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Departments of
* Ophthalmology and Visual Sciences and
Pathology, Washington University School of Medicine, St. Louis, MO 63110; and
Department of Urology, University of Iowa, Iowa City, IA 52241
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is now known that ocular immune privilege is much more complex, and the explanation has been expanded to include the production and action of immunosuppressive cytokines, neuropeptides, and the expression of Fas ligand (FasL)3 (1). FasL is strategically placed within the eye to induce apoptosis in invading lymphoid cells and protect delicate ocular structures (e.g., the retina). FasL-mediated killing of immune cells spares the eye from the damaging effects of inflammation to protect vision, and it may be why ocular inflammatory disease is relatively rare. Interestingly, intraocular tumors (both primary tumors and those metastasizing from distant sites) are also rare (2). Indeed, FasL has been shown to be involved in tumor surveillance (3, 4), but there are many tumors resistant to FasL-induced death. Therefore, it is probable that other tumoricidal mediator(s) is expressed in the eye.
FasL belongs to the TNF superfamily of molecules, which also includes TNF and TRAIL (Apo2L). TRAIL is distinct among members of this superfamily because TRAIL mRNA has been detected in numerous tissues throughout the body, and it appears to have selective apoptotic activity toward transformed cells (5, 6). In humans, TRAIL interaction with either DR4 or DR5 (TRAIL-R1 and TRAIL-R2, respectively) triggers an apoptotic signal by recruitment of the adapter molecule Fas-associated death domain protein to the receptor cytoplasmic death domain (7, 8, 9, 10, 11). A second group of receptors, DcR1 (TRAIL-R3) and DcR2 (TRAIL-R4), lack a death domain, making them unable to induce apoptosis (7, 10, 12, 13, 14, 15). These receptors may act as decoys or transduce an antiapoptotic signal. Interestingly, while all four TRAIL receptors are widely expressed, receptor expression does not correlate with resistance or sensitivity to TRAIL-mediated death (16). This may be related to the presence of antiapoptotic molecules within the cell. The selective apoptotic activity makes TRAIL a promising anticancer therapeutic, and the potential in the treatment of cancer in vivo is being pursued.
The broad tissue expression and tumoricidal activity of TRAIL strongly suggest it is nontoxic for normal tissue and involved in tumor surveillance. We have examined the hypothesis that the paucity of intraocular tumors may be related to TRAIL expression in the eye. Our results show that functional TRAIL is expressed in numerous structures in the eye, suggesting a role for TRAIL in the protection of vision from the blinding effects of tumor growth.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6) and BALB/c mice were purchased from the National Cancer Institute (Frederick, MD). B6-gld mice were originally purchased from The Jackson Laboratory (Bar Harbor, ME) and subsequently bred in our facility. BALB-gld mice were produced in our lab by backcrossing B6-gld onto the BALB/c background. Mice were used for isolation of ocular tissue at 7–10 wk of age.
Cell lines, reagents, and Abs
Recombinant human TRAIL and TRAIL-R2:Fc were obtained from Immunex (Seattle, WA). The anti-mouse TRAIL mAb (N2B2) and the plasmid containing murine TRAIL receptor cDNA (pCEP4-DR5) were provided by H. Yagita (Juntendo University, Tokyo, Japan). The human prostate carcinoma cell line, PC-3, was obtained from M. Cohen (University of Iowa, Iowa City, IA). The human melanoma cell line, WM 98-1, was obtained from M. Herlyn (Wistar Institute, Philadelphia, PA). The murine renal adenocarcinoma cell line, Renca, was obtained from R. Wiltrout (National Cancer Institute). Renca was cultured in RPMI 1640 supplemented with 10% FBS, penicillin, streptomycin, sodium pyruvate, nonessential amino acids, and HEPES (hereafter referred to as complete RPMI). PC-3 and WM 98-1 were cultured in DMEM supplemented with 10% FBS, penicillin, streptomycin, sodium pyruvate, nonessential amino acids, and HEPES.
RT-PCR
Human eye globes (Mid-America Transplantation Association, St.
Louis, MO) were dissected into cornea, retina, iris, and retinal
pigment epithelium (RPE) under dissecting scope, and total RNA was
isolated using RNeasy kit (Qiagen, Valencia, CA), according to the
manufacturer’s instruction. Total RNA was also extracted from whole
eye globes (minus the lens) of mice by the same method. cDNA synthesis
from the RNA samples (1 µg each) was performed using an RNA PCR kit
(PE Biosystems, Foster City, CA), with the supplied
oligo(dT)16 primer, and 2 µl of the reverse
transcription reaction was used for gene-specific PCR amplification.
Reverse transcription was performed using a thermal program of 25°C
for 10 min, 42°C for 30 min, and 95°C for 5 min. PCR were performed
using the following primers: human 
-actin (forward,
5'-GAAACTACCTTCAACTCCATC-3'; reverse, 5'-CGAGGCCAGGATGGAGCCGCC-3');
human TRAIL (forward, 5'-CAACTCCGTCAGCTCGTTAGAAAG-3'; reverse,
5'-TTAGACCAACAACTATTTCTAGCACT-3'); mouse -actin (forward,
5'-TGGAATCCTGTGGCATCCATGAAAC-3'; reverse,
5'-TAAAACGCAGCTCAGTAACAGTCCG-3'); and mouse TRAIL (forward,
5'-TCACCAACGAGATGAAGCAGC-3'; reverse, 5'-CTCACCTTGTCCTTTGAGACC-3'),
giving products of 219, 443, 349, and 513 bp, respectively. Conditions
for PCR were optimized to give only the desired product. Human
-actin PCR cycle conditions were 95°C for 45 s, 55°C for 1
min, and 72°C for 45 s for 30 cycles. Human TRAIL cycle
conditions were 95°C for 45 s, 55°C for 45 s, and 72°C
for 45 s for 30 cycles. Mouse -actin cycle conditions were
95°C for 1 min, 65°C for 1.5 min, and 72°C for 2 min for 18
cycles. Mouse TRAIL cycle conditions were 92°C for 30 s, 65°C
for 30 s, and 72°C for 2 min for 35 cycles. Samples were
resolved on a 2% agarose gel and visualized with ethidium bromide.
Immunohistochemical staining
Human eye globes obtained from the eye bank were punctured with an 18-gauge needle and fixed in 10% neutral buffered Formalin. Mouse globes were punctured with 30-gauge needle before fixation. The fixed globes were embedded in paraffin, and 4-µm sections were obtained. Following blocking with normal donkey serum (Sigma-Aldrich, St. Louis, MO), tissue sections were stained with K-18 anti-TRAIL Ab (1:20; Santa Cruz Biotechnology, Santa Cruz, CA) at 4°C overnight. Then sections were blocked with rabbit serum (Vector, Burlingame, CA), incubated with biotinylated rabbit anti-goat Ab (Vector), streptavidin-HRP (Vector), and Vector VIP substrate sequentially. Between incubations, sections were washed four times in PBS. After final washing, sections were coverslipped with Del/Mount (Biomeda, Foster City, CA). To demonstrate the specificity of the staining, tissues were stained with K-18 Ab after preadsorption with 19-fold weight excess of the blocking peptide (Santa Cruz Biotechnology).
Western blot analysis
Human eye globes were dissected into cornea, retina, iris, and RPE. Corneas were placed in PBS at 37°C for 1 h, and separated into endothelial and epithelial halves. Dissected tissues were placed in PBS containing 1% Nonidet P-40 (Sigma-Aldrich) and protease inhibitor mixture (Roche, Basel, Switzerland). Tissues were ground using a Tissue Tearor (Biospec Products, Bartlesville, OK). The lysed tissues were centrifuged at 14,000 x g to remove cellular debris, and the protein concentration of each sample was determined using the colorimetric bicinchoninic acid assay (Pierce, Rockford, IL). Equal amounts of protein were separated on 10% Bis-Tris gel (Invitrogen, Carlsbad, CA), transferred to 0.2-µm nitrocellulose membrane (Invitrogen), and blocked with 5% skim milk in TBS/0.05% Tween 20 for 2 h. The membrane was incubated with anti-TRAIL Ab (Peprotech, Rocky Hill, NJ) at 4°C overnight. After washing, the membrane was incubated with HRP-conjugated anti-rabbit Ab in Tris-Tween 20 for 1 h. Following several washes, the blot was developed by chemiluminescence (ECL-plus; Amersham-Pharmacia, Piscataway, NJ). Control blots were processed without incubation of the primary Ab.
In vitro killing of tumor cells by corneal endothelium
Whole human corneas were quartered and placed in 48-well plates with endothelium facing up. Tumor cell lines were labeled for 2 h with 5 µCi/ml [3H]thymidine at 37°C in complete DMEM. Cells were washed three times with PBS and resuspended in complete DMEM. The target cells (105 in 5 µl) were placed on the corneal endothelium and cultured for 16–20 h at 37°C. Each culture was divided into two wells of a 96-well plate, and unfragmented DNA was collected by filtration through glass fiber filters (Packard Instruments, Meriden, CT) using a Filtermate 96 cell harvester (Packard Instruments) and counted on a microplate scintillation counter (Packard Instruments). Data are expressed as percentage of DNA fragmentation: (100 x (cpm from cells not cultured with cornea - cpm in experimental group) per cpm from cells not cultured with cornea) ± SEM. Specificity of killing was determined by inclusion of the chimeric protein TRAIL-R2:Fc or Fas:Fc (R&D Systems, Minneapolis, MN). Killing assays using mouse cornea were performed with slight modification. Mouse cornea was dissected with iris attached. Each cornea was placed in U-bottom 96-well plates with endothelium-iris facing up in complete RPMI. Labeled tumor cells (104 in 1 µl) were placed in the pocket between endothelium and iris. Specificity of killing was determined by inclusion of TRAIL-blocking Ab N2B2 or Fas:Fc.
In vivo tumor growth in the anterior chamber (AC) of the eye
The mouse mastocytoma P815 was transfected with murine TRAIL receptor cDNA (P815-DR5) (mouse DR5 is also called MK (17)) or vector control (P815-Ctrl) using Lipofectamine Plus Reagent (Invitrogen). Tumors were then examined for TRAIL and FasL sensitivity in vitro, as described above. None of the lines were sensitive to Fas-mediated death, and only the P815-DR5 cells were TRAIL sensitive (average killing, 70–80%). Tumors were then injected into the AC of BALB/c mice (100 cells/mouse), and tumor growth was monitored daily for 14 days. Data are recorded by a masked observer using a dissecting microscope. They were scored as percentage of the AC that was filled with tumor.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The wide distribution of TRAIL mRNA prompted us to examine the eye
for TRAIL expression. Fig. 1
shows that
human TRAIL mRNA was detectable by RT-PCR throughout the human eye,
including the cornea, iris, retina, and RPE. The presence of human
TRAIL protein was then verified by Western blot analysis in which a
33-kDa band, corresponding to monomeric TRAIL, was detected (Fig. 2). Mouse eye lysates also contained
TRAIL mRNA species (Fig. 1). Immunohistochemical analysis revealed
TRAIL protein was constitutively expressed on both human (Fig. 3, A–C) and mouse ocular tissues
(Fig. 3, E and F). In the cornea, it was
expressed on the endothelium and epithelium (Fig. 3, A and
E), with modest staining in the stroma. TRAIL protein was
also detected on the iris (data not shown), ciliary epithelium (Fig. 3B), RPE, and neurosensory retina (Fig. 3, C and
F) of both species. RPE and iris expressed the highest
levels of TRAIL protein, as determined by immunoblotting (Fig. 2),
while the signal in the corneal layer was less prominent compared with
the immunohistochemistry data. This was most likely due to the dilution
of TRAIL by the high level of matrix proteins found in the corneal
stroma.
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Although TRAIL mRNA is expressed in numerous sites in the body,
studies demonstrating functional expression in organs and organ systems
have been lacking. Therefore, we examined whether biologically active
TRAIL was expressed in the eye of humans and mice. To do this, we took
advantage of an ex vivo culture system developed in our lab
(18), which was used to successfully demonstrate the
presence of functional FasL in the eye. In this assay, isolated corneas
from human or mouse eyes are placed epithelia down in the well of a
tissue culture plate (forming a cup). Labeled target cells are then
placed into this tissue in contact with the endothelium and analyzed
for cell death by harvesting the cells and detecting the extent of
apoptosis following 16- to 20-h incubation. Data in Fig. 4A show that the
TRAIL-sensitive skin melanoma WM 98-1 was induced to undergo apoptosis
by human corneal tissue. The addition of TRAIL-R2:Fc, a specific
inhibitor of TRAIL binding, completely inhibited cell death, confirming
that the target death was indeed TRAIL mediated.
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B show that Renca
cells were killed by gld corneal endothelium, and this
apoptosis was inhibited by inclusion of a TRAIL-specific blocking Ab
(N2B2). We conclude that functional TRAIL is present on the mouse
cornea.
FasL is constitutively expressed on human and mouse corneas, as shown
by its ability to kill Fas-bearing tumor cells (19) and
invading lymphoid cells (18). To determine the
contribution of both TRAIL and FasL, we used the TRAIL- and
FasL-sensitive human prostate adenocarcinoma cell line, PC-3. Fig. 5A shows human corneal tissue
induced apoptosis in PC-3 cells that was inhibited only when both
Fas:Fc and TRAIL-R2:Fc were included in the culture. A similar study in
the mouse cornea revealed the presence of both functional TRAIL and
FasL (Fig. 5B). In this experiment, the killing of Renca
cells by normal B6 corneas was reversed by inclusion of Fas:Fc and
N2B2.
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We then examined the ability of the ocular microenvironment to
inhibit tumor growth in vivo. To do this, we took advantage of the
tumor line P815 that grows readily in the AC of the eye, but grows
poorly in the skin (20). P815 was tranfected with mouse
DR5 (P815-DR5) or the empty plasmid vector (P815-Ctrl). In vitro
cytotoxicity determined that P815, P815-Ctrl, and P815-DR5 were not
sensitive to Fas-mediated death, and that only P815-DR5 was sensitive
to TRAIL-induced apoptosis (not shown). We then injected 100 tumor
cells into the right eye of BALB/c mice and monitored tumor growth
daily for 14 days. Initially, all tumors grew and were visible by day 3
(not shown). However, the majority of the P815 and P815-Ctrl tumors
continued to grow, while the P815-DR5 tumors regressed substantially,
or did not grow at all. Data in Table I
reflect our observations on day 14 and are the sum of two separate
experiments. Nearly all (79%) wild-type P815 tumors were solid tumor
by day 14, filling the entire AC. The vast majority of P815-Ctrl tumors
were either solid tumors (8 of 15) or filled greater than 50% of the
AC (4 of 15). In sharp contrast, no P815-DR5 cells developed into solid
tumors. Most of these eyes were either devoid of tumors (9 of 24), or
tumors filled less than 50% of the AC (12 of 24). Due to the
aggressiveness of the wild-type and P815-Ctrl tumors, these mice were
sacrificed on day 14. In a subsequent study, we monitored the P815-DR5
tumors until day 21 (n = 20). Seventy percent of the
mice had no tumors, while 20% had very small tumors remaining in the
eye. Ten percent of these mice eventually developed solid tumors, but
these were significantly delayed and never to the degree of the
controls. These data suggest that constitutive TRAIL in the eye can
inhibit the growth of TRAIL-sensitive tumor cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The pattern of expression for TRAIL in the eye is remarkably similar to that of FasL, in which these ligands are positioned at sites of interaction between the internal structures of the eye and the outside world. Expression on the corneal epithelium can prevent cells from entering from the conjunctiva, while expression in vascularized iris can prevent entry of cells via iris blood vessels. Expression on the corneal endothelium protects this very important single layer of cells. These nonregenerating cells are essential to the maintenance of corneal integrity and clarity. Finally, expression on the RPE forms a barrier between the photoreceptors and the vascularized choroid. It is interesting to note that most ocular tumors take up residence in the choroid, just outside the barrier formed by TRAIL and FasL. With this in mind, it will be interesting to examine TRAIL and FasL sensitivity of freshly isolated ocular tumors.
Our data show that in human and wild-type mouse corneas, tumor cells can be killed by both FasL and TRAIL. In fact, simultaneous functional inhibition of both FasL and TRAIL is required to completely block apoptosis induced by the corneal endothelium. Corneal tissues from FasL-defective gld mice achieve the same level of killing (35–40%) as that obtained from wild-type mice; however, this cell death is mediated solely by TRAIL. Perhaps the expression of TRAIL compensates for the loss of functional FasL, which is an issue that is currently under investigation.
An important test of our hypothesis was the demonstration of the effects of TRAIL on ocular tumor formation in vivo. Therefore, we examined the growth of the mastocytoma P815, which grows very well when injected in the AC (20). Transfection of this line with mouse DR5 severely inhibited the growth of this tumor in the eye. This suggests that ocular TRAIL can control the growth of DR5+ cells in the eye.
It is not known whether TRAIL contributes to immune privilege nature in the eye, because immune privilege is defined as the prohibition of immune responses. A recent study reported the presence of TRAIL mRNA transcripts and protein in the placenta (21), implying that it may participate in immune privilege in this tissue. TRAIL is not implicated in the activation-induced cell death of normal T lymphocytes (as is FasL) (22), but TRAIL receptors are expressed on activated thymocytes, making these cells sensitive to apoptosis via TRAIL (23). TRAIL is also believed to control autoimmune inflammation, in which it has been implicated in the prevention of cycle progression in arthritogenic lymphocytes (24). In a mouse model of experimental autoimmune encephalomyelitis, TRAIL inhibits encephalomyelitis by preventing activation of autoimmune T cells (25). It is not known whether functional TRAIL is expressed in the tissues affected by these disorders. TRAIL is not expressed on freshly isolated T cells, and TRAIL expression on activated T cells is controversial (22, 26). However, NK cells have been shown to express TRAIL and use this molecule for tumor surveillance (26, 27).
The involvement of the Fas/FasL pathway in tumor surveillance has been proposed, as demonstrated by the higher incidence of metastasis by Fas+ tumors in FasL-defective gld mice (4, 28). The loss of functional Fas by mutation is associated with the progression of adult T cell leukemia (29, 30) and multiple myeloma (31). The increased incidence of certain tumors in lpr and gld mice also supports this idea (32). However, even with the increased risk of lymphoma in autoimmune lymphoproliferative syndrome patients (33), the Fas/FasL system is not sufficient to prevent many malignancies. Indeed, the genetic instability of tumors and potential loss of susceptibility make it unlikely that a single molecule is accountable for the surveillance function. This suggests that there are compensatory mechanisms present, and we propose that the eye uses TRAIL in this capacity.
It is predicted that 2100 cases of eye and orbit tumors will be
diagnosed this year in the U.S. (34), with uveal melanoma
comprising over 70% of these cases. The second most common ocular
tumor is non-Hodgkin’s B cell lymphoma. These tumors frequently reside
in the choroid (melanoma) (35) or between the RPE and
Bruch’s membrane (B cell lymphoma) (36), with infrequent
invasion to the retina and vitreous. The positioning of TRAIL in the
eye suggests that it might contribute to these observations by
preventing entry of tumors into the eye. Tumors that enter the eye may
acquire TRAIL resistance through the induction of antiapoptotic
proteins or mutations in TRAIL receptors. This will require further
study.
The protection of the visual axis by inhibitors of inflammation is well documented. It is clear that the constitutive expression of inhibitory cytokines, inhibitory neuropeptides, blood:ocular barrier, and FasL provides a basis for immune privilege. The addition of TRAIL as an inhibitor of tumor growth and/or invasion provides another dimension to protecting the eye from damage. However, it is clear the important organs such as the eye use multiple strategies to ensure integrity of function and the survival of the species.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas A. Ferguson, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid, Box 8096, St. Louis, MO 63110. E-mail address: Ferguson{at}vision.wustl.edu
3 Abbreviations used in this paper: FasL, Fas ligand; AC, anterior chamber; RPE, retina pigment epithelium.
Received for publication December 4, 2001. Accepted for publication August 22, 2002.
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B and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 7:813.[Medline]
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