1 Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; and 2 Division of Immunopathology, Institute of Pathology, University of Berne, 3010 Berne, Switzerland
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Apoptosis (programmed cell death) has been shown to play a major role in development and in the pathogenesis of numerous diseases. A principal mechanism of apoptosis is molecular interaction between surface molecules known as the "death receptors" and their ligands. Perhaps the best-studied death receptor and ligand system is the Fas/Fas ligand (FasL) system, in which FasL, a member of the tumor necrosis factor (TNF) family of death-inducing ligands, signals death through the death receptor Fas, thereby resulting in the apoptotic death of the cell. Numerous cells in the liver and gastrointestinal tract have been shown to express Fas/FasL, and there is a growing body of evidence that the Fas/FasL system plays a major role in the pathogenesis of many liver and gastrointestinal diseases, such as inflammatory bowel disease, graft vs. host disease, and hepatitis. Here we review the Fas/FasL system and the evidence that it is involved in the pathogenesis of liver and gastrointestinal diseases.
apoptosis; intestine; colitis; hepatitis; transplant
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
KERR, WYLLIE, AND CURRIE published in 1972 (61) what has become recognized as a landmark report, in which they described a controlled, apoptotic cell death that occurs in a wide range of physiological situations and proposed a role in tissue kinetics involving dynamic cell turnover and homeostasis. Remarkable about the cell death they described was not only the diversity of the tissue in which it was observed but also the consistency of the morphological description of the dying cells. Apoptotic cells were observed to undergo shrinkage involving nuclear margination and chromatin condensation as well as a characteristic membrane blebbing followed by engulfment by neighboring cells. Integrity of the plasma membrane was maintained in the dying cell, and cellular contents were not released into the extracellular milieu. Wyllie contributed another major advance in 1980 (143) when he demonstrated that nuclear apoptotic events included activation of an endogenous nuclease that resulted in degradation of chromatin into nucleosome-sized DNA ladders that have become a biochemical hallmark of apoptosis.
One of the major functions of apoptosis is maintaining the appropriate number of cells (i.e., "homeostasis"). Much of our knowledge on this subject is from studies on the nematode Caenorhabditis elegans, which has exactly 1,090 cells of which 131 must die during development to ensure proper maturation (30). The genes that regulate the precise number of cells that C. elegans loses have been shown to have mammalian analogs, and these genes have subsequently been shown to be important in regulation of apoptosis of mammalian cells (50, 83). Similar to the nematode, and unlike most tissues, the size of the liver and the number of intestinal epithelial cells are tightly regulated, and it is reasonable to hypothesize that apoptosis plays a major role in this regulation. The liver has regenerative capability such that after injury or resection the liver normally returns to its original size and function. Similarly, the number of intestinal epithelial cells (IEC) found on the villus and crypt appears to be tightly controlled. IEC develop from stem cells in the crypt where they migrate up to the villus tip in 2-3 days and "slough" off the villus tip (49, 51). With each epithelial cell that sloughs off, a new epithelial cell is generated in the crypt such that the villus height remains constant. Although apoptosis most likely ensures that the liver does not grow too large or that villus height remains constant, it remains to be formally demonstrated that these processes are regulated by apoptosis. Although genetically engineered "knockout" of mammalian analogs of C. elegans genes, which have been shown to regulate apoptosis, resulted in significant kidney, brain, extremity, and craniofacial abnormalities, there have been to date no reported abnormalities of the liver and gastrointestinal tract in these knockout mice (76, 108).
![]() |
FAS-MEDIATED DEATH SIGNALING: MULTIPLE ROADS TO DEATH |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In recent years we have realized that apoptosis is mediated through a
series of biochemical steps. Perhaps the best-characterized apoptotic
pathway is that induced through the surface molecule Fas (Refs. 6, 93;
see Fig. 1). Engagement of Fas by FasL or
anti-Fas antibodies results in trimerization of Fas, followed by
recruitment of a number of proteins to form a complex known as the
death-inducing signaling complex (DISC). After formation of the DISC
with Fas, FADD (20), and pro-caspase-8 (12, 91) as the primary
components, pro-caspase-8 is cleaved and activated. Active caspase-8
then cleaves bid (77), a bcl-2 family member that causes release of
mitochondrial cytochrome c (62, 63, 74). On release from the
mitochondria, cytochrome c interacts with APAF-1 (148) and
caspase-9 (69) to form a complex known as the apoptosome (103).
Formation of the apoptosome results in cleavage and activation of
caspase-9, which in turn leads to the cleavage and activation of
caspase-3 (97), a central executioner caspase that cleaves and
activates downstream caspases that are largely responsible, directly
and indirectly, for systematically dismantling the apoptotic cell from
within. For a comprehensive review of caspases, see Refs. 135 and 142.
Structural breakdown of the cell includes cleavage of gelsolin (65),
which results in cleavage of actin filaments, as well as direct
cleavage of fodrin (nonerythroid spectrin) (81). Together these two
events can be held responsible for the gross morphological changes
observed in programmed cell death. Although caspases have not been
directly linked with membrane events, the asymmetrical distribution of phosphatidylserine (PS) moieties is lost (80, 82) and the resultant
presentation of PS on the external surface of a dying cell facilitates
its engulfment (113) by professional or nonprofessional phagocytes,
thereby minimizing cellular debris and the possibility of an
inflammatory response.
|
Active caspase-3 is also responsible for cleavage of the inhibitor ICAD [Ref. 111; also identified as DFF45 (75)], which releases the caspase-dependent DNase [CAD (31); also DFF for DNA fragmentation factor (75)], the nuclease that gives rise to the DNA laddering that is a signature of apoptosis. These nuclear events in apoptosis have been the subject of some debate since the nucleus has been shown to be dispensable for many apoptotic deaths in a number of cell types by various stimuli (56, 95, 137), but the fact remains that most cells in a physiological setting have functional nuclei that must be properly disposed with the remainder of the cell and nuclear breakdown and DNA laddering have long been hallmarks of apoptosis.
Although the pathway described above is probably valid, recent evidence suggests that the Fas signaling pathway that leads to cell death is significantly more complex and involves at least two major pathways, termed type I and type II. The molecular decision to signal via one pathway or the other occurs at the level of the DISC. In type I cells, caspase-8 is recruited in sufficient amounts at the level of the DISC to directly activate caspase-3, thereby bypassing the need for mitochondrial cytochrome c release (114), whereas if caspase-8 in the DISC is present in lower levels, the pathway described initially occurs and this pathway is deemed type II. That is, caspase-8 cleaves bid, which then induces the release of mitochondrial cytochrome c. Cytochrome c release subsequently induces the formation of the apoptosome, which results in the feed-forward activation of the caspase-protease cascade.
The existence of type I and type II pathways helps explain initially
conflicting findings that, in some circumstances, bcl-2 is capable of
preventing Fas-mediated death, i.e., in type II cells but not type I
cells (114). Furthermore, recent studies in genetically targeted mice
support the possibility that the usage of type I and type II pathways
is determined by tissue specificity. Hepatocytes from
bid/
mice have been shown to be relatively
resistant to Fas-mediated death, yet thymocytes from
bid
/
mice were shown in the same study to be
sensitive to Fas-mediated cell death (145), suggesting that thymocytes
use the type I pathway whereas hepatocytes utilize the type II pathway.
In agreement, Yoshida et al. (147) demonstrated that thymocytes lacking
APAF-1 (a molecule that is predicted from Fig. 1 to be involved in the type II pathway) are extremely resistant to numerous apoptotic stimuli
yet sensitive to Fas-mediated death.
Finally, two other pathways have been implicated in Fas-mediated death. Although the relative importance of these two pathways is unclear and controversial, it should be stressed that more than one pathway for Fas-mediated cell death exists and this is important because, as we have observed with type I and type II cells, the pathway(s) leading to Fas-mediated death in lymphocytes (which is the most commonly described) may not be the same as that in cells found in the liver and gastrointestinal tract. In the first pathway, engagement of Fas has also been shown in some cells to lead to cell death by activation of the JNK pathway via DAXX (144) by a process that does not appear to involve FADD or caspase-8 (20). However, the relevance of Fas-DAXX interactions has been brought into question in light of the phenotype of the DAXX knockout mice (84). In a second pathway, engagement of Fas has been shown to induce rapid increase in ceramide (27, 133), which has been shown to be a potent intracellular mediator of cell death (99). However, if and how ceramide is linked to the presently known Fas-mediated death pathway is unclear. Ceramide levels have been shown to increase under numerous apoptotic stimuli (41, 46), and it is not yet clear whether the increase in ceramide observed after engagement of the Fas receptor is an active participant in the pathway leading to apoptotic cell death or merely a byproduct in dying cells.
It is important to note that not all Fas-bearing cells are susceptible to Fas-mediated killing. One mechanism of protection is by expression of inhibitors such as the inhibitor of apoptosis proteins (IAP) family of protease inhibitors that have been found to block the action of key caspases such as caspase-3, -7, and -9 (28). For example, HepG2 hepatocarcinoma cells are relatively resistant to Fas-mediated killing unless treated in the presence of actinomycin D, during which treatment there is a marked reduction in ILP, a member of the IAP family (128). Another inhibitor of Fas signaling is through FLICE-inhibitory protein (FLIP), which acts by binding to FADD in a nonsignaling complex, thus acting as a dominant negative caspase-8 (FLICE) (54). Elevated levels of c-FLIP have been proposed to impart Fas resistance in resting lymphocytes and may be coordinately downregulated after lymphocyte activation and during S phase of the cell cycle (2, 115). c-FLIP levels are elevated in lymphocytes in G1 phase, which corresponds with reduced sensitivity to death receptor signaling in these cells at this point in the cell cycle. A viral FLIP (v-FLIP) has been identified that is believed to contribute to a viral strategy to prevent cell death of infected cells, thus avoiding immune surveillance (134).
It is also worth mentioning that engagement of Fas on Fas-positive
cells does not lead necessarily to apoptosis or only to apoptosis.
Using Fas+ HT-29 colon cancer cell lines, Abreu-Martin et
al. (1) demonstrated that engagement of Fas by anti-Fas did not result
in apoptosis but instead led to interleukin (IL)-8 secretion.
Interestingly, the addition of interferon- made these cells
susceptible to Fas-mediated death, suggesting that Fas-positive cells
can be resistant to Fas-mediated cell death under normal conditions but
in certain inflammatory conditions can become susceptible. In addition,
Gao et al. (40) demonstrated that engagement of Fas on splenocytes led
to IL-10 secretion. In this later study, it is unclear whether engagement of Fas leads to apoptosis of splenocytes because resting splenocytes normally express very low levels of Fas and are resistant to Fas-mediated cell death.
Another mechanism to downregulate tissue effects of Fas-mediated killing is the expression of decoy receptors. DcR1 and DcR2 are membrane-bound receptors that compete for death ligand binding by DR4 and DR5 but do not transmit a death signal. In this way, a death ligand is rendered unable to engage the apoptotic pathway through a functional death receptor (5). Another decoy receptor, DcR3, is produced in a secreted form and binds competitively to FasL. The DcR3 gene is amplified in a number of colorectal carcinomas, and an increase in DcR3 by these tumors has been proposed to be responsible for immune evasion, thus giving the tumor an additional survival advantage (106).
In some physiological conditions hepatocytes have been found that produce a truncated variant of Fas lacking the transmembrane domain. mRNA encoding a secreted soluble Fas (sFas) has been detected in a number of hepatitis and hepatocellular carcinoma studies (92, 120). It is believed that, like a secreted decoy receptor, sFas binds FasL, thereby preventing engagement of surface Fas, which is required to transmit the death signal. However, without coordinate downregulation of membrane-bound Fas, the effects of sFas would be transient and act only in a limited microenvironment.
![]() |
IMPACT OF FAS AND FASL: LOCATION, LOCATION, AND LOCATION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Fas and FasL in lymphoid cells. Perhaps the best-characterized physiological system involving Fas/FasL-mediated apoptosis is that observed in lymphoid cells. A connection implicating Fas/FasL in lymphoid apoptosis was made when mice bearing the lpr (lymphoproliferative) and gld (generalized lymphoproliferative disorder) phenotypes (25, 94) were discovered to be associated with mutations in the Fas and FasL genes, respectively. Both lpr and gld mice develop lymphadenopathy and splenomegaly, and in some strains we see the penetrance of autoimmune disorders (94). Similarly, mutations of Fas and FasL in humans are associated with autoimmune lymphoproliferative syndrome (ALPS) types Ia and Ib, respectively (9, 67, 68, 79, 125).
A major role of Fas and FasL on lymphoid cells appears to be controlling immune responses by regulating the number of lymphocytes through a process known as activation-induced cell death (AICD) (16, 29, 57). After antigen-driven expansion of lymphocytes, there is an upregulation of FasL on the activated T cells that is required for subsequent death and removal of activated lymphocytes (139). Persistence of a population of activated T cells after the removal of antigen could lead to potential deleterious effects such as autoreactivity. Clearance of activated T cells through FasL has been demonstrated to occur in an autonomous fashion, suggesting a self-limiting feedback inherent in some activated lymphocytes (16). In addition to AICD, activated T cells can also be deleted by expression of FasL in peripheral, nonlymphoid tissues. This is discussed in detail below. It is important to remember that studies on Fas/FasL in controlling an immune response have been done largely on lymphocytes in the periphery or in vitro and not specifically in organs such as the liver and gastrointestinal tract. Although an uncontrolled lymphocyte response may have dire consequences indirectly on the liver and gastrointestinal system, the most potentially harmful effect from FasL present on lymphoid cells is its indiscriminant cytolytic activity toward Fas-positive cells. In many immune reactions lymphocytes (which are presumably activated and express FasL) infiltrate the intestine and liver, and it is in this manner that lymphoid FasL can cause injury in target cells in these organs.Soluble FasL.
Like most members of the TNF family of apoptosis-inducing ligands (with
the exception of LT-), FasL is expressed as a type II transmembrane
molecule (127), associated either with intracellular membranes of
secretory vesicles or with the plasma membrane, where it may mediate
apoptosis through the interaction with its receptor. It was first noted
that transmembrane TNF-
can be proteolytically cleaved by a
metalloprotease to its soluble form. Recently, the TNF-
-converting
enzyme (TACE) protease has been cloned (19), and specific inhibitors of
TACE are therapeutically used to block the generation of soluble
TNF-
in different diseases. Similar to TNF-
, most other members
of the family, including FasL, can be processed by metalloproteases
into their soluble form. Although soluble TNF-
has a
well-characterized inflammatory activity, the physiological role of
soluble FasL (sFasL) is less clear. sFasL still trimerizes efficiently
and thus still binds to its membrane-bound receptor. The cleavage site
of FasL has been recently identified (117). In 293 cells, FasL is
cleaved between amino acids 126 and 127 and the proteolytic processing
does not affect the domain responsible for trimerization. However,
sFasL has been found to be only a poor inducer of apoptosis and very
high concentrations are required to trigger apoptosis in otherwise
sensitive cells. Thus membrane anchoring of the molecule appears to be
important for the apoptosis-inducing activity of FasL. Although both
forms of FasL bind efficiently to their receptors, receptor-bound sFasL appears to be rapidly internalized and leads to the downregulation of
cell surface Fas receptor. Similar observations have been made with
other immunologically important receptors, including T-cell receptor
and chemokine receptors. sFasL may therefore have an antagonistic
rather than agonistic activity and may even compete for the
apoptosis-inducing activity of membrane-bound FasL (126, 131). In
contrast, if sFasL is further polymerized, e.g., through cross-linking
antibodies, it regains its apoptosis-inducing activity (117),
presumably through stabilization of the ligand-receptor complex on the
cell surface.
![]() |
FAS LIGAND IN NONLYMPHOID TISSUES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although the immune system was the first and is still the
best-characterized system in which Fas and FasL are principal mediators of apoptosis, a role for Fas/FasL in nonlymphoid tissues is becoming increasingly evident (Fig. 2).
French et al. (37) observed expression of FasL in nonlymphoid sites in
the developing mouse embryo and in adult mice. In addition to lymphoid
tissues (spleen and thymus), these researchers also detected
significant levels of FasL mRNA in nonlymphoid tissues at sites of
immune privilege (testes, uterus, and ovaries) and at sites that
accommodate frequent lymphocytic infiltration (small intestine, large
intestine, lung, and liver), suggesting, in addition to a role in AICD
as discussed above, a role for FasL in physiological cell turnover and
protection against potentially harmful lymphocytes. Two of the most
closely studied systems involving the expression of FasL in nonlymphoid tissue are the phenomena of immune privilege and peripheral deletion.
|
Immune privilege is the term given to sites that are receptive to transplant because of the lack of resident or infiltrating lymphocytes. It is believed that immune privilege is a mechanism to prevent the slightest inflammatory response that can accompany an immune response (42). For example, when an inflammatory response is generated in the eye, a principal site of immune privilege, there is a dramatic reduction in vision (34). Constitutive expression of FasL in immune privilege sites ensures that any Fas+ lymphocytes that infiltrate these tissues are removed rapidly and efficiently. FasL was shown to be important in immune privilege when Griffith et al. (43, 44) demonstrated that virus-infected cells injected into the anterior chamber of the eye were cleared rapidly and without resulting in recruitment of lymphocytes or granulocytes to the site of infection. Similar infection in the eyes of FasL-defective gld mice resulted in recruitment and lymphocytic infiltration followed by inflammation at the site of infection.
The FasL model of immune privilege has been employed as a technique to
avoid graft rejection. Bellgrau et al. (8) observed that
FasL+ Sertoli cells injected under the kidney capsule of
recipient mice were not rejected, whereas Sertoli cells from
gld mice did not survive transplantation. By virtue of the
presence of surface FasL, the graft is believed to defend itself
against host attack. This strategy, however, does not appear to be
universal, because FasL+ islet -cells transplanted under
the kidney capsule of allogeneic recipient mice resulted in a massive
granulocytic infiltration and efficient clearance of the graft (3). In
this experimental system, expression of FasL on
-cells did not
confer any resistance to rejection compared with that of FasL-negative
-cells.
Expression of FasL does not automatically confer immune privilege on a
tissue. In fact, under some circumstances, the presence of surface FasL
has been shown to evoke an inflammatory response. When Neuro-2a
neuroblastoma cells transfected to express FasL were injected into
syngeneic recipient mice, there was a major infiltration by neutrophils
resulting in inflammation at the site of injection (119). There was no
such inflammatory response if the donor cells were not expressing FasL,
if the animals were treated with neutralizing antibody to FasL, or if
the FasL-transfected Neuro-2a cells were introduced into lpr
mice. In similar model systems, it has been demonstrated that
rejection of FasL-bearing transplanted tumor cells in syngeneic hosts
was carried out by infiltrating CD8+ cytotoxic lymphocytes
(CTL) and natural killer (NK) cells (4, 118). The
inflammatory response observed in these situations appears to be due,
at least in part, to the effects of transforming growth factor
(TGF)- in the microenvironment of the donor cells. Chen
et al. (22) showed that the strong inflammatory response observed after
injection of CT26-CD95L into syngeneic hosts was suppressed if TGF-
was present at the site of injection. The suppressive effects of
TGF-
on the inflammatory response in this experimental system are
believed to be through inhibition of neutrophil activation.
After an antigenic stimulus is removed, the immune system is faced with
the task of removing activated lymphocytes from circulation (Fig.
3). Failure to do so often
leads to autoimmune and lymphoproliferative disorders. In fact, the
characterization of the lymphoproliferative (lpr) and
generalized lymphoproliferative disorder (gld)
phenotypes arise from mutations in the Fas and FasL genes,
respectively (25, 94). It is now clear that peripheral deletion of
activated lymphocytes is mediated by Fas/FasL interactions by one of
two mechanisms. AICD is a process by which lymphocytes act as both
effector and target cells in apoptosis, and it has been demonstrated
that lymphocytes, when properly activated, can induce apoptosis in an
autonomous fashion. A second mechanism of peripheral deletion has been
described recently (13) in which activated Fas-bearing lymphocytes are deleted after an upregulation of FasL expression by nonlymphoid tissues
at common sites of major lymphocytic infiltration, notably, hepatocytes
and intestinal epithelial cells. This model explains, at least in part,
the observation of splenomegaly in lpr and gld mice and
in humans with type I ALPS, which is attributed to genetic defects in
Fas or FasL.
|
![]() |
ROLE OF FAS/FASL IN DISEASES OF LIVER AND GASTROINTESTINAL SYSTEMS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Studying Fas/FasL in gut and liver disease: words of caution. When studying the role of Fas/FasL in gut and liver disease it is important to remember that demonstrating that cells found in diseased tissue express Fas and FasL is not sufficient to demonstrate that Fas-mediated cell death is involved. In fact, as discussed above, not all Fas-expressing cells are susceptible to Fas-mediated cell death (1), and thus it is preferable to demonstrate that Fas+ cells are susceptible to death through the use of either an anti-Fas monoclonal antibody (MAb) (1, 100, 101) or cross-linked sFasL (117).
Similarly, the presence of FasL on the cell membrane does not necessarily imply that the FasL expressed is functional (i.e., capable of mediating death of Fas-sensitive target cells). Depending on the type of tissue, membrane FasL in some tissues can be rapidly cleaved by metalloproteases (60) into a soluble and potentially less cytotoxic form. Furthermore, in an issue perhaps more relevant to tumor cells, mutations in FasL can result in normal levels of FasL expression on the surface, but the FasL that is expressed has lost its ability to induce Fas-mediated cell death. This appears to be the case with the gld mutation, where a point mutation results in a normal level of FasL expression but the FasL that is expressed is nonfunctional (130). Thus, if possible, it is preferable to demonstrate that the FasL that is expressed is capable of inducing death in Fas-sensitive target cells (72, 109). The specificity of cell death in these systems can readily be examined with the use of FasFc (17, 72) or anti-Fas blocking MAbs (47, 60) or by comparing the susceptibility of Fas-transfected and nontransfected target cells (109, 112). If Fas and FasL have a major role in diseases of the liver and gastrointestinal tract, it is probably more so in pathological apoptosis rather than homeostatic apoptosis. Although apoptosis plays a major role in the homeostasis of the liver and gastrointestinal tract, there have been to date no reports of increased liver and intestinal tumors in FasL- and Fas-mutated gld and lpr mice. There is, however, a possibility that Fas and FasL play a role in the homeostasis of the liver. Fas-null mice have been reported to have larger livers composed of hepatocytes with enlarged nuclei typical of senescent cells, suggesting that Fas/FasL may regulate the removal of unwanted old hepatocytes. Interestingly, these findings have not been reported in lpr mice, but it has been suggested that this is the result of leakiness in the lpr mutation, allowing some residual Fas signaling. There are several reasons to believe that the Fas/FasL system is of special importance in pathological disease of the liver and gastrointestinal system. First, many cells in the liver and gastrointestinal system have been shown to express Fas and be highly susceptible to Fas-mediated death. The hepatocytes in the liver appear to be especially susceptible to Fas-mediated death, because injection of anti-Fas induces massive injury to the liver and not elsewhere. In the gastrointestinal tract, T cells in human lamina propria of the colon have been shown to be more susceptible than T cells in the periphery to Fas-mediated apoptosis from either anti-Fas or anti-CD2 activation (11, 27) and IEC have been shown to express Fas and under certain conditions be sensitive to Fas-mediated cell death (45, 72, 112). Finally, in addition to being more susceptible to Fas-mediated death, intestinal lymphocytes, and under certain situations IEC, have been shown in several studies to be able to readily induce Fas-mediated death. Overall, these results suggest that the liver and gastrointestinal tract are organs that are primed for Fas-mediated injury (13, 27, 72).Fas/FasL in GVHD. GVHD is an immunologically mediated disease in which donor (graft) T cells recognize recipient (host) cells as foreign, thereby resulting in the death of host cells (reviewed in Ref. 35). The disease is manifested by systemic injury that results in depletion of host immune cells, wasting, and eventually death. GVHD is important in gastrointestinal and liver disease because the intestinal epithelium and liver hepatocytes are major targets of injury in this disease. Ponec et al. (107) recently reported the observation that intestinal lesions in human GVHD are characterized by apoptosis of intestinal crypt epithelial cells, resulting in crypt destruction. Injury to these two organs can potentially contribute to systemic symptoms because the intestinal epithelium and liver both serve as an important barrier in preventing the translocation of harmful toxins and bacteria found normally in the intestinal lumen. Furthermore, the intestinal epithelium serves as an absorptive organ for vital nutrients, and dysfunction can lead to diarrhea, malabsorption, and malnutrition.
Because GVHD is mediated primarily by donor T cells and T cells mediate cytotoxicity of target cells through two major mechanism of apoptosis, one dependent on perforin and the other dependent on FasL (15), it is reasonable to expect that a major mechanism of injury in GVHD is from FasL present on donor cells inducing death of Fas-positive host cells. Several studies have shown that FasL present on donor cells is involved in mediating some of the systemic symptoms seen in GVHD. Via et al. (140) demonstrated that depletion of host lymphocytes is in part dependent on donor FasL. In addition, two groups have shown that wasting and lethality are significantly attenuated in GVHD when donor cells lack functional FasL (7, 15). However, because most studies using murine models focus on the systemic complication (this is probably because it is difficult to accurately quantify organ injury), it is not evident from these studies whether Fas and FasL play a role in liver and gastrointestinal complications seen in GVHD. In perhaps the only study that addressed the involvement of Fas/FasL in inducing liver injury during GVHD, Baker et al. (7) demonstrated that skin and liver injury in GVHD is almost completely dependent on functional donor FasL, but they stated that they did not observe any differences in intestinal injury. However, how closely the intestine was examined is not clear. Using neutralizing MAbs that block Fas- and TNF-mediated death, Hattori et al. (47) demonstrated that a severe form of intestinal injury seen in GVHD was more likely to be the result of TNF than of FasL. Although we can conclude that Fas/FasL probably does not play a major role in this model of severe intestinal GVHD, it is probably premature to conclude that Fas and FasL have no role in inducing intestinal epithelial injury in GVHD because it is unclear whether the neutralizing anti-Fas ligand antibody used by Hattori et al. might have been more effective in preventing intestinal epithelial injury if used at a larger dose or in a milder form of intestinal GVHD. Using a different model of murine GVHD in which intestinal epithelial injury is milder and quantitated by IEC apoptosis, two groups have demonstrated that donor T cells infiltrating the intestinal epithelium during GVHD are very capable of mediating IEC apoptosis through largely a Fas-mediated process (72, 112). It is likely that both TNF and FasL play a role in inducing intestinal epithelial injury during GVHD, but the importance of each may depend on which model is examined and on how epithelial injury is quantified.Role of Fas/FasL in inflammatory bowel disease. Most studies implicating Fas/FasL in human inflammatory bowel disease have been performed on ulcerative colitis rather than Crohn's disease. The role of Fas/FasL in ulcerative colitis is centered on the hypothesis that Fas+ IEC are targeted by FasL+ lymphocytes resulting in IEC apoptosis. A corollary to this hypothesis is that injury to the IEC subsequently leads to intestinal lymphocytes being exposed to luminal antigens resulting in an uncontrolled inflammatory response. In agreement with this hypothesis, apoptosis of IEC in the crypts has been reported in ulcerative colitis (55, 124) and Fas and FasL have been shown to be upregulated on IEC and intestinal lymphocytes, respectively, in ulcerative colitis (15, 89, 138).
In a different proposed role for Fas/FasL in Crohn's disease, two groups made the interesting observation that lymphocytes found in the inflamed tissue of Crohn's patients expressed Fas yet were relatively resistant to Fas-mediated cell death compared with lymphocytes from noninflamed controls (10, 53). Thus, if Fas/FasL is involved in the eradication of potentially harmful Fas+ T cells in the intestine, then the resistance of intestinal lymphocytes to Fas-mediated death in Crohn's disease may allow potentially harmful lymphocytes to survive longer and induce more damage of the intestine. Interestingly, several studies have shown that nonlymphoid cells found in the intestine are capable of expressing FasL. Paneth cells appear to constitutively express FasL, and in ulcerative colitis IEC express FasL (89). Although the significance of these nonlymphoid cells expressing FasL is speculative, it is possible that FasL expression here is a protective response by these nonlymphoid cells against harmful neighboring Fas+ T cells (analogous to the role of FasL in immune privilege discussed above). Conversely, FasL expression can induce apoptosis of surrounding cells, thereby contributing to the pathogenesis of ulcerative colitis. Despite the availability of numerous models of murine inflammatory bowel disease, very few studies have evaluated the role of Fas/FasL in these models. In a murine model of colitis in which CD4+ cells were transferred into immune-compromised SCID mice, which essentially have no B or T cells, Bonhagen et al. (14) demonstrated that CD4+ cells that infiltrate the colon express FasL and are capable of killing target cells in vitro through a Fas-mediated pathway. In a similar model of murine colitis, in which nonallogeneic bone marrow cells are transferred into T cell- and NK cell-deficient Tg26 mice (BMLiver disease. One of the early indications that Fas/FasL may be important in the maintenance of hepatic homeostasis and therefore in the development of hepatic disorders was the observation that anti-Fas antibody, when administered to mice in vivo, caused massive hepatic apoptosis resulting in hepatic failure and death soon thereafter (101). It was postulated that the effects of anti-Fas antibody were caused by the induction of apoptosis of hepatic lymphocytes; however, it soon became evident that the issue was more complex. Given the high susceptibility of the liver to injury from anti-Fas antibody, it is not surprising that the role of Fas/FasL has been the intense topic of numerous studies of diseases of the liver. It is unlikely, however, that Fas/FasL plays a major role in normal hepatocellular turnover because lpr and gld mice do not display an increased incidence of liver neoplasia despite nonfunctional Fas or FasL (25).
Liver pathologies that arise from dysfunctional Fas or FasL are more likely the result of infiltrating or resident lymphocytes. There are two views on the role of the liver in the deletion of peripheral lymphocytes. It is either a site where dying lymphocytes home and are subsequently removed from action or a site where live, activated lymphocytes are induced to die and are deleted. Regardless of the contribution of each of the scenarios, the liver has been shown to be a site for clearance of lymphocytes (52). Also, if there is a reduction in peripheral deletion such as in the lpr and gld mouse models, as well as in GVHD, the liver is one of the target organs that suffer from distress inflicted by autoreactive or inappropriately active lymphocytes.Fas/FasL in liver transplants. Because of the high sensitivity of the liver to Fas-mediated injury and a major role of CTL in graft rejection, it is not surprising that several studies have focused on the role of Fas/FasL liver transplant rejection (32, 59, 70, 71). In a rodent model of liver transplantation in which donor hepatocytes are injected into host spleen, Kawahara et al. (59) demonstrated that host FasL in the spleen plays a role in rejection of donor hepatocytes. However, from their studies as well as others (70) it appears that the Fas/FasL system is not the only mechanism involved.
Interestingly, despite the high susceptibility of hepatocytes to undergo Fas-mediated death, the issue of whether FasL can be present on donor hepatocytes during rejection or whether FasL+ hepatocytes can help prevent liver graft rejection is still unresolved. FasL mRNA levels have been shown to increase in a transplanted liver undergoing rejection, but it is unclear from these studies whether the increase in FasL mRNA is from infiltrating donor lymphocytes of host hepatocytes (32). At first thought, the idea of hepatocytes upregulating FasL expression to prevent rejection appears unlikely because expression of FasL by adenoviral transfection has been shown to result in massive hepatitis and death (90). However, using liposome vesicles to transfect various levels of FasL into the liver, Li et al. (71) demonstrated that relatively low levels of FasL on hepatocytes did not induce hepatitis and, perhaps more interesting, demonstrated that livers expressing low levels of FasL survived longer when transplanted into allogeneic-mismatch recipients. Finally, Krams et al. (66) made the observation that the liver is capable of producing sFas, which is capable of blocking Fas-FasL interactions and hence Fas-mediated death. Perhaps more intriguing, sFas levels were found to be lower in patients undergoing liver graft rejection compared with patients with stable grafts. This suggests that sFas may provide protection from Fas-mediated injury during rejection and that lower levels of sFas produced by the liver may predispose a liver graft to rejection.Hepatitis B and C. Numerous studies have implicated Fas and FasL in both hepatitis B and C. Although human hepatocytes appear by histochemical studies to express relatively low levels of Fas, they also appear to be extremely sensitive to Fas-mediated cell death (38). Fas expression has been shown to be upregulated on hepatocytes from both hepatitis B and C (39, 48, 88, 102), and the degree of Fas expression correlates with the severity and location of liver inflammation. However, it remains unclear whether upregulation of Fas expression contributes to the pathogenesis of viral liver disease. One study showed that infection of a hepatoma cell line with the hepatitis C core protein increased susceptibility to Fas-mediated death, yet this did not appear to be the result of increased Fas expression (110).
Lymphocytes found in the inflamed region of the liver in viral hepatitis have been shown to express FasL (48, 85). Presumably, it is FasL on these lymphocytes mediating the death of Fas+ hepatocytes that contributes to liver injury, resulting in end-stage liver disease. In agreement with this hypothesis, Kondo et al. (64) demonstrated that CTL specific for the viral hepatitis B surface antigen induced acute liver disease through a Fas-mediated mechanism in transgenic mice expressing the hepatitis B surface antigen on hepatocytes.Alcohol liver disease. Interestingly, there have been very few studies on the role of Fas/FasL in alcohol liver disease. One of these reports demonstrated that Fas is minimally upregulated in alcohol liver disease (38); however, most of the liver examined appeared to have been at the end stage of alcohol liver disease (cirrhosis), where there is normally very little inflammation. Thus it is plausible that Fas expression can be upregulated in acute alcohol hepatitis, a stage in which inflammation is more prominent. Interestingly, the authors reported that hepatocytes from alcohol liver cirrhosis expressed high levels of FasL; however, any contribution to the disease is speculative at this time.
Murine models of hepatitis. In several murine models of hepatitis, several groups have demonstrated that Fas/FasL plays an important role in most inflammatory hepatitis. Using mice that lack functional Fas (lpr) and FasL (gld), two groups have demonstrated that hepatitis induced by injection of the potent T cell stimulator concanavalin A is mediated by Fas (118, 129). In support of the involvement of Fas in murine hepatitis, Kondo et al. (64) demonstrated that Fas-null mice were resistant to the hepatitis induced by Propionibacterium infection and subsequent lipopolysaccharide challenge. Finally, Fleck et al. (36) demonstrated that the hepatitis seen in murine cytomegalovirus is less severe in lpr mice.
Wilson's disease. Copper is usually present as a trace element required for optimal function of such enzymes as cytochrome oxidase and superoxide dismutase, among others, and when present in excess can lead to protein and lipid oxidation that, in turn, leads to production of reactive oxygen species. Wilson's disease (WD) is an autosomal recessive disorder that results from copper overload (116), and in 1993 several groups identified the underlying cause of WD as mutations in a gene encoding a copper-transporting P-type ATPase (18, 21, 105, 132). Clinically, WD manifests with hepatolenticular degeneration in early stages followed by decreased motor control as copper excess accumulates in the brain. A link between copper metabolism deficiencies in WD and apoptosis was drawn by Strand et al. (123), who noted that free radicals observed in cells with excess copper (II) ions could be functioning in a biochemical manner similar to free radicals frequently generated during apoptosis. Using HepG2 hepatocarcinoma cells treated with exogenous copper, these researchers demonstrated that Cu2+-induced apoptosis acts through Fas. Treatment of HepG2 cells with 100 µM Cu2+ resulted in an induced upregulation of FasL, and death in this system was inhibited by the broad-spectrum caspase inhibitor z-VAD-fmk.
Biliary disease. There is also a growing body of evidence that Fas/FasL plays a role in biliary disease in mice. Apoptosis of rodent hepatocytes by bile salt or from hepatic ligation appears to be Fas mediated (33, 87). Finally, Chen et al. (23) recently reported an interesting observation that apoptosis of a biliary epithelial cell line with Cryptosporidia is partially Fas mediated and that the mechanism is in part due to upregulation of FasL on the biliary cells.
Fas/FasL in tumors of liver and gastrointestinal tract. In the absence of T cells, Fas-deficient mice have been shown to develop malignant and lethal B cell lymphoma, suggesting that Fas can function as a tumor suppressor (104). As of yet, there have been no reports of liver and gastrointestinal tumors in these mice, which raises doubt as to whether Fas can function as a tumor suppressor in these organs. Nevertheless, the notion that hepatoma and colon cancer can escape immune surveillance by FasL-bearing tumor-infiltrating lymphocytes by becoming resistant to Fas-mediated death is an attractive hypothesis. Several hepatoma and colon cancer cell lines have been shown to be resistant to Fas-mediated death (96, 136). One interesting mechanism by which colon cancers become resistant to Fas-induced cell death is through the expression of "decoy receptors," which bind and block FasL (106).
Another intriguing role for Fas/FasL in cancer has been proposed and termed "Fas counterattack." According to this theory, tumor cells express FasL, enabling them to evade immune destruction by inducing apoptosis of activated Fas+ T cells. Several colon cancer cell lines have been shown to express functional FasL (98). In addition, expression of functional FasL has been reported to be found more commonly on hepatic metastatic colon cancer than primary colon cancer, raising the possibility that the presence of FasL enables some colon cancer to more easily infiltrate the Fas-sensitive liver (78, 121, 146). Although these studies suggest that FasL expression in colon cancer is advantageous to the tumor, it is not entirely clear that this occurs in vivo. Chen et al. (22) demonstrated that overexpression of FasL in the CT-26 colon cancer line resulted in it being more readily rejected when transferred into immune-deficient mice. ![]() |
CONCLUDING REMARKS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There is significant evidence that Fas and FasL play a significant role
in the pathogenesis of a wide spectrum of liver and gastrointestinal
disease. Although a major mechanism of tissue destruction involving
Fas/FasL is through the death of Fas-positive target cells by
FasL+ lymphoid cells, there are several important issues
that require more clarification. First, there is growing evidence that
nonlymphoid cells found in the liver and gastrointestinal organs
express FasL. Whether the expression of nonlymphoid FasL in these
organs will exacerbate or ameliorate liver and gastrointestinal
diseases remains to be shown. Second, sFasL and sFas have both been
shown to be increased in several liver and gastrointestinal diseases.
However, whether sFas and sFasL play an important role in these
diseases in vivo remains to be shown. Finally, it is important to
remember that Fas is only one member of a growing list of the TNF
receptor family of proteins that are capable of inducing apoptosis in
the presence of their respective ligand. Thus future studies addressing the role of other members of the TNF receptor apoptosis family (TNFR1,
DR3/TRAMP/WSL, and DR4, DR5) with their respective TNF-like ligands
(TNF and LT-, TWEAK/APO-3L, and TRAIL/APO-2L) in the gastrointestinal and liver diseases discussed here will be of extreme interest.
![]() |
ACKNOWLEDGEMENTS |
---|
The excellent secretarial skill of L. Gentry and T. Smith and words of encouragement from Dr. W. A. Olsen are greatly appreciated.
![]() |
FOOTNOTES |
---|
M. J. Pinkoski is a postdoctoral fellow of the Medical Research Council of Canada. This is manuscript no. 327 of the La Jolla Institute for Allergy and Immunology.
Address for reprint requests and other correspondence: Dr. Tesu Lin, Searle #10-541, GI Division, Dept. of Medicine, Northwestern Univ., 303E Chicago, Chicago, IL 60611 (E-mail: ndorachan{at}aol.com).
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abreu-Martin, M. T.,
A. Vidrich,
D. H. Lynch,
and
S. R. Targan.
Divergent induction of apoptosis and IL-8 secretion in HT-29 cells in response to TNF-alpha and ligation of Fas antigen.
J. Immunol.
155:
4147-4154,
1995[Abstract].
2.
Algeciras-Schimnich, A.,
T. S. Griffith,
D. H. Lynch,
and
C. V. Paya.
Cell cycle-dependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis.
J. Immunol.
162:
5205-5211,
1999
3.
Allison, J.,
H. M. Georgiou,
A. Strasser,
and
D. L. Vaux.
Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts.
Proc. Natl. Acad. Sci. USA
94:
3943-3947,
1997
4.
Arai, H.,
D. Gordon,
E. G. Nabel,
and
G. J. Nabel.
Gene transfer of Fas ligand induces tumor regression in vivo.
Proc. Natl. Acad. Sci. USA
94:
13862-13867,
1997
5.
Ashkenazi, A.,
and
V. M. Dixit.
Apoptosis control by death and decoy receptors.
Curr. Opin. Cell Biol.
11:
255-260,
1999[ISI][Medline].
6.
Ashkenazi, A.,
and
V. M. Dixit.
Death receptors: signaling and modulation.
Science
281:
1305-1308,
1998
7.
Baker, M. B.,
N. H. Altman,
E. R. Podack,
and
R. B. Levy.
The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice.
J. Exp. Med.
183:
2645-2656,
1996[Abstract].
8.
Bellgrau, D.,
D. Gold,
H. Selawry,
J. Moore,
A. Franzusoff,
and
R. C. Duke.
A role for CD95 ligand in preventing graft rejection.
Nature
377:
630-632,
1995[ISI][Medline].
9.
Bettinardi, A.,
D. Brugnoni,
E. Quiros-Roldan,
A. Malagoli,
S. La Grutta,
A. Correra,
and
L. D. Notarangelo.
Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.
Blood
89:
902-909,
1997
10.
Boirivant, M.,
M. Marini,
G. Di Felice,
A. M. Pronio,
C. Montesani,
R. Tersigni,
and
W. Strober.
Lamina propria T cells in Crohn's disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis.
Gastroenterology
116:
557-565,
1999[ISI][Medline].
11.
Boirivant, M.,
R. Pica,
R. DeMaria,
R. Testi,
F. Pallone,
and
W. Strober.
Stimulated human lamina propria T cells manifest enhanced Fas-mediated apoptosis.
J. Clin. Invest.
98:
2616-2622,
1996
12.
Boldin, M. P.,
T. M. Goncharov,
Y. V. Goltsev,
and
D. Wallach.
Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.
Cell
85:
803-815,
1996[ISI][Medline].
13.
Bonfoco, E.,
P. M. Stuart,
T. Brunner,
T. Lin,
T. S. Griffith,
Y. Gao,
H. Nakajima,
P. A. Henkart,
T. A. Ferguson,
and
D. R. Green.
Inducible nonlymphoid expression of Fas ligand is responsible for superantigen-induced peripheral deletion of T cells.
Immunity
9:
711-720,
1998[ISI][Medline].
14.
Bonhagen, K.,
S. Thoma,
P. Bland,
S. Bregenholt,
A. Rudolphi,
M. H. Claesson,
and
J. Reimann.
Cytotoxic reactivity of gut lamina propria CD4+ alpha beta T cells in SCID mice with colitis.
Eur. J. Immunol.
26:
3074-3083,
1996[ISI][Medline].
15.
Braun, M. Y.,
B. Lowin,
L. French,
H. Acha-Orbea,
and
J. Tschopp.
Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease.
J. Exp. Med.
183:
657-661,
1996[Abstract].
16.
Brunner, T.,
R. J. Mogil,
D. LaFace,
N. J. Yoo,
A. Mahboubi,
F. Echeverri,
S. J. Martin,
W. R. Force,
D. H. Lynch,
C. F. Ware,
and
D. R. Green.
Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation- induced apoptosis in T-cell hybridomas.
Nature
373:
441-444,
1995[ISI][Medline].
17.
Brunner, T.,
N. J. Yoo,
D. LaFace,
C. F. Ware,
and
D. R. Green.
Activation-induced cell death in murine T cell hybridomas. Differential regulation of Fas (CD95) versus Fas ligand expression by cyclosporin A and FK506.
Int. Immunol.
8:
1017-1026,
1996[Abstract].
18.
Bull, P. C.,
G. R. Thomas,
J. M. Rommens,
J. R. Forbes,
and
D. W. Cox.
The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.
Nat. Genet.
5:
327-337,
1993[ISI][Medline].
19.
Cerretti, D. P.,
K. Poindexter,
B. J. Castner,
G. Means,
N. G. Copeland,
D. J. Gilbert,
N. A. Jenkins,
R. A. Black,
and
N. Nelson.
Characterization of the cDNA and gene for mouse tumour necrosis factor alpha converting enzyme (TACE/ADAM17) and its location to mouse chromosome 12 and human chromosome 2p25.
Cytokine
11:
541-551,
1999[ISI][Medline].
20.
Chang, H. Y.,
X. Yang,
and
D. Baltimore.
Dissecting Fas signaling with an altered-specificity death-domain mutant: requirement of FADD binding for apoptosis but not Jun N-terminal kinase activation.
Proc. Natl. Acad. Sci. USA
96:
1252-1256,
1999
21.
Chelly, J.,
and
A. P. Monaco.
Cloning the Wilson disease gene.
Nat. Genet.
5:
317-318,
1993[ISI][Medline].
22.
Chen, J. J.,
Y. Sun,
and
G. J. Nabel.
Regulation of the proinflammatory effects of Fas ligand (CD95L).
Science
282:
1714-1717,
1998
23.
Chen, X. M.,
S. A. Levine,
P. Tietz,
E. Krueger,
M. A. McNiven,
D. M. Jefferson,
M. Mahle,
and
N. F. LaRusso.
Cryptosporidium parvum is cytopathic for cultured human biliary epithelia via an apoptotic mechanism.
Hepatology
28:
906-913,
1998[ISI][Medline].
24.
Cheng, J.,
T. Zhou,
C. Liu,
J. P. Shapiro,
M. J. Brauer,
M. C. Kiefer,
P. J. Barr,
and
J. D. Mountz.
Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule.
Science
263:
1759-1762,
1994[ISI][Medline].
25.
Cohen, P. L.,
and
R. A. Eisenberg.
Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease.
Annu. Rev. Immunol.
9:
243-269,
1991[ISI][Medline].
26.
Das, H.,
S. Imoto,
T. Murayama,
K. Kajimoto,
T. Sugimoto,
T. Isobe,
T. Nakagawa,
R. Nishimura,
and
T. Koizumi.
Levels of soluble FasL and FasL gene expression during the development of graft-versus-host disease in DLT-treated patients.
Br. J. Haematol.
104:
795-800,
1999[ISI][Medline].
27.
De Maria, R.,
M. Boirivant,
M. G. Cifone,
P. Roncaioli,
M. Hahne,
J. Tschopp,
F. Pallone,
A. Santoni,
and
R. Testi.
Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation.
J. Clin. Invest.
97:
316-322,
1996
28.
Deveraux, Q. L.,
and
J. C. Reed.
IAP family proteinssuppressors of apoptosis.
Genes Dev.
13:
239-252,
1999
29.
Dhein, J.,
H. Walczak,
C. Baumler,
K. M. Debatin,
and
P. H. Krammer.
Autocrine T-cell suicide mediated by APO-1/(Fas/CD95).
Nature
373:
438-441,
1995[ISI][Medline].
30.
Ellis, R. E.,
J. Y. Yuan,
and
H. R. Horvitz.
Mechanisms and functions of cell death.
Annu. Rev. Cell Biol.
7:
663-698,
1991[ISI].
31.
Enari, M.,
H. Sakahira,
H. Yokoyama,
K. Okawa,
A. Iwamatsu,
and
S. Nagata.
A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD.
Nature
391:
43-50,
1998[ISI][Medline].
32.
Fandrich, F.,
X. Lin,
X. Zhu,
R. Parwaresch,
B. Kremer,
and
D. Henne-Bruns.
Spontaneous liver graft acceptance is mediated by intragraft FAS-ligand expression and viable passenger leukocytes.
Transplant. Proc.
30:
2360-2361,
1998[ISI][Medline].
33.
Faubion, W. A.,
M. E. Guicciardi,
H. Miyoshi,
S. F. Bronk,
P. J. Roberts,
P. A. Svingen,
S. H. Kaufmann,
and
G. J. Gores.
Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas.
J. Clin. Invest.
103:
137-145,
1999
34.
Ferguson, T. A.,
and
T. S. Griffith.
A vision of cell death: insights into immune privilege.
Immunol. Rev.
156:
167-184,
1997[ISI][Medline].
35.
Ferrara, J. L.,
and
H. J. Deeg.
Graft-versus-host disease.
N. Engl. J. Med.
324:
667-674,
1991[ISI][Medline].
36.
Fleck, M.,
E. R. Kern,
T. Zhou,
J. Podlech,
W. Wintersberger,
C. K. d. Edwards,
and
J. D. Mountz.
Apoptosis mediated by Fas but not tumor necrosis factor receptor 1 prevents chronic disease in mice infected with murine cytomegalovirus.
J. Clin. Invest.
102:
1431-1443,
1998
37.
French, L. E.,
M. Hahne,
I. Viard,
G. Radlgruber,
R. Zanone,
K. Becker,
C. Muller,
and
J. Tschopp.
Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover.
J. Cell Biol.
133:
335-343,
1996[Abstract].
38.
Galle, P. R.,
W. J. Hofmann,
H. Walczak,
H. Schaller,
G. Otto,
W. Stremmel,
P. H. Krammer,
and
L. Runkel.
Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage.
J. Exp. Med.
182:
1223-1230,
1995[Abstract].
39.
Galle, P. R.,
and
P. H. Krammer.
CD95-induced apoptosis in human liver disease.
Semin. Liver Dis.
18:
141-151,
1998[ISI][Medline].
40.
Gao, Y.,
J. M. Herndon,
H. Zhang,
T. S. Griffith,
and
T. A. Ferguson.
Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis.
J. Exp. Med.
188:
887-896,
1998
41.
Genestier, L.,
A. F. Prigent,
R. Paillot,
L. Quemeneur,
I. Durand,
J. Banchereau,
J. P. Revillard,
and
N. Bonnefoy-Berard.
Caspase-dependent ceramide production in Fas- and HLA class I-mediated peripheral T cell apoptosis.
J. Biol. Chem.
273:
5060-5066,
1998
42.
Green, D. R.,
and
C. F. Ware.
Fas-ligand: privilege and peril.
Proc. Natl. Acad. Sci. USA
94:
5986-5990,
1997
43.
Griffith, T. S.,
T. Brunner,
S. M. Fletcher,
D. R. Green,
and
T. A. Ferguson.
Fas ligand-induced apoptosis as a mechanism of immune privilege.
Science
270:
1189-1192,
1995[Abstract].
44.
Griffith, T. S.,
X. Yu,
J. M. Herndon,
D. R. Green,
and
T. A. Ferguson.
CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance.
Immunity
5:
7-16,
1996[ISI][Medline].
45.
Guy-Grand, D.,
J. P. DiSanto,
P. Henchoz,
M. Malassis-Seris,
and
P. Vassalli.
Small bowel enteropathy: role of intraepithelial lymphocytes and of cytokines (IL-12, IFN-gamma, TNF) in the induction of epithelial cell death and renewal.
Eur. J. Immunol.
28:
730-744,
1998[ISI][Medline].
46.
Haimovitz-Friedman, A.,
C. C. Kan,
D. Ehleiter,
R. S. Persaud,
M. McLoughlin,
Z. Fuks,
and
R. N. Kolesnick.
Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis.
J. Exp. Med.
180:
525-535,
1994[Abstract].
47.
Hattori, K.,
T. Hirano,
H. Miyajima,
N. Yamakawa,
M. Tateno,
K. Oshimi,
N. Kayagaki,
H. Yagita,
and
K. Okumura.
Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies.
Blood
91:
4051-4055,
1998
48.
Hayashi, N.,
and
E. Mita.
Fas system and apoptosis in viral hepatitis.
J. Gastroenterol. Hepatol.
12:
S223-S226,
1997[ISI][Medline].
49.
Hendry, J. H.,
and
C. S. Potten.
Cryptogenic cells and proliferative cells in intestinal epithelium.
Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med.
25:
583-588,
1974[Medline].
50.
Hengartner, M. O.,
and
H. R. Horvitz.
Programmed cell death in Caenorhabditis elegans.
Curr. Opin. Genet. Dev.
4:
581-586,
1994[Medline].
51.
Hermos, J. A.,
M. Mathan,
and
J. S. Trier.
DNA synthesis and proliferation by villous epithelial cells in fetal rats.
J. Cell Biol.
50:
255-258,
1971
52.
Huang, L.,
G. Soldevila,
M. Leeker,
R. Flavell,
and
I. N. Crispe.
The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo.
Immunity
1:
741-749,
1994[ISI][Medline].
53.
Ina, K.,
J. Itoh,
K. Fukushima,
K. Kusugami,
T. Yamaguchi,
K. Kyokane,
A. Imada,
D. G. Binion,
A. Musso,
G. A. West,
G. M. Dobrea,
T. S. McCormick,
E. G. Lapetina,
A. D. Levine,
C. A. Ottaway,
and
C. Fiocchi.
Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance.
J. Immunol.
163:
1081-1090,
1999
54.
Irmler, M.,
M. Thome,
M. Hahne,
P. Schneider,
K. Hofmann,
V. Steiner,
J. L. Bodmer,
M. Schroter,
K. Burns,
C. Mattmann,
D. Rimoldi,
L. E. French,
and
J. Tschopp.
Inhibition of death receptor signals by cellular FLIP.
Nature
388:
190-195,
1997[ISI][Medline].
55.
Iwamoto, M.,
T. Koji,
K. Makiyama,
N. Kobayashi,
and
P. K. Nakane.
Apoptosis of crypt epithelial cells in ulcerative colitis.
J. Pathol.
180:
152-159,
1996[ISI][Medline].
56.
Jacobson, M. D.,
J. F. Burne,
and
M. C. Raff.
Programmed cell death and Bcl-2 protection in the absence of a nucleus.
EMBO J.
13:
1899-1910,
1994[Abstract].
57.
Ju, S. T.,
D. J. Panka,
H. Cui,
R. Ettinger,
M. el-Khatib,
D. H. Sherr,
B. Z. Stanger,
and
A. Marshak-Rothstein.
Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation.
Nature
373:
444-448,
1995[ISI][Medline].
58.
Kanda, Y.,
Y. Tanaka,
K. Shirakawa,
T. Yatomi,
N. Nakamura,
M. Kami,
T. Saito,
K. Izutsu,
T. Asai,
K. Yuji,
S. Ogawa,
H. Honda,
K. Mitani,
S. Chiba,
Y. Yazaki,
and
H. Hirai.
Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease.
Bone Marrow Transplant.
22:
751-754,
1998[ISI][Medline].
59.
Kawahara, T.,
S. Kasai,
H. Yagita,
M. Sawa,
K. Kato,
M. Azuma,
A. Nakajima,
K. Okumura,
S. Futagawa,
and
M. Mito.
Critical role of Fas/Fas ligand interaction in CD28-independent pathway of allogeneic murine hepatocyte rejection.
Hepatology
26:
944-948,
1997[ISI][Medline].
60.
Kayagaki, N.,
A. Kawasaki,
T. Ebata,
H. Ohmoto,
S. Ikeda,
S. Inoue,
K. Yoshino,
K. Okumura,
and
H. Yagita.
Metalloproteinase-mediated release of human Fas ligand.
J. Exp. Med.
182:
1777-1783,
1995[Abstract].
61.
Kerr, J. F.,
A. H. Wyllie,
and
A. R. Currie.
Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.
Br. J. Cancer
26:
239-257,
1972[ISI][Medline].
62.
Kluck, R. M.,
E. Bossy-Wetzel,
D. R. Green,
and
D. D. Newmeyer.
The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis.
Science
275:
1132-1136,
1997
63.
Kluck, R. M.,
S. J. Martin,
B. M. Hoffman,
J. S. Zhou,
D. R. Green,
and
D. D. Newmeyer.
Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system.
EMBO J.
16:
4639-4649,
1997
64.
Kondo, T.,
T. Suda,
H. Fukuyama,
M. Adachi,
and
S. Nagata.
Essential roles of the Fas ligand in the development of hepatitis.
Nat. Med.
3:
409-413,
1997[ISI][Medline].
65.
Kothakota, S.,
T. Azuma,
C. Reinhard,
A. Klippel,
J. Tang,
K. Chu,
T. J. McGarry,
M. W. Kirschner,
K. Koths,
D. J. Kwiatkowski,
and
L. T. Williams.
Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis.
Science
278:
294-298,
1997
66.
Krams, S. M.,
C. K. Fox,
P. R. Beatty,
S. Cao,
J. C. Villanueva,
C. O. Esquivel,
and
O. M. Martinez.
Human hepatocytes produce an isoform of FAS that inhibits apoptosis.
Transplantation
65:
713-721,
1998[ISI][Medline].
67.
Lamy, T.,
J. H. Liu,
T. H. Landowski,
W. S. Dalton,
and
T. P. Loughran, Jr.
Dysregulation of CD95/CD95 ligand-apoptotic pathway in CD3(+) large granular lymphocyte leukemia.
Blood
92:
4771-4777,
1998
68.
Landowski, T. H.,
N. Qu,
I. Buyuksal,
J. S. Painter,
and
W. S. Dalton.
Mutations in the Fas antigen in patients with multiple myeloma.
Blood
90:
4266-4270,
1997
69.
Li, P.,
D. Nijhawan,
I. Budihardjo,
S. M. Srinivasula,
M. Ahmad,
E. S. Alnemri,
and
X. Wang.
Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.
Cell
91:
479-489,
1997[ISI][Medline].
70.
Li, X. K.,
Y. Kita,
A. Tamura,
S. Enosawa,
H. Amemiya,
and
S. Suzuki.
Activation of Fas and perforin pathways in rat liver allograft rejection.
Transplant. Proc.
30:
19-21,
1998[ISI][Medline].
71.
Li, X. K.,
T. Okuyama,
A. Tamura,
S. Enosawa,
Y. Kaneda,
S. Takahara,
N. Funashima,
M. Yamada,
H. Amemiya,
and
S. Suzuki.
Prolonged survival of rat liver allografts transfected with Fas ligand-expressing plasmid.
Transplantation
66:
1416-1423,
1998[ISI][Medline].
72.
Lin, T.,
T. Brunner,
B. Tietz,
J. Madsen,
E. Bonfoco,
M. Reaves,
M. Huflejt,
and
D. R. Green.
Fas ligand-mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease.
J. Clin. Invest.
101:
570-577,
1998
73.
Liu, Q. Y.,
M. A. Rubin,
C. Omene,
S. Lederman,
and
C. A. Stein.
Fas ligand is constitutively secreted by prostate cancer cells in vitro.
Clin. Cancer Res.
4:
1803-1811,
1998[Abstract].
74.
Liu, X.,
C. N. Kim,
J. Yang,
R. Jemmerson,
and
X. Wang.
Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c.
Cell
86:
147-157,
1996[ISI][Medline].
75.
Liu, X.,
P. Li,
P. Widlak,
H. Zou,
X. Luo,
W. T. Garrard,
and
X. Wang.
The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis.
Proc. Natl. Acad. Sci. USA
95:
8461-8466,
1998
76.
Los, M.,
S. Wesselborg,
and
K. Schulze-Osthoff.
The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice.
Immunity
10:
629-639,
1999[ISI][Medline].
77.
Luo, X.,
I. Budihardjo,
H. Zou,
C. Slaughter,
and
X. Wang.
Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
Cell
94:
481-490,
1998[ISI][Medline].
78.
Mann, B.,
A. Gratchev,
C. Bohm,
M. L. Hanski,
H. D. Foss,
G. Demel,
B. Trojanek,
I. Schmidt-Wolf,
H. Stein,
E. O. Riecken,
H. J. Buhr,
and
C. Hanski.
FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas.
Br. J. Cancer
79:
1262-1269,
1999[ISI][Medline].
79.
Martin, D. A.,
L. Zheng,
R. M. Siegel,
B. Huang,
G. H. Fisher,
J. Wang,
C. E. Jackson,
J. M. Puck,
J. Dale,
S. E. Straus,
M. E. Peter,
P. H. Krammer,
S. Fesik,
and
M. J. Lenardo.
Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.
Proc. Natl. Acad. Sci. USA
96:
4552-4557,
1999
80.
Martin, S. J.,
D. M. Finucane,
G. P. Amarante-Mendes,
G. A. O'Brien,
and
D. R. Green.
Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity.
J. Biol. Chem.
271:
28753-28756,
1996
81.
Martin, S. J.,
G. A. O'Brien,
W. K. Nishioka,
A. J. McGahon,
A. Mahboubi,
T. C. Saido,
and
D. R. Green.
Proteolysis of fodrin (non-erythroid spectrin) during apoptosis.
J. Biol. Chem.
270:
6425-6428,
1995
82.
Martin, S. J.,
C. P. Reutelingsperger,
A. J. McGahon,
J. A. Rader,
R. C. van Schie,
D. M. LaFace,
and
D. R. Green.
Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl.
J. Exp. Med.
182:
1545-1556,
1995[Abstract].
83.
Metzstein, M. M.,
G. M. Stanfield,
and
H. R. Horvitz.
Genetics of programmed cell death in C. elegans: past, present and future.
Trends Genet.
14:
410-416,
1998[ISI][Medline].
84.
Michaelson, J. S.,
D. Bader,
F. Kuo,
C. Kozak,
and
P. Leder.
Loss of daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development.
Genes Dev.
13:
1918-1923,
1999
85.
Mita, E.,
N. Hayashi,
S. Iio,
T. Takehara,
T. Hijioka,
A. Kasahara,
H. Fusamoto,
and
T. Kamada.
Role of Fas ligand in apoptosis induced by hepatitis C virus infection.
Biochem. Biophys. Res. Commun.
204:
468-474,
1994[ISI][Medline].
86.
Mitsiades, N.,
V. Poulaki,
V. Kotoula,
A. Leone,
and
M. Tsokos.
Fas ligand is present in tumors of the Ewing's sarcoma family and is cleaved into a soluble form by a metalloproteinase.
Am. J. Pathol.
153:
1947-1956,
1998
87.
Miyoshi, H.,
C. Rust,
P. J. Roberts,
L. J. Burgart,
and
G. J. Gores.
Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas.
Gastroenterology
117:
669-677,
1999[ISI][Medline].
88.
Mochizuki, K.,
N. Hayashi,
N. Hiramatsu,
K. Katayama,
Y. Kawanishi,
A. Kasahara,
H. Fusamoto,
and
T. Kamada.
Fas antigen expression in liver tissues of patients with chronic hepatitis B.
J. Hepatol.
24:
1-7,
1996[ISI][Medline].
89.
Moller, P.,
H. Walczak,
S. Reidl,
J. Strater,
and
P. H. Krammer.
Paneth cells express high levels of CD95 ligand transcripts: a unique property among gastrointestinal epithelia.
Am. J. Pathol.
149:
9-13,
1996[Abstract].
90.
Muruve, D. A.,
A. G. Nicolson,
R. C. Manfro,
T. B. Strom,
V. P. Sukhatme,
and
T. A. Libermann.
Adenovirus-mediated expression of Fas ligand induces hepatic apoptosis after systemic administration and apoptosis of ex vivo-infected pancreatic islet allografts and isografts.
Hum. Gene Ther.
8:
955-963,
1997[ISI][Medline].
91.
Muzio, M.,
A. M. Chinnaiyan,
F. C. Kischkel,
K. O'Rourke,
A. Shevchenko,
J. Ni,
C. Scaffidi,
J. D. Bretz,
M. Zhang,
R. Gentz,
M. Mann,
P. H. Krammer,
M. E. Peter,
and
V. M. Dixit.
FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex.
Cell
85:
817-827,
1996[ISI][Medline].
92.
Nagao, M.,
Y. Nakajima,
M. Hisanaga,
N. Kayagaki,
H. Kanehiro,
Y. Aomatsu,
S. Ko,
H. Yagita,
T. Yamada,
K. Okumura,
and
H. Nakano.
The alteration of Fas receptor and ligand system in hepatocellular carcinomas: how do hepatoma cells escape from the host immune surveillance in vivo?
Hepatology
30:
413-421,
1999[ISI][Medline].
93.
Nagata, S.
Apoptosis by death factor.
Cell
88:
355-365,
1997[ISI][Medline].
94.
Nagata, S.,
and
T. Suda.
Fas and Fas ligand: lpr and gld mutations.
Immunol. Today
16:
39-43,
1995[ISI][Medline].
95.
Nakajima, H.,
P. Golstein,
and
P. A. Henkart.
The target cell nucleus is not required for cell-mediated granzyme- or Fas-based cytotoxicity.
J. Exp. Med.
181:
1905-1909,
1995[Abstract].
96.
Natoli, G.,
A. Ianni,
A. Costanzo,
G. De Petrillo,
I. Ilari,
P. Chirillo,
C. Balsano,
and
M. Levrero.
Resistance to Fas-mediated apoptosis in human hepatoma cells.
Oncogene
11:
1157-1164,
1995[ISI][Medline].
97.
Nicholson, D. W.,
A. Ali,
N. A. Thornberry,
J. P. Vaillancourt,
C. K. Ding,
M. Gallant,
Y. Gareau,
P. R. Griffin,
M. Labelle,
Y. A. Lazebnik,
N. A. Munday,
S. M. Raju,
M. E. Smulson,
T. Yamin,
V. L. Yu,
and
D. K. Miller.
Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.
Nature
376:
37-43,
1995[ISI][Medline].
98.
O'Connell, J.,
G. C. O'Sullivan,
J. K. Collins,
and
F. Shanahan.
The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand.
J. Exp. Med.
184:
1075-1082,
1996[Abstract].
99.
Obeid, L. M.,
C. M. Linardic,
L. A. Karolak,
and
Y. A. Hannun.
Programmed cell death induced by ceramide.
Science
259:
1769-1771,
1993[ISI][Medline].
100.
Ogasawara, J.,
T. Suda,
and
S. Nagata.
Selective apoptosis of CD4+CD8+ thymocytes by the anti-Fas antibody.
J. Exp. Med.
181:
485-491,
1995[Abstract].
101.
Ogasawara, J.,
R. Watanabe-Fukunaga,
M. Adachi,
A. Matsuzawa,
T. Kasugai,
Y. Kitamura,
N. Itoh,
T. Suda,
and
S. Nagata.
Lethal effect of the anti-Fas antibody in mice.
Nature
364:
806-809,
1993[ISI][Medline].
102.
Okazaki, M.,
K. Hino,
K. Fujii,
N. Kobayashi,
and
K. Okita.
Hepatic Fas antigen expression before and after interferon therapy in patients with chronic hepatitis C.
Dig. Dis. Sci.
41:
2453-2458,
1996[ISI][Medline].
103.
Pan, G.,
K. O'Rourke,
and
V. M. Dixit.
Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex.
J. Biol. Chem.
273:
5841-5845,
1998
104.
Peng, S. L.,
M. E. Robert,
A. C. Hayday,
and
J. Craft.
A tumor-suppressor function for Fas (CD95) revealed in T cell-deficient mice.
J. Exp. Med.
184:
1149-1154,
1996[Abstract].
105.
Petrukhin, K.,
S. G. Fischer,
M. Pirastu,
R. E. Tanzi,
I. Chernov,
M. Devoto,
L. M. Brzustowicz,
E. Cayanis,
E. Vitale,
J. J. Russo,
D. Matseoane,
B. Boukhgalter,
W. Wasco,
A. L. Figus,
J. Loudianos,
A. Cao,
I. Sternlieb,
G. Evgrafov,
E. Parano,
L. Pavone,
D. Warburton,
J. Ott,
G. Penchaszaden,
I. H. Scheinberg,
and
T. C. Gilliam.
Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.
Nat. Genet.
5:
338-343,
1993[ISI][Medline].
106.
Pitti, R. M.,
S. A. Marsters,
D. A. Lawrence,
M. Roy,
F. C. Kischkel,
P. Dowd,
A. Huang,
C. J. Donahue,
S. W. Sherwood,
D. T. Baldwin,
P. J. Godowski,
W. I. Wood,
A. L. Gurney,
K. J. Hillan,
R. L. Cohen,
A. D. Goddard,
D. Botstein,
and
A. Ashkenazi.
Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer.
Nature
396:
699-703,
1998[ISI][Medline].
107.
Ponec, R. J.,
R. C. Hackman,
and
G. B. McDonald.
Endoscopic and histologic diagnosis of intestinal graft-versus-host disease after marrow transplantation.
Gastrointest. Endosc.
49:
612-621,
1999[ISI][Medline].
108.
Rathmell, J. C.,
and
C. B. Thompson.
The central effectors of cell death in the immune system.
Annu. Rev. Immunol.
17:
781-828,
1999[ISI][Medline].
109.
Rouvier, E.,
M. F. Luciani,
and
P. Golstein.
Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity.
J. Exp. Med.
177:
195-200,
1993[Abstract].
110.
Ruggieri, A.,
T. Harada,
Y. Matsuura,
and
T. Miyamura.
Sensitization to Fas-mediated apoptosis by hepatitis C virus core protein.
Virology
229:
68-76,
1997[ISI][Medline].
111.
Sakahira, H.,
M. Enari,
and
S. Nagata.
Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis.
Nature
391:
96-99,
1998[ISI][Medline].
112.
Sakai, T.,
Y. Kimura,
K. Inagaki-Ohara,
K. Kusugami,
D. H. Lynch,
and
Y. Yoshikai.
Fas-mediated cytotoxicity by intestinal intraepithelial lymphocytes during acute graft-versus-host disease in mice.
Gastroenterology
113:
168-174,
1997[ISI][Medline].
113.
Savill, J.,
V. Fadok,
P. Henson,
and
C. Haslett.
Phagocyte recognition of cells undergoing apoptosis.
Immunol. Today
14:
131-136,
1993[ISI][Medline].
114.
Scaffidi, C.,
S. Fulda,
A. Srinivasan,
C. Friesen,
F. Li,
K. J. Tomaselli,
K. M. Debatin,
P. H. Krammer,
and
M. E. Peter.
Two CD95 (APO-1/Fas) signaling pathways.
EMBO J.
17:
1675-1687,
1998
115.
Scaffidi, C.,
I. Schmitz,
P. H. Krammer,
and
M. E. Peter.
The role of c-FLIP in modulation of CD95-induced apoptosis.
J. Biol. Chem.
274:
1541-1548,
1999
116.
Schaefer, M.,
R. G. Hopkins,
M. L. Failla,
and
J. D. Gitlin.
Hepatocyte-specific localization and copper-dependent trafficking of the Wilson's disease protein in the liver.
Am. J. Physiol. Gastrointest. Liver Physiol.
276:
G639-G646,
1999
117.
Schneider, P.,
N. Holler,
J. L. Bodmer,
M. Hahne,
K. Frei,
A. Fontana,
and
J. Tschopp.
Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss liver toxicity.
J. Exp. Med.
187:
1205-1213,
1998
118.
Seino, K.,
N. Kayagaki,
K. Takeda,
K. Fukao,
K. Okumura,
and
H. Yagita.
Contribution of Fas ligand to T cell-mediated hepatic injury in mice.
Gastroenterology
113:
1315-1322,
1997[ISI][Medline].
119.
Shimizu, M.,
A. Fontana,
Y. Takeda,
H. Yagita,
T. Yoshimoto,
and
A. Matsuzawa.
Induction of antitumor immunity with Fas/APO-1 ligand (CD95L)-transfected neuroblastoma neuro-2a cells.
J. Immunol.
162:
735-707,
1999
120.
Shiota, G.,
K. Oyama,
N. Noguchi,
Y. Takano,
S. Kitaoka,
and
H. Kawasaki.
Clinical significance of serum soluble Fas ligand patients with acute self-limited and fulminant hepatitis.
Res. Commun. Mol. Pathol. Pharmacol.
101:
3-12,
1998[ISI][Medline].
121.
Shiraki, K.,
N. Tsuji,
T. Shioda,
K. J. Isselbacher,
and
H. Takahashi.
Expression of Fas ligand in liver metastases of human colonic adenocarcinomas.
Proc. Natl. Acad. Sci. USA
94:
6420-6425,
1997
122.
Simpson, S. J.,
Y. P. De Jong,
S. A. Shah,
M. Comiskey,
B. Wang,
J. A. Spielman,
E. R. Podack,
E. Mizoguchi,
A. K. Bhan,
and
C. Terhorst.
Consequences of Fas-ligand and perforin expression by colon T cells in a mouse model of inflammatory bowel disease.
Gastroenterology
115:
849-855,
1998[ISI][Medline].
123.
Strand, S.,
W. J. Hofmann,
A. Grambihler,
H. Hug,
M. Volkmann,
G. Otto,
H. Wesch,
S. M. Mariani,
V. Hack,
W. Stremmel,
P. H. Krammer,
and
P. R. Galle.
Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis.
Nat. Med.
4:
588-593,
1998[ISI][Medline].
124.
Strater, J.,
S. M. Mariani,
H. Walczak,
F. G. Rucker,
F. Leithauser,
P. H. Krammer,
and
P. Moller.
CD95 ligand (CD95L) in normal human lymphoid tissues: a subset of plasma cells are prominent producers of CD95L.
Am. J. Pathol.
154:
193-201,
1999
125.
Straus, S. E.,
M. Sneller,
M. J. Lenardo,
J. M. Puck,
and
W. Strober.
An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome.
Ann. Intern. Med.
130:
591-601,
1999
126.
Suda, T.,
H. Hashimoto,
M. Tanaka,
T. Ochi,
and
S. Nagata.
Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing.
J. Exp. Med.
186:
2045-2050,
1997
127.
Suda, T.,
T. Takahashi,
P. Golstein,
and
S. Nagata.
Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.
Cell
75:
1169-1178,
1993[ISI][Medline].
128.
Suzuki, A.,
Y. Tsutomi,
K. Akahane,
T. Araki,
and
M. Miura.
Resistance to Fas-mediated apoptosis activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP.
Oncogene
17:
931-939,
1998[ISI][Medline].
129.
Tagawa, Y.,
S. Kakuta,
and
Y. Iwakura.
Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis.
Eur. J. Immunol.
28:
4105-4513,
1998[ISI][Medline].
130.
Takahashi, T.,
M. Tanaka,
C. I. Brannan,
N. A. Jenkins,
N. G. Copeland,
T. Suda,
and
S. Nagata.
Generalized lymphoproliferative disease mice, caused by a point mutation in the Fas ligand.
Cell
76:
969-976,
1994[ISI][Medline].
131.
Tanaka, M.,
T. Itai,
M. Adachi,
and
S. Nagata.
Downregulation of Fas ligand by shedding.
Nat. Med.
4:
31-36,
1998[ISI][Medline].
132.
Tanzi, R. E.,
K. Petrukhin,
I. Chernov,
J. L. Pellequer,
W. Wasco,
B. Ross,
D. M. Romano,
E. Parano,
L. Pavone,
L. M. Brzustowicz,
M. Devoto,
J. Peppercorn,
A. I. Bush,
I. Sternlieb,
M. Pirastu,
J. F. Gusella,
O. Exgrafov,
G. K. Penchaszadeh,
B. Honig,
I. S. Edelman,
M. B. Soares,
I. H. Sheinberg,
and
T. C. Gilliam.
The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.
Nat. Genet.
5:
344-350,
1993[ISI][Medline].
133.
Tepper, C. G.,
S. Jayadev,
B. Liu,
A. Bielawska,
R. Wolff,
S. Yonehara,
Y. A. Hannun,
and
M. F. Seldin.
Role of ceramide as an endogenous mediator of Fas-induced cytotoxicity.
Proc. Natl. Acad. Sci. USA
92:
844-837,
1995.
134.
Thome, M.,
P. Schneider,
K. Hofmann,
H. Fickenscher,
E. Meinl,
F. Neipel,
C. Mattmann,
K. Burns,
J. L. Bodmer,
M. Schroter,
C. Scaffidi,
P. H. Krammer,
M. E. Peter,
and
J. Tschopp.
Viral FLICE-inhibitory proteins FLIPs prevent apoptosis induced by death receptors.
Nature
386:
517-521,
1997[ISI][Medline].
135.
Thornberry, N. A.,
and
Y. Lazebnik.
Caspases: enemies within.
Science
281:
1312-1316,
1998
136.
Tillman, D. M.,
F. G. Harwood,
A. A. Gibson,
and
J. A. Houghton.
Expression of genes that regulate Fas signalling and Fas-mediated apoptosis in colon carcinoma cells.
Cell Death Differ.
5:
450-457,
1998[ISI][Medline].
137.
Ucker, D. S.,
P. S. Obermiller,
W. Eckhart,
J. R. Apgar,
N. A. Berger,
and
J. Meyers.
Genome digestion is a dispensable consequence of physiological cell death mediated by cytotoxic T lymphocytes.
Mol. Cell. Biol.
12:
306-309,
1992.
138.
Ueyama, H.,
T. Kiyohara,
N. Sawada,
K. Isozaki,
S. Kitamura,
S. Kondo,
J. Miyagawa,
S. Kanayama,
Y. Shinomura,
H. Ishikawa,
T. Ohtani,
R. Nezu,
S. Nagata,
and
Y. Matsuzawa.
High Fas ligand expression on lymphocytes in lesions of ulcerative colitis.
Gut
43:
48-55,
1998
139.
Van Parijs, L.,
A. Biuckians,
and
A. K. Abbas.
Functional roles of Fas and Bcl-2-regulated apoptosis of T lymphocytes.
J. Immunol.
160:
2065-2071,
1998
140.
Via, C. S.,
P. Nguyen,
A. Shustov,
J. Drappa,
and
K. B. Elkon.
A major role for the Fas pathway in acute graft-versus-host disease.
J. Immunol.
157:
5387-5393,
1996[Abstract].
141.
Walker, P. R.,
P. Saas,
and
P. Y. Dietrich.
Tumor expression of Fas ligand (CD95L) and the consequences.
Curr. Opin. Immunol.
10:
564-572,
1998[ISI][Medline].
142.
Wolf, B. B.,
and
D. R. Green.
Suicidal tendencies: apoptotic cell death by caspase family proteinases.
J. Biol. Chem.
274:
20049-20052,
1999
143.
Wyllie, A. H.
Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation.
Nature
284:
555-556,
1980[ISI][Medline].
144.
Yang, X.,
R. Khosravi-Far,
H. Y. Chang,
and
D. Baltimore.
Daxx, a novel Fas-binding protein that activates JNK and apoptosis.
Cell
89:
1067-1076,
1997[ISI][Medline].
145.
Yin, X. M.,
K. Wang,
A. Gross,
Y. Zhao,
S. Zinkel,
B. Klocke,
K. A. Roth,
and
S. J. Korsmeyer.
Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis.
Nature
400:
886-891,
1999[ISI][Medline].
146.
Yoong, K. F.,
S. C. Afford,
S. Randhawa,
S. G. Hubscher,
and
D. H. Adams.
Fas/Fas ligand interaction human colorectal hepatic metastases: a mechanism of hepatocyte destruction to facilitate local tumor invasion.
Am. J. Pathol.
154:
693-703,
1999
147.
Yoshida, H.,
Y. Y. Kong,
R. Yoshida,
A. J. Elia,
A. Hakem,
R. Hakem,
J. M. Penninger,
and
T. W. Mak.
Apaf1 is required mitochondrial pathways of apoptosis and brain development.
Cell
94:
739-750,
1998[ISI][Medline].
148.
Zou, H.,
W. J. Henzel,
X. Liu,
A. Lutschg,
and
X. Wang.
Apaf1, a human protein homologous to C. elegans CED4, participates in cytochrome c-dependent activation of caspase-3.
Cell
90:
405-413,
1997[ISI][Medline].