Fas Ligand

8 Pages·2000·0.103 MB·English

by  Nagata S.

Fas Ligand
Shigekazu Nagata
*
Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
*corresponding author tel: [phone], fax: [phone],
e-mail: [email protected]
DOI: 10.1006/rwcy.2000.05005.
SUMMARY Alternative names
FasL is a type II membrane protein belonging to the CD95L.
TNFfamily, which induces apoptosis in Fas-bearing
cells.FasLcanbecleavedofffromthemembranebya Structure
metalloprotease(s), and the soluble FasL displays a
much lower cytotoxic activity than its membrane-
FasL is a type II membrane protein belonging to the
bound form. FasL is one of the effector molecules of
TNF family (Suda et al., 1993; Takahashi et al.,
cytotoxicTcellsandNKcells.FasLisalsoexpressed
1994b).
instromacellsoftheeye,andcontributestotheeye’s
privilegedimmunestatus.Themurinegld(generalized
Main activities and
lymphoproliferative disease) mutation is a loss-of-
functionmutationofFasL.Themicedeveloplympha- pathophysiological roles
denopathy and splenomegaly, produce a large amount
of immunoglobulin, and develop autoimmune dis-
FasL kills the Fas-bearing cells by activating the
eases. Administration of FasL into these mice causes
apoptotic program (Enari et al., 1995; Enari et al.,
hepatitis, and quickly kills them. CTL-induced hepa-
1996; Nagata, 1997; Suda et al., 1993).
titis or graft-versus-host disease can be inhibited by
soluble Fas or neutralizing anti-FasL antibody, sug-
gestingthatvariousformsofCTL-inducedtissuedest- GENE AND GENE REGULATION
ructionareprobablycausedbyoverexpressionofFasL.
Accession numbers
BACKGROUND
Human FasL: U11821
Discovery Mouse FasL: M83649
Fas ligand (FasL) was discovered on the cell surface Chromosome location
of cytotoxic T lymphocytes (CTLs) (a mouse-rat T
cellhybridoma,d10Sclone)asaproteinthat killsthe FasL is on human chromosome 1q23 (Takahashi
Fas-bearing cells (Rouvier et al., 1993). The FasL et al., 1994b) and mouse chromosome 1 (Takahashi
protein was purified from the membrane fraction of et al., 1994a).
d10S cells (Suda and Nagata, 1994), and its cDNA
was cloned from the d10S cDNA library by expres-
Relevant linkages
sion cloning (Suda et al., 1993). Human FasL cDNA
was subsequently identified in human peripheral
blood cDNA library by crosshybridization with the The mouse FasL gene is linked to gld mutation
rodent cDNA (Takahashi et al., 1994b). (Takahashi et al., 1994a).
450 Shigekazu Nagata
Regulatory sites and corresponding Figure 1 Amino acid sequence for FasL.
transcription factors
Human FasL
1 MQQPFNYPYP QIYWVDSSAS SPWAPPGTVL
T lymphocytes can be activated through the T cell 31 PCPTSVPRRP GQRRPPPPPP PPPLPPPPPP
61 PPLPPLPLPP LKKRGNHSTG LCLLVMFFMV
receptor to express the FasL gene. This induced
91 LVALVGLGLG MFQLFHLQKE LAELRESTSQ
expression of FasL in T cells is mediated by NF(cid:20)B
121 MHTASSLEKQ IGHPSPPPEK KELRKVAHLT
and Egr-3 in the 5’ flanking region of the FasL gene 151 GKSNSRSMPL EWEDTYGIVL LSGVKYKKGG
(Kasibhatla et al., 1999; Matsui et al., 1998; 181 LVINETGLYF VYSKVYFRGQ SCNNLPLSHK
Mittelstadt and Ashwell, 1998). Exposure of T cells 211 VYMRNSKYPQ DLVMMEGKMM SYCTTGQMWA
241 RSSYLGAVFN LTSADHLYVN VSELSLVNFE
to various stress such as UV radiation and gamma-
271 ESQTFFGLYK L
irradiation also induces the FasL gene expression
(Kasibhatla et al., 1998). This induced expression of
FasLisdependentonactivationofMEKK1andJNK
(Faris et al., 1998), which leads to binding of c-Jun Sequence
and ATF2 to the AP-1site on the 5’ promoterregion
of the human FasL gene. Withdrawal of survival
See Figure 1.
factors activates JNK and p38 via a transient
activation of MEKK1 and MAPKKK in neuronal
cells such as PC12, which induces FasL in nerve cells Description of protein
(Le et al., 1999).
A single transmembrane region (22 amino acids)
divides the molecule into an N-terminal cytoplasmic
Cells and tissues that express
region of 80 amino acids, and a C-terminal extra-
the gene cellular region of 179 amino acids. The N-terminal
cytoplasmic region is extremely rich in proline
residues (about 40% amino acids in this region are
T cells and NK cells express FasL upon activation
prolines) (Suda et al., 1993; Takahashi et al., 1994b).
(Sudaetal.,1995;Vignauxetal.,1995;Tanakaetal.,
1996). FasL gene in T cells can also be activated by A metalloproteinase cleaves the membrane-bound
stress such as UV radiation and gamma-irradiation FasL to produce its soluble form (Kayagaki et al.,
(Kasibhatla et al., 1998). Large granular lymphocytic 1995; Tanaka et al., 1995, 1996). The soluble FasL
leukemia (LGL) of NK or T cell origin, and NK exists as a homotrimer (Tanaka et al., 1995).
lymphoma cells constitutively express FasL (Tanaka
et al., 1996).Normalliver does notexpress FasL, but
Discussion of crystal structure
when damaged with alcohol, it expresses a high level
of FasL (Galle et al., 1995). Immune privileged sites
The crystal structure is not known. However, the
such as the eye and testis constitutively express FasL
amino acid sequence of FasL predicts an elongated,
(Bellgrauetal.,1995;Griffithetal.,1995;Sudaetal.,
antiparallel(cid:12)-pleatedsheetsandwichwitha‘jelly-roll’
1993). Some carcinoma cells such as those of colon
topology,basedonitssimilaritytothatofTNF(Suda
carcinoma, hepatocarcinoma, and melanoma were
et al., 1993; Peitsch and Tschopp, 1995; Schneider
reportedtoexpressFasL,constitutively(Hahneetal.,
et al., 1997).
1996; O’Connell et al., 1996; Strand et al., 1996).
However one group could not detect FasL in any of
the melanoma cell lines examined (Arai et al., 1997). Important homologies
The amino acid sequence of extracellular region of
PROTEIN
FasL is significantly related to that of other TNF
family members (Suda et al., 1993).
Accession numbers
Posttranslational modifications
Human:PIDg595431(Aldersonetal.,1995),g1345957
(Takahashietal.,1994b);SwissProtP48043
Mouse: PID g729462 (Lynch et al., 1994; Takahashi HumanFasLhasthreepotentialN-glycosylationsites
et al., 1994a); SwissProt P41047 (Asn184, Asn250, and Asn260). N-glycosylation
Fas Ligand 451
seems to be essential for expression of FasL on the Regulatory molecules: Inhibitors
cell surface (Schneider et al., 1997; Tanaka et al.,
and enhancers
1997).
Adecoyreceptor(DcR3),asolublereceptorbelonging
to the TNF receptor family, binds to FasL with a K
CELLULAR SOURCES AND d
of 1nM, and antagonizes the function of FasL (Pitti
TISSUE EXPRESSION et al., 1999). The DcR3 gene is amplified in 50% of
cases of human lung carcinoma and colon carcinoma.
Cellular sources that produce
Bioassays used
T cells and NK cells produce FasL upon activation
(Vignaux et al., 1995; Arase et al., 1995; Suda et al.,
FasL kills Fas-bearing cells, which can be assayed by
1995; Tanaka et al., 1996). Stroma cells in the eye MTT or [3H]thymidine-incorporation. FasL-induced
constitutively produce FasL (Griffith et al., 1995).
apoptosis can be directly assayed by stainingthe cells
Large granular cell leukemia (LGL) cells, NK cell
with fluorescence-labeled Annexin V, by quantitating
lymphoma cells, and some other cancer cells also
DNA fragmentation on agarose gel, or by measuring
constitutively express FasL (Hahne et al., 1996;
the caspase activity using fluorescent substrates.
O’Connell et al., 1996; Strand et al., 1996; Tanaka
et al., 1996). Recombinant glycosylated soluble FasL
can be produced in a large scale in the yeast Pichia IN VIVO BIOLOGICAL
pastoris (Tanaka et al., 1997).
ACTIVITIES OF LIGANDS IN
ANIMAL MODELS
Eliciting and inhibitory stimuli,
Normal physiological roles
including exogenous and
endogenous modulators
FasLexpressedonthecell-surfaceofactivatedTcells
kills T cells (activation-induced suicide of T cells)
The activation stimuli of T cells such as PMA and (Russelletal.,1993;Brunneretal.,1995;Dheinetal.,
ionomycin (Suda et al., 1993), and high doses of IL-2 1995; Ju et al., 1995), as well as the activated B cells
stimulates FasL gene expression (Suda et al., 1995). (Fukuyama et al., 1998), thus leading to down-
The oncogene c-myc activates FasL gene expression regulation ofimmune reaction(Nagataand Golstein,
in T cells, while TGF(cid:12) inhibits the FasL expression 1995). FasL on cytotoxic T lymphocytes (CTLs) or
byinhibitingc-mycexpression(Genestieretal.,1999). NK cells works as an effector of these cytotoxic cells
Anticancer drugs and gamma-irradiation were (Araseetal.,1994;Juetal.,1994;Kojimaetal.,1994;
reported to stimulate FasL gene expression in some Ka¨gi et al., 1994; Lowin et al., 1994; Oshimi et al.,
cancer cells (Friesen et al., 1996; Kasibhatla et al., 1996; Bradley et al., 1998; Halaas et al., 1998; Zamai
1998; Muller et al., 1997). et al., 1998), and kills the cells infected by virus, or
cancerous cells. FasL expressed in the stroma cells of
the eye counterattacks CTLs and neutrophils infil-
trated into the eye, thus contributing to the immune-
RECEPTOR UTILIZATION
privileged state of the eye (Griffith et al., 1995).
FasL specifically binds to its receptor Fas (K of
d
Species differences
about 1nM).
There is no species-specificity between rat, mouse,
and human (Takahashi et al., 1994b).
IN VITRO ACTIVITIES
In vitro findings Knockout mouse phenotypes
FasL kills cells by activating apoptotic program in No FasL-knockout mice have been developed. The
Fas-bearing cells. spontaneousmousemutationgldisaloss-of-function
452 Shigekazu Nagata
mutationofFasL(Lynchetal.,1994;Takahashietal., patients seems to be due to the FasL produced by
1994a). FasL in gld mice carries a point mutation in leukemia cells.
the extracellular region of FasL that causes aggrega- Patients with systemic lupus erythematosus, rheu-
tion of FasL and blocks its binding to the Fas matoid arthritis, Sjo¨gren’s syndrome, lymphohistocy-
receptor(Schneideretal.,1997).Thegldmicedevelop tosis, and myocarditis, and alcoholicliver diseasealso
lymphadenopathy and splenomegaly, produce auto- show a high level of the soluble FasL in the serum
antibodies,and develop autoimmune diseases suchas (Nozawaetal.,1997;Hasegawaetal.,1998;Toyozaki
nephritis (Cohen and Eisenberg, 1991). et al., 1998). The joints of patients with severe
rheumatoid arthritis contain a high level of FasL
(Hashimoto et al., 1998).
Transgenic overexpression
Role in experiments of nature
No FasL transgenic mice have been developed.
and disease states
Pharmacological effects
Infection of eyes of the mice expressing no functional
FasL (gld mice) with herpes simplex virus causes
AhighdoseofFasL(500mg,i.v.)causeshemorrhagic inflammation and severe damage of the eye (Griffith
necrosis in the liver (Tanaka et al., 1997). When the et al., 1995), symptoms that do not occur in the wild-
mice are pretreated with Propionibacterium acnes, type mice, indicating that FasL blocks the inflamma-
they become very sensitive to FasL and administra- tion by killing the inflammatory cells infiltrated into
tion of30mgofFasLwill kill themice within4hours the eye. It has been suggested that exogenous expres-
by causing hepatitis. The agonistic anti-Fas anti- sion of FasL in organ transplants induces tolerance
body (Jo2) has been reported to have a stronger by killing the cytotoxic T cells (Lau et al., 1996). In
cytotoxic activity in vivo than the soluble FasL: an contrast, the FasL-expressing grafts were rapidly
i.p. administration of 50mg of the antibody kills the rejectedbyneutrophilsrecruitedtothegrafts(Allison
mice within 3 hours by causing hepatitis (Ogasawara etal.,1997;Kangetal.,1997;Seinoetal.,1997;Miwa
et al., 1993). et al., 1998). Diabetes in NOD mice is not developed
in mice lacking Fas (lpr mice) (Chervonsky et al.,
1997; Itoh et al., 1997), suggesting that FasL
Endogenous inhibitors and
expressed in CTLs is involved in killing (cid:12) cells in
enhancers the pancreas. Development of experimental allergic
encephalomyelitis (EAE) is also significantly reduced
TreatmentofcellswithIFN(cid:13) and/orTNF(cid:11)sensitizes inlprmice(Sabelkoetal.,1997;Waldneretal.,1997),
the cells for killing by FasL or agonistic anti-Fas suggesting a role of FasL in various forms of CTL-
antibody (Yonehara et al., 1989; Itoh et al., 1991; induced tissue destruction.
Mo¨ller et al., 1993).
IN THERAPY
PATHOPHYSIOLOGICAL ROLES
Preclinical – How does it affect
IN NORMAL HUMANS AND
disease models in animals?
DISEASE STATES AND
DIAGNOSTIC UTILITY
Administration of an agonistic anti-Fas antibody
(anti-Apo1), which has a function similar to that of
Normal levels and effects
FasL, kills lymphomas growing in nude mice. This
suggestedausefortheagonisticantibodyorFasLfor
The serum level of soluble FasL in healthy persons is cancer therapy (Trauth et al., 1989). However, the
less than 50pg/mL (Tanaka et al., 1996). Patients strong cytotoxicity of FasL or agonistic anti-Fas
with NK-LGL leukemia, T-LGL leukemia, or NK- antibody, e.g. on liver (see above), suggests that a
lymphoma have 0.3–7.0ng/mL of sFasL in their method of delivering FasL specifically to the tumor
serum. Treatment of the patients with chemotherapy should be developed before it is used for cancer
reduces the serum level of FasL (Sato et al., 1996). patients.SolubleFas(Fas-Fc,theextracellularregion
Neutropenia and hepatitis, often observed in LGL fusedtotheFcportionofhumanIgG)orneutralizing
Fas Ligand 453
anti-Fasligandantibodypreventsthedevelopmentof Ware, C. F., and Green, D. R. (1995). Cell-autonomous Fas
CTL-inducedhepatitisinamousemodel(Kondoetal., (CD95)/Fas-ligand interaction mediates activation-induced
apoptosisinT-cellhybridomas.Nature373,441–444.
1997).
Chervonsky, A. V., Wang, Y., Wong, F. S., Visintin, I., and
Graft-versus-host disease caused by allogenic bone
Flavell,R.A.(1997).TheroleofFasinautoimmunediabetes.
marrow transplantation can also be blocked by anti- Cell89,17–24.
FasL antibody, indicating that FasL expressed in Cohen,P.L.,andEisenberg,R.A.(1991).Lprandgld:singlegene
alloreactive CTLs is at least in part responsible for modelsofsystemicautoimmunityandlymphoproliferativedis-
development of graft-versus-host disease (Hattori ease.Annu.Rev.Immunol.9,243–269.
Dhein, J., Walczak, H., Ba¨umler, C., Debatin, K.-M., and
etal.,1998).AdenoviruscarryingFasLgenewasused
Krammer, P. H. (1995). Autocrine T-cell suicide mediated by
to infect tumor cells in vivo (Arai et al., 1997). The
APO-1/(Fas/CD95).Nature373,438–441.
tumor cells expressing Fas were killed directly by Enari, M., Hug, H., and Nagata, S. (1995). Involvement of an
FasL/Fas interaction. The tumor cells that do not ICE-like protease in Fas-mediated apoptosis. Nature 375,
express Fas were also eliminated by inflammatory 78–81.
Enari,M.,Talanian,R.V.,Wong,W.W.,andNagata,S.(1996).
cells recruited by FasL.
SequentialactivationofICE-likeandCPP32-likeproteasesdur-
ingFas-mediatedapoptosis.Nature380,723–726.
Toxicity Faris, M., Latinis, K. M., Kempiak, S. J., Koretzky, G. A., and
Nel,A.(1998).Stress-inducedFasligandexpressioninTcellsis
mediatedthroughaMEKkinase1-regulatedresponseelement
Administration of FasL or agonistic anti-Fas anti-
intheFasligandpromoter.Mol.Cell.Biol.18,5414–5424.
body to mice kills the mice by causing hepatitis Fiedler, P., Scaetzlein, C. E., and Eibel, H. (1998). Constitutive
(Ogasawara et al., 1993; Tanaka et al., 1997). expressionofFasLinthyrocytes.Science279,2015a.
Friesen,C.,Herr,I.,Krammer,P.H.,andDebatin,K.M.(1996).
InvolvementoftheCD95(APO-1/FAS)receptor/ligandsystem
Clinical results in drug-induced apoptosis in leukemia cells. Nature Med. 2,
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Fukuyama, H., Adachi, M., Suematsu, S., Miwa, K., Suda, T.,
No clinical trials with FasL or the antibody against Yoshida, N., and Nagata, S. (1998). Transgenic expression of
FasL have been carried out. FasinTcellsblockslymphoproliferationbutnotautoimmune
diseaseinMRL-lprmice.J.Immunol.160,3805–3811.
Galle, P., Hofmann, W., Walczak, H., Schaller, H., Otto, G.,
Stremmel, W., Krammer, P., and Runkel, L. (1995).
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