic acid, and dexamethasone (17, 20, 21, 22). Promoter analysis has revealed that the activation of
CD95L transcription requires NF-B (23, 24), NF-AT
(25, 26), Nurr-77 (27), ALG-4
(28), Egr-3 (29), and AP-1 (30).
Several of these transcription factors have been shown to directly
regulate CD95L transcription in response to TCR activation. In
addition, we have reported that activation-induced CD95L expression
requires the participation of the protooncogene c-myc
(31).
Receptor activator of NF-B ligand (RANKL)/TNF-related
activation-induced cytokine (TRANCE) has been shown to be expressed in
T cells and other cell types (32, 33, 34). Its major function
has been attributed to the regulation of skeletal homeostasis acting in
concert with its decoy receptor osteoprotegerin (OPG) (35, 36). Therefore, this molecule has also been referred to as OPG
ligand (OPGL)/ODF (osteoclast differentiation factor). Because this
molecule is expressed on activated T cells and dendritic cells
(35, 37), its principal function in the immune system has
been suggested to be involved in T cell-dendritic cell interaction
during an immune response (32, 38, 39). Interestingly, the
expression of RANKL in B cells is also found to be induced by CD40L
(35). Surprisingly, RANKL is also crucial for early
lymphocyte development and lymph node organogenesis
(40).
TNF-related apoptosis-inducing ligand (TRAIL) (Apo2 ligand) is another member of TNF cytokine family. It shares homology with CD95L and also activates rapid apoptosis in many types of cancer cells (41). TRAIL is expressed in a wide variety of tissues. It can bind to several receptors including those containing a cytoplasmic death domain and those lacking a functional cytoplasmic death domain (decoy receptors) (1, 42). Most tissues are resistant to TRAIL cytotoxic action due to the presence of decoy receptors (1). In T cells, TRAIL expression induced by activation is blocked by cyclosporin A, rapamycin, and inhibitors of phosphatidylinositol-3 kinase, PKC, and protein tyrosine kinases (43). In addition, activation-induced TRAIL expression is enhanced by type I IFNs (44, 45).
Therefore, it is clear that the expression of these genes is
differentially regulated. However, the information regarding the
regulatory mechanisms of these genes is derived from various cell types
in response to different stimuli. In the present study, we employed
monoclonal T cell hybridoma A1.1 cells and examined the expression of
TNF-, TRAIL, RANKL, and CD95L. We have found that the expression of
these proteins follows different kinetics in response to TCR
stimulation. Interestingly, these genes exhibited different responses
to inhibitors known to modulate TCR signals. Taken together, these
studies begin to clarify the diverse biochemical events modulating the
expression of genes of TNF superfamily. More detailed analysis of the
expression patterns of these ligands and receptors on lymphocyte
subpopulations will be necessary to define their different roles in
immune activation and suppression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Murine T cell hybridoma A1.1 cells were originally obtained from Dr. Bhagirath Singh (University of Alberta, Edmonton, Canada) (46). They were recloned and selected for the expression of TCR and the responsiveness to activation signals. A1.1 cells were maintained in RPMI 1640 medium (Life Technologies/BRL, Gaithersburg, MD), supplemented with 2 mM L-glutamine, 50 mM 2-ME, 10% heat-inactivated FBS (Sigma, St. Louis, MO), and 10 mM gentamicin. Cell cultures were incubated at 37°C in humidified atmosphere with 5% CO2/95% air.
Reagents
Ab to CD3 was produced by a hamster B cell hybridoma,
145-2C11
(from Dr. Jeffery Bluestone, University of Chicago,
Chicago, IL). PMA,
N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004),
1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), GÖ6976,
bisindolylmaleimide I, Calphostin C, and ionomycin were purchased from
Calbiochem (San Diego, CA). An inhibitor for intracellular
Ca2+ mobilization,
8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8),
dexamethasone, and retinoic acid were obtained from Sigma. Cyclosporine
was a gift from Novartis Pharmaceuticals (East Hanover, NJ). FR901228
was obtained from Fujisawa Pharmaceutical Company (Osaka, Japan). rDR5
was kindly provided by Dr. Youhai Chen (University of Pennsylvania,
Philadelphia, PA). Anti-murine CD95L, MFL3, was purchased from
PharMingen (La Jolla, CA), and rOPG was from R&D Systems (Minneapolis,
MN). Other chemicals used were the purest grade available from
Sigma.
TCR activation
A1.1 cells were activated with anti-CD3 coated on tissue culture plastic. Plastic coating was conducted by overnight incubation with 0.05 M Tris-HCl (pH 9) containing 2.5 µg anti-CD3. Unbound Ab was washed away with PBS. Alternatively, the cells were also activated with the combination of PMA plus ionomycin. Activation was conducted for different periods, and samples were harvested for analysis.
TRAIL-mediated apoptosis in breast cancer cells
A1.1 cells (2 x 106/ml) were stimulated with plastic-bound anti-CD3 for 6 h. Supernatant was collected at 6 h postculture. Breast cancer cells (MDA-231, 80% confluence in 24-well plate) were treated with cycloheximide (8 µg/ml) for 2 h and then incubated with supernatant of activated A1.1 cells at 1/1 dilution with or without blocking reagents (DR5 at 16 µg/ml, or OPG at 500 ng/ml). Cells were collected at 16 h after treatment and assessed for apoptosis by DNA content analysis.
DNA content analysis
Flow cytometric analysis was employed to assay cellular DNA content, in which apoptotic cells were shown as a hypodiploid peak. After treatments, splenocytes were fixed with 70% ethanol for 30 min at 4°C, followed by two washes with PBS. The fixed splenocytes were then incubated in PBS containing propidium iodide (Sigma) at 50 µg/ml and RNase (Boehringer Mannheim, Indianapolis, IN) at 0.1 mg/ml at room temperature for 30 min. DNA content was determined by flow cytometry on FACScan (Becton Dickinson, San Jose, CA). The FL2 intensity was plotted as histograms on a linear scale.
Northern blotting
Total RNA was isolated with affinity columns (Qiagen, Chatsworth, CA), according to the protocol recommended by the manufacturer. RNA samples were fractionated on 1% agarose/2.2 M formaldehyde denaturing gel, and transferred onto Nytran membrane (Schleicher & Schuell, Keene, NH). The DNA probes were labeled with [32P]dCTP by random priming (Boehringer Mannheim) according to manufacturer’s instructions. Prehybridization and hybridization were conducted at 42°C in a solution containing 5x SSC (10x SSC is 1.5 M NaCl, 0.15 M sodium citrate), 2.5 mM EDTA, 0.1% SDS, 5x Denhardt’s solution, 2 mM sodium pyrophosphate, 50 mM sodium phosphate, and 50% formamide. After washing with 0.2x SSC, 0.1% SDS at 56°C for 1 h, hybridization signals were detected by autoradiography.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of the genes in the TNF family has been studied in
various cellular systems in response to different stimuli. However, due
to the inconsistency of the experimental systems, it is difficult to
conclude the expression kinetics of these genes. The T cell hybridoma
system has been employed as a model system to investigate
activation-induced cell death (AICD) in T cells (47, 48, 49).
It has been shown that AICD in this model system depends on
activation-induced expression of CD95 and CD95L (20, 50).
In the present study, we show that activation through the TCR also
induces the expression of TNF-, RANKL, and TRAIL. Therefore, this T
cell hybridoma system provides us with a unique opportunity to
investigate the expression kinetics of various TNF family members after
activation through the TCR. We stimulated A1.1 cells with plastic-bound
anti-CD3. Total RNA was isolated from these cells at half-hour
intervals for a maximum of 9.5 h and transferred onto blotting
membrane. The same membrane was examined for the expression of CD95L,
TRAIL, RANKL, TNF-, IL-2, and GAPDH by Northern blot analysis (Fig. 1
). The induction of IL-2 indicates that
the plastic-bound anti-CD3 activated this T cell hybridoma, and
GAPDH reveals equal loading of the total RNA samples. CD95L starts to
appear at 3.5–4 h after stimulation. The expression of TNF- could
be observed as early as 1.5 h postactivation. In contrast, the
expression of RANKL was observed at 2.5 h after activation.
Interestingly, A1.1 cells constitutively express TRAIL at low levels.
Upon activation, there is an initial reduction and then an increase in
the level of TRAIL. Therefore, our studies revealed differential
expression of various TNF family genes in the same cell in response to
the same stimulus, indicating that these genes are regulated by
different mechanisms.
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Previous studies have demonstrated that activation-induced
apoptosis in T cell hybridomas is mediated by the interaction between
CD95 and CD95L, as it could be blocked by soluble rCD95 protein
(51). Because other members of the TNF family are also
induced in A1.1 cells upon activation, we determined whether the
proteins other than CD95L also participate in the induction of
apoptosis. We employed OPG fusion protein (a decoy receptor of RANKL
and TRAIL), DR5 fusion protein (an inhibitor of TRAIL)
(52), anti-TNF, CD95 fusion protein, and
anti-CD95L. We found that both CD95 fusion protein and
anti-CD95L completely blocked activation-induced apoptosis.
Blocking of TNF, RANKL, and TRAIL does not have any effect on
anti-CD3-induced apoptosis (Fig. 2).
The concentrations of OPG, anti-TNF, and DR5 used in our studies
all blocked the biological activity of their respective ligands (data
not shown). Therefore, even though several members of the TNF family
proteins are expressed in A1.1 cells upon TCR activation, only CD95L
participates in the induction of apoptosis. Nevertheless, this cellular
system provides us with a model to examine the regulatory mechanisms
controlling TCR signal-mediated expression of TNF family members.
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Signals generated by ligating the TCRs initiate a cascade of
phosphorylation and enzyme activation, including the activation of
multiple tyrosine kinases, phospholipases, PKC, and influx of
Ca2+ (53, 54, 55).
Ca2+ influx and the activation of PKC have been
shown to be the key events of activation-induced cytokine production
and proliferation in T cells, because the combination of PMA and
Ca2+ ionophores could completely mimic the
signals from the TCR (55, 56). Furthermore, inhibition of
the Ca2+-dependent calcineurin phosphatase by
cyclosporin A results in immune suppression (57), and the
inhibition of apoptosis (48, 58). We tested the
requirement for PKC translocation and Ca2+
mobilization in the regulation of the expression of the TNF family
genes. We activated A1.1 cells with either PMA or ionomycin or their
combination for 4 h and examined the expression of different genes
by Northern blot analysis. Similar to our previous report
(17), the expression of CD95L is induced only minimally by
ionomycin. PMA treatment does not have any effect on CD95 expression.
CD95 expression was, however, dramatically enhanced when treated with
both PMA and ionomycin (Fig. 3).
Interestingly, TRAIL is constitutively expressed at low levels. This
expression is inhibited by atni-CD3 treatment for 4 h. The
inhibitory effect by anti-CD3 is most likely through the activation
of PKC, because ionomycin treatment did not alter TRAIL expression,
while PMA did. With regard to the expression of RANKL, we found that
the RANKL expression is mediated by Ca2+
mobilization alone. PKC activation is not required, nor does it affect
Ca2+ mobilization-induced RANKL expression. The
expression of TNF in this experimental system is induced by PKC
activation. Ionomycin-induced Ca2+ mobilization
has no effect on TNF production (Fig. 3).
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. Cyclosporin A also has no
effect on constitutive expression of TRAIL (Fig. 3
).
Because cyclosporin A does not have any effect on cytosolic
Ca2+ levels and thus does not interfere with the
interaction of Ca2+ with other proteins, we
tested the effect of a general inhibitor of intracellular
Ca2+ mobilization,
8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8)
(59). We have reported that TMB-8 completely blocked AICD
and CD95L, but not CD95, expression (17). Similar to our
finding of the role of ionomycin in the regulation of CD95L, we show
that TCR activation-induced RANKL expression is also blocked by TMB-8.
However, this inhibitor has no effect on TNF- expression (Fig. 3).
Thus, the effect of Ca2+ mobilization on the
induction of RANKL and CD95L is exerted through the
cyclosporine-sensitive calcineurin pathway. Interestingly, the
constitutive expression of TRAIL is inhibited by TMB-8, but not by
cyclosporine, indicating a role of calcineurin-independent
Ca2+ in maintaining TRAIL expression.
Differential effect of dexamethasone on TCR activation-induced expression of TNF family genes
Dexamethasone, a synthetic glucocorticoid hormone, is one of the
best-known immunosuppressants. It has been used to control
autoimmunity, inflammation, and rejection of transplanted organs and
tissues (60). Its immunosuppressive effect has been
attributed to the inhibition of TCR-stimulated activation,
proliferation, expression of cell surface molecules, and the production
of soluble cytokines (61). Earlier studies have
demonstrated that dexamethasone also inhibits activation-induced
apoptosis in T cell hybridomas and in the thymocytes
(62, 63, 64), a finding that leads to the discovery of the
role of steroid hormones in positive selection (63, 65, 66). Interestingly, the inhibitory effect of dexamethasone on
activation-induced T cell hybridoma death has been revealed due to its
effect on activation-induced CD95L expression (20, 67). We
have examined the effect of dexamethasone on anti-CD3-induced
expression of various TNF family genes. Dexamethasone inhibited
activation-induced expression of CD95L. It also blocked constitutive
expression of TRAIL. Dexamethasone only has moderate effect on
anti-CD3-induced TNF production. Interestingly, it does not have
any effect on the activation-induced expression of RANKL (Fig. 4).
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To determine whether the regulation of the TNF family members is
at the transcriptional level, it is of interest to test whether it
requires de novo protein synthesis. This possibility was examined in
aggregates incubated in the presence of a 5 µM concentration of the
protein synthesis inhibitor cycloheximide (Fig. 5). In the presence of cycloheximide,
induction of the CD95L, RANKL, and TNF gene by anti-CD3 was
blocked, providing evidence that de novo protein synthesis was required
for these two genes. Interestingly, the constitutive expression of
TRAIL was also blocked by cycloheximide (Fig. 5). As a positive
control, we show that OX40L expression is not affected by
cycloheximide. The requirement for ongoing protein synthesis for the
expression of these genes suggests either that the key transcription
factors are turned over rapidly or that anti-CD3 induces the de
novo synthesis of a missing regulatory protein (for CD95L, RANKL,
and TNF).
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It has been shown that breast cancer cell line MDA-231 is
sensitive to TRAIL-induced apoptosis (68). We examined
whether these cells are sensitive to the supernatant of
anti-CD3-activated A1.1 cells. We found that the supernatant of
activated A1.1, but not unactivated A1.1 cells, exhibited cytotoxic
activity to MDA-231 cells (Fig. 6). To
investigate whether the activity is due to activation-induced
production of TRAIL, we employed soluble TRAIL receptor DR5
(69) and a decoy receptor OPG. DR5 is specific to TRAIL,
and OPG blocks the activity of both TRAIL and RANKL (70).
We found that both fusion proteins effectively blocked the cytotoxic
activity of supernatant from activated A1.1 cells, indicating that the
cytotoxic activity of the supernatant from activated A1.1 cells is due
to the presence of TRAIL. Therefore, although not involved in AICD,
activation-induced TRAIL expression is functional.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, TRAIL, RANKL, and CD95L under identical
conditions, i.e., examined on the same blotting membranes. We show that
the expression of these genes follows distinct kinetics in response to
TCR stimulation. The expression of these genes requires continued
protein synthesis. Ca2+ mobilization is important
for the induction of RANKL and CD95, while PKC is important for
modulating TRAIL and CD95L. Activation-induced RANKL and CD95L are
blocked by cyclosporin A. Dexamethasone only blocked CD95L, TRAIL, and
to some extent TNF. However, it has no effect on RANKL. Taken together,
the expression of the genes of the TNF superfamily is regulated by
distinct signals. A summary of our data is presented in Table I.
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One important function of the members of the TNF family is to induce apoptosis in target cells in a receptor-specific manner (5). The best-characterized proteins that execute apoptosis are CD95L and TRAIL. It is well established that, upon activation, primary T cells express various members of the TNF/TNFR families. Among them, CD95L is the best studied. It has been shown to be involved in peripheral deletion of activated T cells and thus limiting the extent of an immune response. Mice with mutations in CD95 (lpr) or CD95L (gld) exhibit lymphoproliferative disorder and often develop autoimmune diseases (72). Human patients showing phenotypes (Canale-Smith syndrome or autoimmune lymphoproliferative syndrome) similar to those in lpr or gld mice also carry mutations in CD95 or CD95L (73). Therefore, activation-induced CD95L expression represents a key element in immune regulation. In our present study, we have found that CD95L is a key molecule in the modulation of AICD in T cell hybridomas.
Among the TNF family members, TRAIL is another apoptosis-inducing
molecule. A recent study has revealed that this molecule on activated T
cells is more important in causing tissue damage during autoimmune
diseases (74) or in eliminating cancer cells
(68). In fact, upon activation, TRAIL receptor expression
was decreased, whereas TRAIL was up-regulated (74). Thus,
unlike CD95L, TRAIL may not be involved in the regulation of T cell
viability. We have found that even though TRAIL is not involved in
AICD, it could induce apoptosis in breast cancer cells (Fig. 6). With
regard to activation-induced TNF expression in A1.1 cells, we have
shown that activation of 5 x 105 A1.1 cells
in 200 µl media could lead to the production of TNF- at 210
± 27 pg/ml. This TNF- is highly cytotoxic to cycloheximide-treated
L929 cells, and the activity could be blocked by rabbit anti-murine
TNF- (data not shown).
We have mainly used mRNA levels as a determination of gene expression.
An advantage of detecting mRNA is that one could use the same Northern
blot membrane to examine the expression of several genes. The increase
in mRNA levels correlated well with protein expression. We have
determined CD95L expression on cell surface by surface staining and the
cytotoxicity to B cell lymphoma A20 (data not shown).
Activation-induced surface expression of CD95L is time dependent (data
not shown). The expression of TRAIL could also be detected on the cell
surface at 5–6 h after activation (data not shown). Secreted TRAIL
could kill breast cancer cells (Fig. 6). In addition, we have found
that activation-induced RANKL expression could be detected by Western
blot analysis (data not shown). Interestingly, RANKL expressed on A1.1
cells could induce osteoclast formation. Therefore, the expression of
mRNA correlated with the protein expression.
From our studies, it is clear that the expression of TNF family
molecules is regulated by different mechanisms. Although it has been
reported that activation of T cells could result in the up-regulation
of both molecules, we have found that the initial activation signals
are actually inhibitory to the expression of TRAIL in this T cell
hybridoma system. Its expression only comes up at a later time. One
explanation for this observation is that the TCR signal does not
directly mediate the expression of TRAIL. The signals for TRAIL
expression may just well be secondary to the production of some
factor(s). Nevertheless, it has been reported that mature NK cells use
Ca2+-dependent granule exocytosis and release of
cytotoxic proteins, FasL, and membrane-bound or secreted TNF- to
induce target cell death. In contrast, TRAIL is expressed on immature
NK cells (75). This is consistent with our observation
that TRAIL is constitutively expressed, while activation leads to the
reduction of TRAIL and simultaneously increases the expression of TNF
and CD95L.
It is interesting to note that activation of this T cell hybridoma also induced expression of RANKL, a factor not only important for the formation of osteoclasts but that also plays an important role in the interaction between T cells and dendritic cells (39). Our study is the first to characterize the signaling mechanisms leading to the expression of RANKL in T cells. One question remaining is why the immune system and the skeletal system share the same molecule and how these two important functions are conserved on one molecule during evolution. One possible explanation is that during an immune response, an increase in blood calcium level released from the bone may be critical for full function of the immune system. Overall, the data reported in this study provide the first direct evidence for the differential regulation of the expression of TNF family members. We hope that our studies begin to clarify the diverse biochemical events modulating the expression of genes of the TNF superfamily. More detailed analysis of the expression patterns of these ligands and receptors on lymphocyte subpopulations will be necessary to define their different roles in immune activation and suppression.
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Acknowledgments |
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Footnotes |
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2 This is publication number 107 of the Department of Immunology, Holland Laboratory of the American Red Cross.
3 Address correspondence and reprint requests to Dr. Yufang Shi, Department of Immunology, Jerome H. Holland Laboratory of the American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855.
4 Abbreviations used in this paper: CD95L, CD95 ligand; AICD, activation-induced cell death; FasL, Fas ligand; OPG, osteoprotegerin; PKC, protein kinase C; RANKL, receptor activator of NF-B ligand; TMB-8, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride; TRAIL, TNF-related apoptosis-inducing ligand.
Received for publication March 27, 2000. Accepted for publication October 31, 2000.
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 Q.-S. Mi, D. Ly, S.-E. Lamhamedi-Cherradi, K. V. Salojin, L. Zhou, M. Grattan, C. Meagher, P. Zucker, Y. H. Chen, J. Nagle, et al. Blockade of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Exacerbates Type 1 Diabetes in NOD Mice Diabetes, August 1, 2003; 52(8): 1967 - 1975. [Abstract] [Full Text] [PDF]
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 I. Muller, S. M. Pfister, U. Grohs, J. Zweigner, R. Handgretinger, D. Niethammer, and G. Bruchelt Receptor Activator of Nuclear Factor {kappa}B Ligand Plays a Nonredundant Role in Doxorubicin-induced Apoptosis Cancer Res., April 15, 2003; 63(8): 1772 - 1775. [Abstract] [Full Text] [PDF]
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 A. Omezzine, S. Chater, C. Mauduit, A. Florin, E. Tabone, F. Chuzel, R. Bars, and M. Benahmed Long-Term Apoptotic Cell Death Process with Increased Expression and Activation of Caspase-3 and -6 in Adult Rat Germ Cells Exposed in Utero to Flutamide Endocrinology, February 1, 2003; 144(2): 648 - 661. [Abstract] [Full Text] [PDF]
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N. Giuliani, S. Colla, R. Sala, M. Moroni, M. Lazzaretti, S. La Monica, S. Bonomini, M. Hojden, G. Sammarelli, S. Barille, et al. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease Blood, December 15, 2002; 100(13): 4615 - 4621. [Abstract] [Full Text] [PDF]
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L. Li, X. Qi, M. Williams, Y. Shi, and A. D. Keegan Overexpression of Insulin Receptor Substrate-1, But Not Insulin Receptor Substrate-2, Protects a T Cell Hybridoma from Activation-Induced Cell Death J. Immunol., June 15, 2002; 168(12): 6215 - 6223. [Abstract] [Full Text] [PDF]
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