Anti-CD95-induced Lethality Requires Radioresistant
Fc
RII+ Cells
A NOVEL MECHANISM FOR FULMINANT HEPATIC FAILURE*
Satoshi
Jodo
,
John T.
Kung§,
Sheng
Xiao¶,
Derek V.
Chan¶,
Seiichi
Kobayashi
,
Masatoshi
Tateno**,
Robert
Lafyatis
, and
Shyr-Te
Ju
¶
§§
From the
Arthritis Center, Department of Medicine,
Boston University School of Medicine, Boston, Massachusetts 02118, § Institute of Molecular Biology, Academia Sinica,
Taipei, Taiwan, the ¶ Department of Pathology and Laboratory
Medicine, Boston University School of Medicine,
Boston, Massachusetts 02118, the
Department of Laboratory
Technology, College of Medical Technology, Hokkaido University,
Hokkaido, Japan, the ** Department of Pathology, Sapporo
City General Hospital, Sapporo, Japan, and

Division of Rheumatology and Immunology,
Department of Internal Medicine, University of Virginia Health System,
Charlottesville, Virginia 22908-0412
Received for publication, November 4, 2002, and in revised form, December 4, 2002
 |
ABSTRACT |
The Jo2 anti-mouse CD95 monoclonal antibody
induces lethality in mice characterized by hepatocyte death and liver
hemorrhage. Mice bearing a defect in Fas expression or in the
Fas-mediated apoptotic pathway are resistant to Jo2. Here we show that
Fc
RII knockout mice or mice with monoclonal antibody-blocked
Fc
RII are also resistant to Jo2. The critical
Fc
RII+ cells are radioresistant and could not be
reconstituted with splenic cells. Death of sinusoidal lining cells and
destruction of sinusoids were observed, consistent with the
characteristic liver hemorrhage and the selective Fc
RII expression
in sinusoidal lining cells but not hepatocytes. Hemorrhage developed
coincident with hepatocyte death and the sharp rise of serum alanine
aminotransferase and alanine aminotransferase. Invariably, moribund
mice showed severe liver hemorrhage and destruction of sinusoids. The
data demonstrate a novel mechanism by which the destruction of liver sinusoids, induced by the Jo2-mediated co-engagement of Fas and Fc
RII, leads to severe hemorrhage and lethal fulminant hepatitis.
 |
INTRODUCTION |
Cross-linking of CD95 (Fas), a type I transmembrane protein with a
cytoplasmic death domain (1), induces cells to undergo apoptosis (2).
Jo2, a hamster-derived mAb1
directed against mouse Fas, is lethal when administered into mice
either intravenously or intraperitoneally (3). Mice defective in either
Fas expression or Fas-mediated apoptotic pathways are resistant to
Jo2-induced lethality (4, 5). Jo2-induced lethality is associated with
extensive hepatocyte death and marked elevation of serum AST and ALT
(3). Injection of a caspase inhibitor protects mice against Jo2-induced
apoptosis of hepatocytes and lethality (6). These observations suggest
that hepatocytes are the primary target and that the Jo2-induced death
of hepatocytes is the cause of lethality. However, freshly isolated
hepatocytes are highly resistant to Jo2, displaying weak apoptosis only
after prolonged incubation in the presence of cycloheximide, which
facilitates Fas-mediated apoptosis (7-9). Thus, whereas lethality
could be induced within 2 h after application, death of
hepatocytes in in vitro experiments could only be induced
after 12 h of treatment or more (3, 7-9). In addition, direct
binding of Jo2 to hepatocytes in vivo has not been reported.
Like hepatocyte damage, massive hemorrhage in the liver invariably
accompanies Jo2-induced lethality (3). Jo2-induced hemorrhage is highly
specific, restricted only in the liver but not in other tissues whose
cells often express a higher level of Fas than hepatocytes.
Thus, the selective toxicity of Jo2 toward liver cannot be
explained either by its Fas expression level or by the in
vitro sensitivity of hepatocytes. Conversely, a direct attack of
hepatocytes by Jo2 cannot explain the induction of severe hemorrhage in liver.
Jo2 but not other anti-Fas mAb effectively induces lethality in mice
(7). Still, the apparent liver toxicity of Jo2 has raised a serious
concern regarding the use of Fas cross-linking agents as therapeutics.
We noted that Jo2-mediated cytotoxicity is critically dependent on
target Fc
R expression. Both hepatocytes and sinusoidal lining cells
express Fas, but only the latter express Fc
R (10-12). Because a
co-engagement of Fas and Fc
R can facilitate binding and strengthen
the subsequent signaling process, we asked the question of whether the
Jo2-induced lethality requires co-engagement of Fas and Fc
R. We
found that Jo2-induced lethality is critically dependent on host
Fc
RII expression. This observation and additional studies described
herein provide strong evidence for a novel mechanism for Jo2-induced
hepatic injury in which hemorrhage and hepatocyte death are secondary
to the killing of sinusoidal lining cells, which are the primary target
of Jo2 and the deciding factor for Jo2-induced lethality. In addition,
this study revives the possibility of using Fas cross-linking agents
that lack the Fc
RII binding activity as useful therapeutic agents.
 |
MATERIALS AND METHODS |
Cytotoxicity Assays--
Cytotoxicity assays against the
Fc
R+ A20 and the Fc
R
variant IIA1.6
target cells (obtained from Dr. C. J. Janeway, Yale University, New Haven, CT) were conducted as described previously (13). Target
cells (2 × 104), labeled with
Na251CrO4 (PerkinElmer Life
Sciences), were cultured with various doses of Jo2 (BD Biosciences) or
FasL vesicle preparation (FasL VP) (13, 14) in 0.2 ml in individual
wells of a 96-well plate. Supernatants were removed at 5 h after
culture, and radioactivity (counts/min) was determined. Background
release was determined by culturing cells alone. Cytotoxicity is
expressed as % specific 51Cr release, which is determined
by the formula: 100% × (experimental release
background
release)/(total cpm released by 0.5% Nonidet P-40
background
release). Assays were carried out in duplicate, and the experiment was
repeated three times. The amount of human FasL protein present in FasL
VP was determined using a capture enzyme-linked immunosorbent assay kit
(Oncogene, Boston, MA) (14).
Jo2-induced Lethality--
B6, B6;129SF2/J,
B6;129S-Fcgr2tm1Rav (Fc
RII KO),
C57BL/6-Fcgr3tm1Sjv (Fc
RIII KO),
and B6.MRL-Faslpr mice were obtained from The
Jackson Laboratory, Bar Harbor, ME. In accordance with IACUC
guidelines, mice were treated under various conditions as described in
the legends of the figures and tables. To determine the lethality, mice
were injected intraperitoneally with various doses of Jo2 or were
untreated. Mice were euthanized at the time that the Jo2-treated
B6 mice became moribund. Tissues were fixed with 10%
paraformaldehyde and photographed. Sera were collected and assayed for
aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
using a commercial kit (Sigma). In some experiments, mice were
euthanized at various times after injection of Jo2. Livers were fixed
and examined for apoptotic cells using the in situ apoptosis
detection kit (Trevigen, Inc., Gaithersburg, MD).
Radioresistance of the Target of Jo2--
To determine the role
of Fc
R and target radiosensitivity in the Jo2-induced lethal
fulminant hepatitis, B6 and Fc
RII KO mice were
irradiated with 600 rads and used 4 days later. In some experiments,
mice were reconstituted 24 h before the injection of Jo2 with
B6 splenic cells (108/mouse) by intravenous
injection of single cell suspension prepared from B6 spleen
cells. In other experiments, mice were injected intravenously with
purified, Fc
R-specific 2.4G2 or control rat Ig (Jackson
ImmunoResearch, Atlanta, GA) 2 h before the intraperitoneally injection of Jo2.
Treatment with D-Gal Plus Lipopolysaccharide
(LPS)--
Both B6 and Fc
RII KO mice, 3 mice
per group, were injected with D-Gal (0.5 g/kg body weight)
plus bacterial LPS (50 µg/kg body weight) intraperitoneally as
described (15, 16). Neither agent alone induced lethality. Mice were
observed for 24 h. Sera and tissues of moribund mice were
collected. Samples of control mice were collected at the same times
when moribund mice were euthanized.
 |
RESULTS |
Fc
R Expression on Target Cells Regulates the Cytotoxicity of
Jo2--
We tested Jo2 anti-Fas mAb for Fc
R-dependent
cytotoxicity using 51Cr-labeled, Fc
R+ A20
and Fc
RII
variant IIA1.6 cells (derived from A20) as
targets in a 5-h cytotoxicity assay (Fig.
1). Jo2 effectively killed
Fc
R+ A20 cells but not IIA1.6 cells (Fig.
1a). Both targets were equally sensitive to FasL VP, the
apoptosis-inducing membrane vesicles that induce cell death independent
of target Fc
R expression (Fig. 1b). In addition, the
killing of Fc
R+ A20 targets by Jo2 was inhibited by
2.4G2 mAb that blocks Fc binding to Fc
RII and Fc
RIII (17, 18).
The control rat IgG2b did not inhibit the killing (Fig. 1c).
In addition, 2.4G2 did not inhibit FasL VP-mediated killing (Fig.
1d). These results indicate that the acute cytotoxicity of
Jo2 depends on Fc
R binding.

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Fig. 1.
Jo2 mediates
Fc R-dependent cytotoxicity.
Varying concentrations of Jo2 mAb (a) or FasL-bearing
vesicles (FasL VP) (b) were used to kill Fc R+
target A20 and the Fc R target IIA1.6 in a 5-h
cytotoxicity assay. The anti-Fc R mAb 2.4G2 (300 ng/ml) but not
control rat IgG2b inhibited the killing of A20 by Jo2 (c).
2.4G2 did not inhibit the killing of A20 by FasL VP
(d).
|
|
Fc
RII KO Mice Are Resistant to Jo2--
Because 2.4G2 blocked
both Fc
RII and Fc
RIII, we determined whether Jo2 induces
lethality in Fc
RII KO mice
(B6;129S-Fcgr2tm1Rav) or Fc
RIII KO
mice (C57BL/6-Fcgr2tm1Sjv). Control
groups included B6129SF2/J, B6, and
B6.MRL-Faslpr mice. Fc
RII KO mice were
completely resistant to Jo2, including those treated with a high dose
of Jo2 (5 mg/kg body weight, Table I). In
contrast, almost all of the control B6;129SF2/J
mice died even when treated with a lower dose of Jo2 (1.5 mg/kg body
weight). In addition, all of the Fc
RIII KO mice died
after injection of a lower dose of Jo2.
B6.MRL-Faslpr mice were resistant to the high dose
of Jo2 (5 mg/kg body weight). Thus, Jo2-induced lethality requires the
presence of Fc
RII+ and Fas+ cells and
correlates with Fc
R-dependent cytotoxicity in
vitro.
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Table I
The Jo2-induced lethality depends on host Fc RII expression
Mice, 5-7 weeks old, were weighed and injected, intraperitoneally,
with various doses of Jo2. Mortality was determined within 24 h
after injection. The fatality was usually observed within 7 h. All
survived mice were followed up for additional 3 days and all remained
alive.
|
|
Fc
RII KO Mice Are Sensitive to
D-Gal/LPS-induced Lethality--
To exclude the
possibility that Fc
RII KO mice are inherently resistant
to death-inducing regimens that cause liver damage, they were tested
with a bacterial peritonitis/endotoxin shock model in which lethality
is induced by injecting D-Gal and LPS (15, 16). The
molecule responsible for the lethality is TNF-
(19), which, like
Jo2, induces caspase-dependent fulminant hepatic failure
(20). In contrast to Jo2 treatment, however, Fc
RII KO,
B6;129SF2/J, and B6 mice were equally
sensitive to this regimen and died within 7 h after treatment
(Table II). Thus, Fc
RII KO mice are specifically resistant to Jo2-induced lethality.
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Table II
Jo2 elevates serum transaminase of B6 but not Fc RII KO mice
Mice were either untreated, injected with Jo2 (3 mg/kg. body weight,
intraperitoneally), or treated with D-Gal/LPS as described
under "Materials and Methods." Mortality developed within 3-7 h
after injection. All moribund mice displayed severe hemorrhage in the
liver. Sera were collected from moribund mice. Sera of viable mice were
collected at 7 h after treatment. The serum levels (units/ml) of
AST and ALT were determined with a commercial kit.
|
|
Serum Transaminase and Liver Hemorrhage Are Not Induced in
Jo2-treated Fc
RII KO Mice--
The serum levels of ALT and AST
increased dramatically in Jo2-susceptible mice but remained normal in
Jo2-treated Fc
RII KO mice (Table II). However, the
Fc
RII KO mice that succumbed to D-Gal/LPS
treatment showed high levels of serum AST and ALT. Although the
lethality correlated with hepatocyte damage as indicated by high serum
transaminase activities, a complete concordance between hemorrhage in
liver and lethality was also observed. Extensive hemorrhage in the
liver was observed in Jo2-treated B6 mice and D-Gal/LPS-treated Fc
RII KO mice but not in
Jo2-treated Fc
RII KO mice (Fig.
2). Hemorrhage was selectively induced in
liver but not in kidney (Fig. 2a), spleen, thymus,
intestine, or heart. Livers from B6 mice taken at 2 h
after treatment showed congestion, infiltration of erythrocytes,
distorted sinusoids, and hepatocyte death, whereas livers from
Jo2-treated Fc
RII KO mice displayed normal structure,
similar to those observed in untreated mice (Fig. 2, b and
c). These observations indicate that an
Fc
RII-dependent event that mediates lethality
by Jo2 must occur before the death of hepatocytes and the hemorrhage in
the liver.

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Fig. 2.
Jo2 induces hemorrhage and death of
hepatocytes in the livers of B6 mice but not
Fc RII KO mice. a, from
left to right: hemorrhagic liver (top
row) was observed in Jo2-treated B6 mice
(2nd), but not in untreated B6 mice
(1st), untreated Fc RII KO mice
(3rd), or Jo2-treated Fc RII KO mice
(4th). Hemorrhage was not observed in kidneys (middle
row) from the corresponding mice. Hemorrhage in liver
(bottom row) was observed in D-Gal/LPS-treated
B6 mice (2nd) and Fc RII KO mice
(4th) but not in untreated B6 mice
(1st) and Fc RII KO mice (3rd) mice.
b and c, show the H/E staining of Jo2-treated
B6 and Jo2-treated Fc RII KO mice,
respectively. Magnification, ×200. Please note the congestion of
red blood cells, the distortion of sinusoids, and nuclear
condensation of hepatocytes.
|
|
The Target Cells of Jo2 Responsible for Lethality Are
Radioresistant--
In the hematopoietic system, Fc
RII is
abundantly expressed on macrophages, B cells, neutrophils, eosinophils,
and platelets (10, 17, 18). In the liver, Fc
RII is found on the
sinusoidal lining cells but not on hepatocytes, and Fc
RIII
expression on the sinusoidal lining cells is controversial (11, 12).
Because many Fc
RII+ hematopoietic cells are
radiosensitive, mice were treated with 600 rads of
-irradiation and
tested 4 days later for susceptibility to Jo2. Although irradiation
eliminated more than 98% of the spleen and blood leukocytes, the mice
remained susceptible to Jo2. Conversely, irradiated Fc
RII
KO mice remained resistant to Jo2 (Table
III). Irradiated Fc
RII KO
mice that had been reconstituted with B6 splenic cells
24 h earlier remained resistant to Jo2. In addition, we blocked
Fc
R in irradiated B6 mice with 2.4G2 and 2 h later injected Jo2. Fc
R blockade prevented Jo2-induced death of irradiated mice. In contrast, irradiated mice that were either untreated or
treated with normal rat Ig succumbed to Jo2 within 4-16 h (Table III).
These observations indicate that under the experimental conditions, the
critical cells controlling mouse susceptibility to Jo2 were radioresistant Fc
RII+ cells.
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Table III
Anti-Fc R mAb 2.4G2 blocks Jo2-induced lethality
Mice were irradiated with 600 rads and used 4 days later. Some mice
were injected intravenously with 2.4G2 or control rat Ig 2 h
before the injection of Jo2 (3 mg/kg body weight, intraperitoneally).
|
|
Coincidental Display of Sinusoid Destruction, Hemorrhage, and
Hepatocyte Death--
Because Fc
R express in sinusoidal lining
cells but not hepatocytes, the critical requirement of Fc
RII for
Jo2-induced lethality strongly suggests that the primary targets of Jo2
are sinusoidal lining cells. As sinusoidal lining cells separate blood
from liver mesenchyma, destruction of sinusoids should lead to
hemorrhage. According to this interpretation, hepatocyte death is
secondary to sinusoid destruction. Consequently, hepatocyte death
should be observed around damaged sinusoids but not in areas where
sinusoids remain intact. TUNEL assays indicated that the sinusoidal
lining cells become apoptotic at 1 h after injection of Jo2 (Fig.
3, top versus middle
panels). At 2 h after injection, focal hemorrhage and more
cells, including apoptotic hepatocytes, became apparent around the
damaged sinusoids (Fig. 3, bottom panel). Jo2-induced toxicity of hepatocytes is prevalent around damaged sinusoids. By
contrast, hepatocytes around areas where destruction of sinusoids was
not induced did not become apoptotic. The data suggest that the
Fc
RII-dependent destruction of sinusoids is the primary
mechanism for Jo2-induced lethality by causing severe hemorrhage in
liver and hepatocyte apoptosis.

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Fig. 3.
Sinusoid destruction
proceeds with apoptosis of sinusoidal lining cells and
coincident with hemorrhage and hepatocyte apoptosis. B6
mice were injected intraperitoneally with Jo2 (5 mg/kg body weight).
Untreated B6 mice were used as control as 0 h of
treatment (top panel). At 1 h after treatment
(middle panel), TUNEL+ nuclei of sinusoidal
lining cells (arrows) appear at sinusoidal margins, whereas
the large nuclei of intact hepatocytes remain TUNEL . At
2 h after treatment (lower panel), severe sinusoid
destruction was observed. Apoptotic hepatocytes (arrows)
with large and strongly stained nuclei were abundant around damaged
sinusoids. Note the TUNEL+ nuclei of sinusoidal lining
cells are smaller than the TUNEL+ hepatocytes. Hemorrhage,
clusters of erythrocytes, and breakdown of hepatic architecture were
evident around the damaged sinusoids. Hepatocyte apoptosis and focal
hemorrhage occurred mainly around the damaged sinusoids. Magnification,
×200.
|
|
 |
DISCUSSION |
A Novel Mechanism for Jo2-induced Lethal Fulminant
Hepatitis--
Our study supports a model in which the critical
targets of Jo2 are the sinusoidal lining cells that co-express Fc
RII
and Fas. As sinusoidal lining cells are the gateway for blood
components to enter liver parenchyma, our data indicate that Jo2
travels through the blood, encounters sinusoidal lining cells, and
delivers a Fas-mediated apoptotic signal that is dependent on target
Fc
RII expression. Under in vitro conditions, we showed
that the co-engagement of Fas and Fc
RII provided a strong apoptotic
signal, and presumably the Fc
R-engaged Jo2 could enhance binding and
resist endocytosis. Under in vivo conditions and within
1 h of application, Jo2 induces the detachment of sinusoidal
lining cells and inhibits their microvascular perfusion function (21).
Within the next hour, nuclear condensation in the sinusoidal lining
cells and congestion/extravasation of erythrocytes becomes obvious (21)
(Figs. 2 and 3). Death of sinusoidal lining cells could damage vascular
integrity, resulting in focal hemorrhage. Our data suggest that focal
hemorrhage induces secondary damage to hepatic parenchymal cells and
further loss of sinusoid integrity. As the process progresses, the
liver becomes severely hemorrhagic. Massive bleeding is always observed
in the livers of moribund mice and is coincident with death. Together with the Fc
R-dependent induction of apoptosis of targets
in vitro, our in vivo study provides strong
evidence that hemorrhage in the liver is responsible for the lethality
induced by Jo2.
Transgenic mice in which the bcl-2 transgene is controlled
by a pyruvate kinase regulatory sequence are resistant to Jo2 (23). In
contrast, transgenic mice in which the bcl-2 transgene is
linked with the
1-antitrypsin promoter
(pAAT-bcl-2) are susceptible (9, 24). Our model can explain
this conundrum. The resistance is likely due to the expression of the
bcl-2 transgene in sinusoidal lining cells because the
pyruvate kinase regulatory sequence used is not cell type-specific. In
contrast, the
1-antitrypsin promoter is
hepatocyte-specific. Therefore, the sinusoidal lining cells in the
pAAT-bcl-2 transgenic mice should remain susceptible to Jo2.
Also of great relevance to the present study is the observation that
anti-FLAG-aggregated FasL is lethal to the pATT-bcl-2 mice (9), whereas recombinant sFasL alone is not even toward normal mice.
According to our model, the anti-FLAG-aggregated FasL are focused onto
sinusoidal lining cells by the co-engagement of Fas and Fc
RII.
Interestingly, lethality occurs with severe hemorrhage in liver but
little apoptosis of hepatocytes in the pATT-bcl-2 mice (9,
24), providing further support that hepatocyte death is not necessary
for lethality.
In addition to the study using anti-FLAG-aggregated rsFasL, several
other observations also support the critical role of Fc
R in
Jo2-induced lethality. At present, Jo2 is the only anti-Fas mAb capable
of inducing lethal fulminant hepatitis. The acute Fc
R-facilitated
cytotoxicity was not reported for other anti-Fas mAbs that do not
induce lethal fulminant hepatitis (7). It appears that Jo2-induced
lethality is unique to this mAb. Thus, Fc
RII-nonreactive anti-Fas
mAb and FasL and their derivatives may not induce hepatic toxicity,
raising the possibility that they may be used as therapeutic agents. It
should be noted, however, that lethality has been induced with an
excessive amount of rsFasL (25, 26), suggesting that the relative
sensitivity of target tissues versus liver to
Fc
RII-nonreactive, Fas-binding agents is an important factor to
consider for therapeutic purposes.
Because sinusoidal lining cells form the barrier between blood and
hepatocytes, their death leads to focal hemorrhage. As the welfare of
hepatocytes depends on a functional barrier, hemorrhage-induced biochemical events and the loss of sinusoidal integrity may induce secondary damage to hepatocytes. This hypothesis could reconcile the
strong resistance of hepatocytes to Jo2 in in vitro study and their rapid death upon Jo2 administration in vivo
(3, 9, 21). This hypothesis predicts that circulating Jo2 would attack sinusoidal lining cells first. Indeed, injected fluorescein
isothiocyanate-Jo2 (100 µg intravenously) strongly stained sinusoidal
lining cells but not hepatocytes, whereas fluorescein
isothiocyanate-conjugated hamster Ig did not stain sinusoidal lining
cells (data not shown). TUNEL assays indicated focal hemorrhage and
apoptotic sinusoidal lining cells around the damaged sinusoids (Fig.
3). Jo2-induced toxicity of hepatocytes apparently emanates from
damaged sinusoids, and regions where sinusoids are intact the
hepatocytes remained viable. Our study suggests that sinusoidal lining
cells are the primary targets, and hepatocyte death is secondary to the
destruction of sinusoids. This is reasonable because the welfare of
hepatocytes depends on functional and intact sinusoids. The mechanism
by which hepatocyte death is induced requires further study.
Implication for Sinusoidal Lining Cells as Critical Targets for
Hepatic Damage--
In addition to Jo2-induced lethality, severe
hemorrhage in the liver is observed in several other models of lethal
hepatic failure. The acute liver toxicity of acetaminophen has been
shown to be the result of a preferential toxicity toward sinusoidal endothelial cells (27). Consistent with the present study, severe hemorrhage in liver was observed in moribund mice (27). In the lethal
fulminant hepatitis in which the apoptosis-inducing factor implicated
is TNF-
or FasL, the lethality has been attributed to hepatocyte
death (19, 26, 28). Our hypothesis suggests that hemorrhage is the
underlying cause for lethality in these models. As with the
Fc
RII-mediated focusing of Jo2 on the sinusoidal lining cells,
TNF-
produced by the LPS-activated Kupffer cells could
preferentially attack the neighboring sinusoidal endothelial cells (20,
28). Although the Jo2-induced lethality is an acute model for fulminant
hepatitis, sinusoidal lining cells can be critical targets in chronic
hepatic injury as well. Sinusoidal endothelial cells have been
implicated as early targets in veno-occlusive disease observed in the
setting of hematopoietic cell transplantation (29). In this setting,
following injury of the sinusoidal endothelial cells, a series of
biochemical processes lead to circulatory compromise of centrilobular
hepatocytes, fibrosis, and obstruction of liver blood flow. Other
clinical settings include the inflammation around sinusoidal lining
cells in lpr bone marrow chimera in irradiated MRL hosts (30), the reperfusion injury of sinusoidal lining cells associated with liver transplantation (31), and liver hemorrhage
observed after a successful post-operative period in patients of liver
transplantation (32). Finally, recent studies (6, 21) have shown that
caspase inhibitors can block the lethality and hepatocyte death induced
by Jo2 and TNF-
. Our study indicates that these inhibitors could
potentially be used to treat certain hepatic injuries such as
peritonitis or perfusion-induced liver damage by protecting the
sinusoidal lining cells and hepatocytes from apoptosis.
 |
FOOTNOTES |
*
This work was supported by National Institutes of Health
Grants AI-36938 and ES-10244.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.
§§
To whom correspondence and reprint requests should be addressed:
Division of Rheumatology and Immunology, Dept. of Internal Medicine,
University of Virginia Health System, P. O. Box 800412, Charlottesville, VA 22908-0412. Tel.: 434-243-6358; Fax: 434-243-6454; E-mail: sj8r@virginia.edu.
Published, JBC Papers in Press, December 10, 2002, DOI 10.1074/jbc.M211229200
 |
ABBREVIATIONS |
The abbreviations used are:
mAb, monoclonal
antibody;
FasL, Fas ligand;
ALT, alanine aminotransferase;
AST, aspartate aminotransferase;
D-Gal, D-galactosamine;
KO, knockout;
LPS, lipopolysaccharide;
sFasL, soluble FasL;
VP, vesicle preparation;
TNF-
, tumor necrosis
factor-
;
TUNEL, terminal dUTP nick-end labeling.
 |
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