By
From the * Department of Immunobiology, the Department of Bioinformatics, and the § Department of
Discovery Research, Immunex Corporation, Seattle, Washington 98101
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Abstract |
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TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a molecule that displays potent antitumor activity against selected targets. The results presented here demonstrate that human monocytes rapidly express TRAIL, but not Fas ligand or TNF, after activation
with interferon (IFN)- or -
and acquire the ability to kill tumor cells. Monocyte-mediated
tumor cell apoptosis was TRAIL specific, as it could be inhibited with soluble TRAIL receptor. Moreover, IFN stimulation caused a concomitant loss of TRAIL receptor 2 expression,
which coincides with monocyte acquisition of resistance to TRAIL-mediated apoptosis. These
results define a novel mechanism of monocyte-induced cell cytotoxicity that requires TRAIL,
and suggest that TRAIL is a key effector molecule in antitumor activity in vivo.
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Introduction |
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Mononuclear phagocytes (M)1 circulate in the peripheral blood before differentiation into non-lymphoid
and lymphoid tissue-associated macrophages (1). M
mediate several host defense mechanisms through activation of
MHC class I- and class II-restricted T lymphocytes (2, 3),
release of inflammatory mediators (4), and killing of virus-infected cells (5). In addition, M
effectively kill tumor
cells through both antibody-dependent and antibody-independent mechanisms (6, 7). A critical prerequisite for these
M
functions is cellular activation. Two potent mediators
of M
activation, IFN-
and IFN-
, dramatically enhance
the cytolytic potential of human M
(8, 9). The mechanisms responsible for this IFN-induced tumoricidal activity
remain poorly defined. Nitric oxide (NO) is known to be
produced by M
and is a potent mediator of tumor cell
death (10, 11). However, several reports have demonstrated
that IFN-
and IFN-
stimulation of human M
does not
increase the level of NO release, suggesting that NO does not play a significant role in the cytotoxic activity of IFN-stimulated human M
(12). Although TNF possesses
cytolytic activity and is produced by M
after certain types
of activation (e.g., LPS), several studies have shown that
IFN does not induce TNF production in human M
(15-
17). These data indicate that other cell death-inducing molecules may be involved with the M
-mediated tumoricidal activity after IFN stimulation.
Two TNF family members capable of inducing cell death
are Fas ligand (FasL) and TNF-related apoptosis-inducing
ligand (TRAIL). FasL participates in many physiological
events, including autoimmunity, activation-induced cell death
(AICD) of lymphocytes, immune privilege, and tumor
evasion from the immune system (18). Dysregulation of
physiological Fas/FasL interactions results in immune disease states characterized by enhanced levels of Fas-mediated
apoptosis and a variety of forms of hepatitis (22) or diseases with decreased levels of lymphocyte death (e.g.,
human autoimmune lymphoproliferative syndrome [18]).
Human M contain high levels of intracellular FasL that
can be released after cellular activation (25). Recent evidence indicates that FasL-expressing M
are essential in the elimination of activated effector T cells in homeostasis and
in disease, suggesting that they may also play an important
physiological role in a variety of other immunological settings (23, 26).
In contrast to FasL, the role of TRAIL in immune regulation remains enigmatic (30). Recent studies have identified four distinct cell surface TRAIL receptors, with two
(DR4 and DR5/TRAIL-R2; hereafter referred to as
TRAIL-R1 and -R2, respectively) that contain a cytoplasmic death domain and signal for apoptotic cell death upon
receptor cross-linking, and two (TRID/DcR1/TRAIL-R3 and TRAIL-R4/DcR2; hereafter referred to as TRAIL-R3
and -R4, respectively) that lack a death domain, making
them unable to signal for cell death (31). Recombinant,
soluble forms of TRAIL are potent mediators of tumor cell
apoptosis, while demonstrating minimal cytotoxicity toward normal tissues in vitro and in vivo (38). The cell
death induced by TRAIL displays many of the same characteristics observed with other apoptotic molecules (i.e., FasL and TNF), such as caspase activation, DNA fragmentation into oligonucleosomal "ladders," annexin V binding,
and the morphological membrane blebbing and apoptotic
body release (30, 38, 41). This tumoricidal activity occurs
on ~2/3 of the >30 hematopoietic and nonhematopoietic
tumor cell lines tested (30, 36, 38, 42). Such studies not
only support the potential use for TRAIL as an antitumor
therapeutic agent (30, 38, 40), but suggest that TRAIL may
be an innate effector molecule involved in the elimination
of a broad range of spontaneously arising tumor cells. The
results presented here identify a novel mechanism by which M induce tumor cell apoptosis via TRAIL.
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Materials and Methods |
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Reagents and mAbs.
Reagents and sources were as follows: IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-15, GM-CSF (100 ng/ml; Immunex); IFN-Cell Lines.
The ovarian carcinoma cell line (OVCAR3) was obtained from Dr. Richard F. Camalier, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (Bethesda, MD). The human melanoma cell lines (WM 793 and 164) were obtained from Dr. M. Herlyn, Wistar Institute (Philadelphia, PA). The human prostate carcinoma cell line (PC-3) was obtained from Dr. Michael Cohen, University of Iowa (Iowa City, IA). The human colon carcinoma cell line (Colo205) and the human lung adenocarcinoma cell line (H2126) were provided by Dr. Brian Gliniak and Tim Lofton, respectively (Immunex). L929 cells and normal human foreskin fibroblasts were obtained from American Type Culture Collection. All tumor cell lines were cultured as directed. The normal human lung fibroblasts were purchased from Clonetics Corporation and cultured as directed.Isolation of Human M.
Flow Cytometry.
Untreated or cytokine-stimulated MTRAIL-mediated Killing of Human Tumor Cells.
MInhibition of NO Synthesis.
The specific inhibitor of NO synthase, NG-monomethyl-L-arginine (L-NMMA; AerBio, Ltd.), was used to block MTNF-mediated Killing of L929 Cells.
MTRAIL-mediated Killing of M.
Reverse Transcription PCR.
Total RNA was isolated from M ![]() |
Results |
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To compare the difference in TRAIL, FasL, and TNF surface expression, peripheral blood human M were isolated
and cultured with several molecules known to induce M
activation and differentiation (IFN-
, IFN-
, GM-CSF,
and LPS), and then examined by flow cytometry. Significant TRAIL expression was detected on the M
cultured
for 12 h in the presence of either IFN-
or IFN-
, but not
with either GM-CSF or LPS (Fig. 1 A). In contrast, FasL
expression on M
was undetectable after either 2- or 12-h
stimulation with any of the cytokines or LPS in the presence of the metalloproteinase inhibitor, KB8301 (Fig. 1 A).
Analysis of the surface levels of TNF demonstrated no measurable increase after stimulation with IFN-
or IFN-
; however, stimulation with LPS for 2 h led to increased surface levels of TNF that disappeared by 12 h (Fig. 1 B). To
inhibit the cleavage of membrane TNF, M
were cultured
in the presence of the metalloproteinase inhibitor, TAPI
(TNF protease inhibitor [43]). These data demonstrate that
TRAIL, but not FasL and TNF, is induced after IFN stimulation, and that the expression of TRAIL and TNF on
M
is regulated by distinct activation stimuli and with different kinetics.
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The results from Fig. 1 demonstrate that
M stimulated with IFN upregulate the expression of TRAIL
on the cell surface. Thus, to examine the functional activity
of TRAIL in this setting, M
were stimulated with either
GM-CSF, IFN-
, or IFN-
for 12 h and then cultured in
the presence of OVCAR3, a TRAIL-sensitive human ovarian carcinoma cell line. Although the unstimulated or
GM-CSF-treated M
demonstrated minimal tumoricidal
activity toward OVCAR3, the M
stimulated with IFN-
or IFN-
were potent killers of these TRAIL-sensitive tumor cells over a broad range of E/T ratios (Fig. 2 A). A titration of both IFN-
and IFN-
concentrations revealed that as little as 10 pg/ml led to enhanced M
cytotoxicity
against the tumor cells; however, GM-CSF did not induce
any antitumor activity at any concentration tested (100 ng/ml
to 10 pg/ml; data not shown). Moreover, the IFN-stimulated M
were as effective in killing the tumor target cells as
recombinant, soluble TRAIL (LZ-TRAIL [34]). The tumoricidal activity of IFN-stimulated M
was also examined
on a TRAIL-resistant human melanoma cell line, WM 164, and a TRAIL-sensitive human melanoma cell line, WM 793 (38). The TRAIL-resistant melanoma (WM 164) was also
resistant to the M
-mediated cytotoxicity, whereas the
TRAIL-sensitive melanoma (WM 793) was quite sensitive
to the cytotoxic activity of either IFN-
- or IFN-
-stimulated M
(Fig. 2, B and C). The tumoricidal activity of both
IFN-
- or IFN-
-stimulated M
was seen from multiple donors and with other TRAIL-sensitive tumor cells (Table
I). Two normal human fibroblast cell types were also tested
for sensitivity to the cytokine-stimulated M
and were
found to be resistant in all conditions from multiple donors.
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Although FasL was not detected on the surface of the activated M (Fig. 1 A), activated M
have been shown to
release soluble FasL from intracellular stores (25). Therefore, to confirm that the observed tumoricidal activity was
specific to TRAIL and not FasL, IFN-
-stimulated M
were pretreated with either TRAIL-R2:Fc (35) or Fas:Fc
before adding the tumor cell targets. The TRAIL-R2:Fc reduced target cell death to control (unstimulated M
effector) levels, whereas Fas:Fc did not alter the ability of
the IFN-
-treated M
to mediate tumor lysis (Fig. 2 D).
Finally, to determine whether M
NO production contributed to the measured cytotoxic activity, M
were stimulated as above but in the absence or presence of the NO
synthase inhibitor, L-NMMA (44). The cytotoxic activity of the IFN-
- and IFN-
-stimulated M
was not decreased in the presence of L-NMMA compared with M
stimulated in the absence of the inhibitor (Fig. 2, E and F).
Similar results were observed with other tumor cell targets
(data not shown). Furthermore, analysis of NO production
by the M
after 12 h stimulation, as measured by the accumulation of nitrite, revealed no increase in nitrite levels in
the culture supernatants with any of the different stimuli compared with unstimulated M
(data not shown). Collectively, these results confirm that the TRAIL expressed
on M
mediates the killing of tumor cells, demonstrating a
novel mechanism of M
-mediated apoptosis.
Although the release of 51Cr from the tumor cell targets as measured in Fig. 2 indicates the amount
of cell death, it does not discriminate between apoptotic
and necrotic cell death. Previous reports have demonstrated
that TRAIL-induced cell death occurs through an apoptotic mechanism (30, 34, 38, 41). To confirm that the tumor cell death induced by the IFN-stimulated M was mediated through an apoptotic mechanism, the binding of
FITC-conjugated annexin V to the tumor cells was analyzed. Annexin V preferentially binds to phosphatidylserine, a phospholipid component of the inner leaflet of the
plasma membrane that is rapidly externalized during apoptosis (45, 46). Upon staining the OVCAR3 tumor cells after 6 h incubation with unstimulated or cytokine-stimulated
M
(E/T ratio 2:1) or soluble LZ-TRAIL, only those tumor
cells incubated with IFN-stimulated M
or LZ-TRAIL
were positive for FITC-annexin V binding (Fig. 3), indicating that these cells were dying from the induction of
apoptosis. Morphological changes (membrane blebbing and
release of apoptotic bodies) were also observed using light microscopy (data not shown).
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Having demonstrated that
IFN-stimulated M express functional TRAIL, the differences between TRAIL and TNF-mediated tumoricidal activity by M
were examined. The results presented in Fig.
1 show that TNF was only expressed on M
after incubation with LPS. Thus, to demonstrate the biologic activity
of the cell surface TNF detected after LPS stimulation, 2- and 12-h LPS-stimulated M
were evaluated for the ability
to kill the TNF-sensitive target cell, L929 (17). In direct
correlation with the flow cytometric results, the 2-h LPS-stimulated M
, but not the 12-h LPS-stimulated M
,
killed L929 target cells to levels comparable to soluble TNF (Fig. 4 A). When tested for sensitivity to LZ-TRAIL, the
L929 cells were found to be resistant (data not shown).
This killing was TNF-specific as demonstrated by the significant inhibition of the lysis of L929 cells upon the addition of TNFR:Fc, but not TRAIL-R2:Fc (Fig. 4 B). To
further demonstrate that the cytotoxic activity of IFN-
-stimulated M
was mediated by TRAIL and not TNF,
tumor cell lysis was measured in the presence of TRAIL-R2:Fc or TNFR:Fc. Only TRAIL-R2:Fc, and not TNFR:
Fc, inhibited the IFN-
-stimulated M
from killing the
tumor cell targets (Fig. 4 C). Thus, human M
have multiple mechanisms for killing a variety of target cells depending on the activation mechanism.
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Because TRAIL can interact with two death-inducing and two non-death-inducing receptors, the distribution
of the four known TRAIL receptors on the M surface using receptor-specific mAbs was investigated. Unstimulated
M
expressed both TRAIL-R2 and -R3, whereas the levels of TRAIL-R1 and -R4 were at or below detection (Fig. 5 A). However, mRNA for each of the four TRAIL
receptors could be detected by reverse transcription (RT)-
PCR analysis (Fig. 5 B). The kinetics of TRAIL, TRAIL-R2,
and TRAIL-R3 expression after IFN-
stimulation were
then measured at both the protein level by flow cytometry
and the mRNA level by RT-PCR. Increased TRAIL expression could be detected by 2 h on the cell surface after
addition of IFN-
(Fig. 5 C), whereas RT-PCR analysis
demonstrated that TRAIL mRNA levels increased by 1 h
(Fig. 5 D). No consistent change in TRAIL protein or
mRNA levels was detected after GM-CSF treatment compared with untreated M
(Fig. 5, C and D).
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Examination of the surface levels of TRAIL-R2 and
-R3 during this same 8-h period revealed that IFN--stimulated M
downregulated TRAIL-R2 expression, whereas
TRAIL-R3 was only slightly downmodulated (Fig. 5 C).
In contrast, incubation with GM-CSF for 8 h resulted in a
slight increase in TRAIL-R2 expression. Analysis of mRNA from IFN-
-stimulated M
revealed that TRAIL-R2
mRNA levels remained relatively constant over the 8-h period, whereas the TRAIL-R2 mRNA levels increased in
M
stimulated with GM-CSF over time (Fig. 5 D). No
changes in TRAIL-R3 mRNA were observed with IFN-
or GM-CSF incubation during this period of time (Fig. 5 D),
nor were any changes in TRAIL-R1 or -R4 mRNA or
protein detected (data not shown). Thus, TRAIL expression can be detected on M
within 2 h after IFN-
stimulation, paired with a concomitant loss in cell surface expression of the cognate death-inducing TRAIL-R2. Similar
results examining TRAIL and TRAIL receptor expression on IFN-
-stimulated M
were also detected (data not shown).
The loss of TRAIL-R2 expression suggested that peripheral blood M stimulated with IFN-
would be resistant to
TRAIL-mediated death. Thus, M
were cultured in the
absence or presence of GM-CSF or IFN-
and then examined for sensitivity to LZ-TRAIL. M
treated with GM-CSF
displayed increased sensitivity to TRAIL-induced death compared with untreated M
; in contrast, IFN-
treatment significantly decreased TRAIL-induced M
death
(Fig. 6 A). Similar results were obtained with IFN-
-stimulated M
(data not shown). No significant changes in M
sensitivity to TRAIL were seen with the other cytokines tested (IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IL-12,
and IL-15; data not shown) compared with untreated M
.
These results suggest that M
stimulated with IFN-
minimize TRAIL-mediated suicide or fratricide with the downregulation of TRAIL-R2 surface levels. However, it remains possible that additional mechanisms may contribute
to the protection of the M
from TRAIL-induced death.
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The rendering of M resistant to TRAIL-mediated apoptosis after stimulation with IFN-
suggested that the tumor
cell targets used in Fig. 2 could be affected in a similar fashion upon culture with IFN-
. OVCAR3 tumor cells were
incubated in the absence or presence of IFN-
for 12 h, and
then tested for sensitivity to LZ-TRAIL or IFN-
-stimulated
M
. In contrast to the M
, the sensitivity of OVCAR3 tumor cells was not altered after incubation with IFN-
(Fig.
6, B and C). Similar results were seen with other tumor cells (WM 793 and PC-3; data not shown). These results
imply that not all cell types respond to IFN-
by gaining resistance to TRAIL-induced death as observed with
the M
.
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Discussion |
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M not only influence the activities of other immune
and nonimmune cells in the body, but also function as effector cells under a variety of conditions (1). Activated M
display potent tumoricidal activity against several different
tumor cell types (7, 47). The results presented here
demonstrate that one of the mechanisms by which M
kill
tumor cells is through expression of TRAIL. M
stimulation with either IFN-
or IFN-
resulted in the rapid expression of TRAIL on the cell surface, but not FasL or
TNF. Because TRAIL mediates apoptosis in a high percentage (approximately two thirds) of hematopoietic and
nonhematopoietic cell types (30, 36, 38, 42), M
have the
potential to mediate apoptosis of a broad range of tumor
cell types via TRAIL. Expression of TRAIL appeared to be
specific to the IFNs, as M
stimulation with either IL-1,
IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IL-12, IL-15, or GM-CSF resulted in no detectable TRAIL expression (data not
shown). Interestingly, a concomitant loss of TRAIL-R2 (and to a lesser extent TRAIL-R3) expression was detected
upon IFN stimulation, rendering the M
resistant to
TRAIL-mediated death. To our knowledge, this is the first
demonstration of inducible TRAIL expression on a particular human peripheral blood cell population, as well as
modulation of the death-inducing TRAIL-R2 by a proinflammatory cytokine on the same cell population.
Although the expression of TRAIL on the IFN-stimulated M is critical for the tumoricidal activity in our assay
system, the sensitivity of the tumor cell to TRAIL-induced
apoptosis is also an essential component of this phenomenon, as demonstrated by the fact that the tumor cell lines
and normal cells that were resistant to TRAIL-mediated
apoptosis were also resistant to TRAIL-expressing M
.
The identification of two TRAIL receptors with death-
inducing ability and two without led to the initial hypothesis
that the expression of TRAIL-R3 and/or -R4 conferred
resistance to TRAIL-induced death (32, 33, 37). However,
it is important to note that this hypothesis was formulated
from reports examining the distribution of TRAIL receptor mRNA in several normal tissues and tumor cell lines
and from experiments where TRAIL-R3 or -R4 was
overexpressed in transfected cells. Most of the tumors used
in this study express TRAIL-R3 and/or -R4 (38, 42).
When the OVCAR3, WM793, and PC3 tumor cells were
cultured with IFN-
before incubation with LZ-TRAIL or
IFN-stimulated M
, the TRAIL receptor levels remained unchanged, and no significant change in the level of TRAIL
sensitivity was observed (data not shown). Thus, the differences in sensitivity of the tumor cells to the TRAIL expressed on the M
or the recombinant TRAIL added in solution are probably regulated by a variety of molecular
mechanisms, both inside the cell and at the surface.
While our results focused on the tumoricidal activity of
TRAIL-expressing M, previous reports have shown these
cells can also produce cytotoxic inorganic oxidants, such as
NO (10, 11). A role for NO in tumor cell killing has been
documented for both human and mouse activated macrophages (4, 44, 50), where the toxicity of NO is mediated
via mitochondrial damage, inhibition of DNA synthesis,
and disruption of the tricarboxylic acid cycle, ultimately resulting in apoptosis (51, 52). Although murine macrophages release high levels of NO after either LPS or IFN-
stimulation, studies with human peripheral blood M
have
reported contradictory findings (10). In some reports, M
stimulated with either LPS or IFN-
(or in combination)
failed to release significant levels of NO (12, 44, 53),
whereas others have reported that IFN-
stimulation results in a slight increase in NO production (54). In our
studies, addition of the NO inhibitor L-NMMA to the cytotoxicity assays did not decrease the ability of the IFN-
-
and IFN-
-stimulated M
to kill the tumor cell targets. Moreover, analysis of the culture supernatants for nitrites
revealed no increase after 12 h stimulation with GM-CSF,
IFN-
, or IFN-
(data not shown). These observations,
coupled with the fact that TRAIL-R2:Fc completely inhibited the tumoricidal activity of the M
to background
(unstimulated M
) levels, imply that TRAIL is the primary
mediator of the tumoricidal activity after IFN stimulation. Coexpression of TRAIL and TNF, and perhaps other unidentified death-inducing molecules, would theoretically
increase both the cytolytic potential of the M
and the
range of different tumor targets susceptible to M
-mediated death.
The importance of IFN in the management of spontaneously arising tumors was recently demonstrated in vivo using mice that lack sensitivity to IFN- (55). Compared
with wild-type mice, the IFN-
-insensitive mice develop
tumors more rapidly and with greater frequency when
challenged with a chemical carcinogen. Part of this "IFN
effect" is via the interaction of the IFN with the tumor
cells by enhancing the tumor cell tumorigenicity through heightened MHC class I expression. IFN-
may also enhance an innate antitumor mechanism through the induction of TRAIL on cells of the M
lineage (55). Although
our data suggest that M
would confer this antitumor activity, further studies are required to determine if other cell
types, such as NK cells, neutrophils, and dendritic cells, are
also able to express TRAIL after IFN stimulation (56).
Finally, in addition to a role in tumoricidal activity, these
data suggest that M TRAIL-expression may contribute to
other physiologic and pathologic situations, such as the
AICD of T cells during HIV infection. Recently, Katsikis
et al. (57, 58) have demonstrated that activation-induced
peripheral blood T cell apoptosis in HIV-infected individuals was Fas independent, and a potential role for TRAIL in
this phenomenon was identified. It was observed that a
blocking mAb to TRAIL could inhibit the AICD of T cells in a mixed population of HIV+ PBMCs (58). However, it
was unclear which PBMC subset was expressing TRAIL
and responsible for death of the T cells. Thus, the results presented here may provide an explanation for these experimental observations, as well as a basis for examining other
activities mediated by activated M
.
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Footnotes |
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Address correspondence to Neil A. Fanger, Department of Discovery Research, Immunex Corporation, 51 University St., Seattle, WA 98101. E-mail: nfanger{at}immunex.com
Received for publication 14 January 1999 and in revised form 12 February 1999.
We thank Drs. David Cosman, Ray Goodwin, David Lynch, Craig Smith, Michael Widmer, and Doug Williams for careful reading of the manuscript, Gary Carlton for figure preparation, and Anne Aumell for editorial assistance.
Abbreviations used in this paper
AICD, activation-induced cell death;
L-NMMA, NG-monomethyl-L-arginine;
LZ, leucine zipper;
M, mononuclear phagocyte(s);
NO, nitric oxide;
RT, reverse transcription;
TRAIL, TNF-related apoptosis-inducing ligand.
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