Download Interleukin-1-beta changes the expression of

Interleukin-l-/3 Changes the Expression of
Metalloproteinases in the Vitreous Humor and
Induces Membrane Formation in Eyes Containing
Preexisting Retinal Holes
William Kosnosky,* Ting H. Li,-f Vytautas A. Pakalnis* Alvin
and Richard C. Hunt *f
Purpose. Proliferative vitreoretinopathy occurs when cells migrate into the vitreous humor,
where they proliferate and produce a membrane composed of extracellular matrix. Interleukin-1-beta (IL-1-/?) may be involved in these processes because it is chemotactic and mitogenic,
and it stimulates metalloproteinase production. In the present study, the effects of intravitreally injected IL-1-/3 on retinal membrane formation and the associated changes in metalloproteinase content of vitreous humor were examined.
Methods. Rabbit eyes were injected with IL-1-/? in a buffer, with or without the prior creation
of retinal holes. Control eyes received the buffer alone or no injection, with or without retinal
holes. Animals were examined by slit lamp biomicroscopy and indirect ophthalmoscopy for
1 month. Zymography was performed on a portion of vitreous humor to assess collagenase
content, and the remaining tissue was subjected to histologic analysis.
Results. Intraocular IL-1-/? induced perilimbal vessel engorgement, keratic precipitates, synechiae, flare, lens deposits, optic disk hyperemia, and granulomatous formations that gradually
subsided during the first week. Intravitreal injection of IL-1-/3 in eyes with preexisting retinal
holes additionally induced membrane formation. Zymographic analysis of vitreous humor
from animals sacrificed 24 hours after IL.-1-/3 injection showed a 100-kd and a 65-kd gelatinase,
whereas control vitreous humor contained predominantly a single gelatinase species of approximately 65 kd. Retinal holes did not affect IL-1-/3 induction of the 100-kd gelatinase.
Conclusions. IL-1-/3 induces a 100-kd gelatinase in the vitreous humor and epiretinal membrane
formation in eyes containing preexisting retinal holes. The presence of retinal holes and
abnormal production of cytokines may lead to a cascade of events, including aberrant extracellular matrix remodeling, that result in proliferative diseases of the eye. Invest Ophthalmol
Vis Sci. 1994;35:4260-4267.
X roliferative vitreoretinopathy (PVR) is one of the
major causes of failure of surgery for the repair of
retinal detachments. This pathologic condition can be
separated into three distinct phases. The first phase
involves an infiltration of cells into the preretinal or
subretinal space, or both, where the cells begin to
From the Departments of'* Ophthalmology and ^Microbiology and Immunology,
University of South Carolina School of Medicine, Columbia, South Carolina.
Supported by National Institutes of Health grants EY06164 and EY10516 (RCH)
and a grant from Research to Prevent Blindness, Inc. THL was supported by a
Chinese Provinces Fellowship.
Submitted for publication April 12, 1994; revised fune 7, 1994; accepted July 5,
1994.
Proprietary interest category: N.
Reprint requests: Dr. Richard C. Hunt, Department of Microbiology and
Immunology, University of South Carolina School of Medicine, Columbia, South
Carolina, 29208.
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proliferate. The next includes the continuation of cell
proliferation and the production of an extracellular
matrix (ECM). The final phase involves the contraction of the ECM resulting in retinal detachments.
Studies of PVR membranes taken from human
subjects show a complex mixture of cell types, including retinal pigment epithelial (RPE), glial, and fibroblast-like cells.1"5 More recent studies of PVR membranes have found inflammatory cells, suggesting that
the immune system may be involved.6"8
The ECM of PVR membranes includes collagen,
laminin, and fibronectin and is similar in composition
to the basement membrane of the eye (Bruch's membrane) maintained by RPE cells.9"12 The production
and remodeling of ECM, which must occur during
Investigative Ophthalmology & Visual Science, December 1994, Vol. 35, No. 13
Copyright © Association for Research in Vision and Ophthalmology
Intraocular Membrane Induction by Interleukin-1
PVR membrane formation, involves interaction of secretory cells producing membrane components (including collagen) and a family of enzymes (matrix
metalloproteinases [MMPs], collagenases).13 Modulation of the finely controlled interaction between the
ECM and MMP in inflammation causes cellular proliferation, migration, and tissue morphogenesis13 and
may lead to the development of pathologic conditions
including PVR.
Interleukin-1-beta (IL-1-/?) is involved in the
acute-phase response. It is chemotactic for neutrophils, monocytes, and RPE cells in vitro, and it stimulates proliferative responses in many tissues.14'15 This
cytokine has been shown to be produced by ocular
cells, including RPE and corneal cells,1617 and has
been found in ocular fluids during inflammation,
trauma, and PVR.18"20 Moreover, an in vitro model of
retinal membrane contraction, as occurs in PVR, is
modulated by IL-1-/?.21
Previous investigations have noted that locally injected IL-1 elicits an acute inflammation of the anterior segment.22"24 However, in these studies, clinical
features such as might be involved in PVR formation
in the posterior segment were not studied. The metalloproteinase content of normal and inflamed vitreous
humor also has not been previously investigated, yet
ECM turnover is likely to be a fundamental process
in proliferative eye disease. To mimic the surgical condition, where cytokines are likely to be present, the
synergism between retinal surgery and cytokines
in membrane formation and MMP production was
studied.
MATERIALS AND METHODS
Intraocular Effects of Interleukin-l-/3
Rabbits weighing between 4 and 5 pounds were used
in accordance with the ARVO Statement for the Use
of Animals in Ophthalmic and Vision Research. Eyes
were dilated using a 1:1 solution of 1% phenylephrine
hydrochloride/2.5% cyclopentolate hydrochloride.
Intramuscular ketamine was used to maintain anesthesia. For all intravitreal injections, 250 U of recombinant human IL-1-/? (Eli Lilly, Indianapolis, IN) in 0.1
ml balanced saline solution (BSS) were used. The activity of IL-1-/? was determined by a thymocyte proliferation assay using cells from C3H/HeJ mice. One unit
of IL-1-/? is denned as that which results in 50% of
maximum thymidine incorporation.
In experiment 1, six animals were anesthetized, a
lid speculum was inserted, and the eye was entered
with a 30-gauge needle just above the equator. The
experimental eyes received IL-1-/? in 0.1 ml BSS over
the optic nerve under indirect visualization using a
contact lens and operating microscope. The contralateral eye was used as a control and received 0.1 ml of
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4261
BSS alone. This group was examined at 2, 4, 8, and
24 hours before they were killed. Eyes were enucleated
and bisected. Half of each eye was used to obtain
samples for zymography, and the remaining half was
used for histology. Tissue used for histology was fixed
with 10% phosphate buffered formaldehyde at room
temperature, dehydrated in a graded ethanol series,
and embedded in paraffin wax. Eight-micron sections
were stained with hematoxylin and eosin.
In experiment 2, 16 animals were anesthetized,
eyelids were retracted, and a retrobulbar injection of
2% lidocaine was given. The conjunctiva was retracted,
and a 25-gauge sclerotomy was performed just above
the equator, allowing access to the globe's interior.
Two or three retinal holes (approximately a half-disc
diameter) were created by aspiration inferiorly to the
medullated nerve fiber layer using a 30-gauge cannula.
Holes were created in both eyes of 11 rabbits and in
a single eye of the remaining 5 rabbits. Two of the eyes
were excluded from the study because of excessive
hemorrhaging after the surgical procedure. All animals were allowed to heal for 1 week. The rabbits
were anesthetized again with ketamine hydrochloride.
Experimental eyes were injected with IL-1-/? in BSS.
Controls either were injected with BSS or were not
injected. Six animals (six eyes with IL-1-/? and retinal
holes and six eyes with BSS and retinal holes) were
killed after 24 hours to collect vitreous samples for
zymography. The remaining 10 animals were examined each day for 1 week and once per week thereafter
for approximately 1 month. This resulted in four
groups of eyes that were examined before euthanasia
and sample collection for zymography and histology,
as follows: (1) IL-1-/? and holes [six eyes]; (2) BSS
and holes [six eyes]; (3) holes without injection [four
eyes]; and (4) IL-1 without holes [four eyes].
Metalloproteinase Activity of Vitreous
Samples of vitreous humor were centrifuged at
30,000g-for 10 minutes, and the supernatant fraction
containing soluble proteins was collected and frozen
at — 70°C until further study. The presence of gelatinases was determined using zymography. Before separation by SDS-polyacrylamide gel electrophoresis, the
vitreous supernatant fractions were incubated for 1
hour in either 0.1 mM p-amino phenylmercuric acetate (APMA) or a sample buffer containing 0.05 M
tris, 1.0% SDS, 10% glycerol, and 0.1% bromophenol
blue. In the case of APMA incubation, the sample
buffer was added immediately before loading the samples onto the gel. The supernatant fractions were then
separated at 25 mA in either a 7% or a 12% polyacrylamide gel containing 1 mg pigskin gelatin/ml (Sigma,
St. Louis, MO). The gel was washed twice in a 50-mM
Tris buffer (pH 7.5) containing 2.5% Triton X-100,
then rinsed once and incubated for 18 hours at 37°C
in a 50 mM Tris buffer (pH 7.5) containing 5 mM
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Investigative Ophthalmology & Visual Science, December 1994, Vol. 35, No. 13
CaCl2 to allow enzymatic degradation of the gelatin.
Gels were stained with Coomassie blue R-250 and destained with methanol:acetic acid:water (5:1:4). Unstained bands were observed in regions of gelatinase
activity. Standard molecular weight markers (Bio-Rad,
Richmond, CA) containing myosin, /3-galactosidase,
phosphorylase b, bovine serum albumin, and ovalbumin were included in each gel. Molecular weights
of the enzymes found by zymography were determined
by first-order regression using the standards as the
reference points.
RESULTS
Preliminary studies demonstrated that IL-1-/? alone
elicited posterior inflammation accompanied by an
increase in vitreous protein levels at 24 hours.26 Protein levels (mean mg/ml ± SD) were 5.08 ± 1.59 (n
= 12) for Il-l-/3-injected eyes, 1.51 ± 0.81 (n = 16)
for BSS-injected eyes, and 1.36 ± 0.44 (n = 22) for
uninjected eyes. Analysis of variance of these sample
sets showed a highly significant difference between
the Il-1-^-injected set and BSS-injected set (P< 10~6).
There was no significant difference found between
the BSS-injected set and the uninjected set. These preliminary experiments involving periods of 1 month
showed that retinal detachments occurred in 4 of 30
IL-l-/3-injected eyes. Further experimentation revealed that I1-1-/5 introduced into eyes with surgically
created retinal holes caused membrane formation in
5 of 7 eyes.
Clinical Observations
During the first 24 hours, eyes injected with IL-1-/0
(six eyes from experiment 1 and 10 eyes from experiment 2) showed an intense inflammatory response in
the anterior segment while all controls showed little
or no reaction. The presence of a hole made no difference in the early clinical observations. After 4 hours,
the perilimbal blood vessels (those surrounding the
cornea just below the limbus) of the IL-l-/?-injected
eyes began to show signs of engorgement (Fig. 1A).
This steadily increased and peaked at 24 hours, after
which it slowly decreased and finally resolved by the
end of the second week. Punctate keratic precipitates
denoted by small grayish flecks of protein and inflammatory cells located on the endothelium were
seen in 9 of 16 IL-l-/?-injected eyes by 24 hours (Fig.
1A). By the end of the first week, 8 of 10 IL-l-/?-injected eyes had developed keratic precipitates that resolved by 8 days. Anterior chamber flare including
protein, fibrous material, and a few cells steadily increased over time. At 8 hours, the flare reached moderate to severe levels. At 24 hours, anterior chamber
flare was so extreme in two animals that a small hemorrhage in the iris caused an accumulation of blood in
the lower portion of the anterior chamber. At 24
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hours, all 16 IL-l-/3-injected eyes had fixed clumps of
fibrous material attached to the anterior lens capsule
(Fig. IB). Adhesions of the iris to the anterior lens
capsule (posterior synechiae) were present in 11 of
16 eyes after 1 week (Fig. 1C). Synechiae were severe
in 8 eyes (encompassing >25% of the pupil) and moderate in 8 eyes (<25% of the pupil). All IL-l-/3-injected
eyes showed "iris pattern blur" representing iris
edema and engorged capillaries but inflammatory
lens opacities or corneal edema could not be found.
Initial examinations using indirect ophthalmoscopy
of eyes that received IL-1-/? from experiments 1 and 2
showed an inflammatory response within 24 hours that
included vitreous haze and disk hyperemia. Delayed observations of eyes from experiment 2 showed that the
inflammation reached its maximum within 3 days and
subsided within 1 week. These eyes also exhibited white
aggregates located in the mid to inferior vitreous body.
These aggregates peaked in size from 6 to 9 days. The
aggregates were completely absorbed by the end of the
study in 8 of 10 eyes. However, highly retractile points
were present in the vitreous body, suggesting cells or
unabsorbed breakdown products. The remaining two
eyes contained only remnants of the initial aggregates.
The posterior segment of all eyes not injected with ILr
1-/3 from experiments 1 and 2 showed only trace inflammation caused by the needle.
By the end of 1 month, extensive membranes developed in 3 of 6 eyes with retinal holes injected with IL1-/3 (Fig. 2A), whereas eyes without retinal holes injected
with ILrl-P or eyes with retinal holes injected with BSS
(Fig. 2B) remained free of membrane formation. Membranes originated over a retinal hole, extended into the
vitreous body, and formed adhesions to other portions
of the retina. A traction retinal detachment of the medullated nerve fiber layer near the optic disk developed
in one eye containing a membrane.
Histopathology
ILrl-/?-injected eyes, irrespective of the presence of a
retinal hole, contained a cellular infiltrate in the anterior
and posterior segments. At 24 hours, the infiltrate included predominantly neutrophils, with some plasma
cells and lymphocytes. Sections of an eye 7 days after IL1-0 injection showed a cellular aggregate opposing the
internal limiting membrane (Fig. 3A). Higher magnification showed this aggregate to be a granulomatous formation composed of monocytes, red blood cells, and
ascites (Fig. 3B). Eyes with holes injected with BSS or
not injected showed minimal response to the injection
consisting of a few mononuclear cells.
Eyes without retinal holes injected with IL-1-/?
showed a minimal cellular infiltrate remaining after 1
month, and these cells were mainly monocytes. The
membranes formed in IL-l-injected eyes containing retinal holes originated from the holes and extended to
other areas of the retina, forming traction (Fig. 4A). The
Intraocular Membrane Induction by Interleukin-1
4263
FIGURE 1. Slit lamp photographs of the anterior segment of
eyes 24 hours after injection with IL-1-/3 (A) showing keratic
precipitates (arrow) and perilimbal vessel engorgement (arroiohead), (B) white fibrous anterior capsular deposits, and
(C) synechiae.
RPE cell layer had a highly cystic appearance, indicating
hyperplasia. Higher magnification of the membrane
(Fig. 4B) showed that it involved retinal and inflammatory elements. Several distinct cell types were seen within
a lightly staining extracellular matrix. These included
inflammatory cells with darkly staining nuclei covering
a major portion of die cytoplasm, spindle-shaped cells
indicating cells of fibroblast or RPE origin, and rounded
cells with lightly staining nuclei indicating glial cells,
possibly Muller cells, from die inner nuclear layer. Control eyes with retinal holes injected with BSS remained
free of membranes (Fig. 4C), but four eyes with retinal
FIGURE 2. Fundus photographs of eyes containing preexisting retinal holes. (A) An eye
injected 1 month earlier with IL-1-/?. A membrane has formed over the hole and extends
into the vitreous body, forming adhesions with other portions of the retina. (B) An eye
injected with balanced saline solution. The retinal hole is defined by the upturned edges
of the neural retina. Notice that the hole remains clear and the retinal pigment epithelial
cell layer remains undisturbed.
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Investigative Ophthalmology 8c Visual Science, December 1994, Vol. 35, No. 13
FIGURE 3. Hematoxylin and eosin-stained section from a preliminary experiment showing a
granulomatous formation in an eye enucleated 7 days after IL-1-/3 injection. (A) Low power:
A granulomatous formation is seen in the vitreous body opposing the inner limiting membrane of the retina. Original magnification, X121. (B) High power: The granulomatous
formation is composed of mononuclear cells and erythrocytes. Original magnification, X483.
holes showed signs of basement membrane thickening
and some disruption of the RPE cell layer; fibrosis was
seen in one control eye.
Zymography
The formation and remodeling of collagen-containing
membranes in eyes treated with IL-1-/? after retinal
hole formation must require synthesis and degradation of ECM components, particularly collagen. Primary among the enzymes involved in such processes
is a series of MMPs.27 Zymography was used to determine the effect of intravitreal injection of IL-1-/? on
the collagen-degrading MMPs of the vitreous humor
(Fig. 5). Normal vitreous humor contains almost ex-
FIGURE 4. Hematoxylin and eosin-stained sections of the posterior segment in eyes enucleated 1 month after an intravitreal injection. (A) An eye with preexisting retinal holes
injected witfi IL-1-/3 showing a membrane (arrow) extending
processes to other portions of the retina, creating a retinal
traction (open arrows). Retinal pigment epithelial hyperplasia
is also evident (arrowhead). Original magnification, X24. (B)
Higher magnification of the membrane in Figure 4A showing mononuclear cells, gliai cells, and spindle-shaped cells.
Original magnification, X483. (C) An eye with preexisting
retinal holes injected with balanced saline solution showing
a hole remaining free of membrane formation. Original
magnification, X121.
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4265
Intraocular Membrane Induction by Interleukin-1
200
FIGURE 5. Zymography of gelatinolytic activity in vitreous humor from rabbit eyes with 1-month-old retinal holes without
injection (lane 1), without retinal holes 1 month after the
injection of IL-1-/7 (lane 2), with retinal holes 1 month after
balanced saline solution injection (lane 3), with retinal holes
1 month after the injection of IL-1-/3 (lane 4), without retinal
holes 24 hours after balanced saline solution injection (lane
5), and without retinal holes 24 hours after IL-1-/5 injection
(lane 6). Lane 7: High molecular weight standards. Samples
were separated using a 7% SDS-PAGE gel containing a gelatin substrate. After incubation, bands of gelatinase activity
were detected by staining with Coomassie blue. The presence of gelatinases is indicated by clear bands.
inantly the 65-kd enzyme; the induced 100-kd enzyme
disappeared (Fig. 5).
Zymographic analysis suggested that the MMPs
might have been involved in the formation of retinal
membranes; however, retinal hole formation alone
had no effect on MMP production, and IL-1-/3 alone
did not produce membranes. It appears, therefore,
that MMP induction alone is insufficient to cause the
changes observed.
SDS used in zymographic analysis activates MMP
proenzymes by a conformational change. To determine if the MMPs detected in samples of vitreous humor were in their active or proenzyme form, the supernatant fractions were incubated in the presence of
APMA (Fig. 7). Activation of the proenzyme with
APMA involves autoproteolytic cleavage of a peptide
fragment from the amino-terminus, resulting in size
reduction.27 Supernatant fractions incubated in APMA
before gel separation contained a mixture of the 65kd form and a smaller form. Those not incubated
showed predominantly the 65-kd form. This confirms
that the 65-kd enzyme present in vitreous humor was
largely present in a latent form. The 100-kd enzyme
also showed a size reduction after APMA incubation,
suggesting it, too, was present in a latent form,
DISCUSSION
clusively a 65-kd gelatinase, whereas two predominant
forms of gelatinase (100 kd and 65 kd) could be demonstrated in vitreous humor 24 hours after the injection of IL-1-/3. Retinal holes were found to have no
effect on MMP production (Fig. 6). One month after
injection of IL-1-/?, vitreous humor contained predom-
FIGURE 6. Zymography of gelatinolytic activities in vitreous
humor from rabbit eyes with preexisting retinal holes enucleated 24 hours after intravitreal injection of IL-1-/? (lanes
2, 4, and 6) or balanced saline solution lanes (1,3, and 5).
Lane 7: Molecular weight standards. Preexisting retinal
holes did not affect MMP induction. MMP = matrix metalloproteinase.
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The neural retina may act as a barrier preventing access of vitreous humor components, including growth
a oo
FIGURE 7. Zymography of gelatinolytic activities in vitreous
humor from rabbit eyes enucleated 24 hours after IL-1-/3
injection (lane 1, after APMA incubation; or lane 2, after
SDS incubation) or balanced saline solution (lane 3, after
APMA incubation; or lane 4, after SDS incubation). Lane 5
shows high molecular weight standards. Supernatant fractions were separated on a 12% gelatin substrate gel. Note
the decrease in molecular weight of the gelatinase activity
in fractions incubated in APMA, indicating that the metalloproteinases are normally present predominantly in a latent
form.
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Investigative Ophthalmology 8c Visual Science, December 1994, Vol. 35, No. 13
factors, to the pigment epithelium. It may also maintain the integrity of the underlying cell layers. Because
the formation of PVR membranes may result from a
surgical breach of the neural retina, attempts have
been made to mimic this process in an animal model.
However, damage to the barrier in the form of created
retinal holes, although able to cause RPE cell proliferation, 28 does not allow membrane formation. This indicates that factors other than components of vitreous
humor have access to the RPE layer for membrane
induction. Such factors might result from the inflammatory aspect of PVR. In PVR, cytokine production is elevated.20 It has been well established that the
intravitreal injection of interleukin-1 produces inflammatory changes, including a cellular infiltrate in
the eye, but most studies have emphasized changes in
the anterior segment of the eye. In view of the wellknown chemotactic and mitogenic activity of IL-1, the
possible synergistic effects of the presence of a retinal
hole and IL-1-/? in the promotion of retinal membranes were studied.
As expected, cell and flare were observed by slit
lamp and indirect ophthalmoscopy in eyes injected
with IL-1-/?. The acute response consisted predominantly of neutrophils, as reported by others, 22 and the
inflammation elicited by the cytokine did not differ
in eyes with or without holes. However, membranes
developed only in eyes containing a retinal hole and
IL-1-/?, suggesting the cooperation of both inflammatory and vitreous humor factors in the cellular migration and proliferation that is typical of PVR. Nevertheless, it should be noted that there are limitations in
the model system used in this study. In humans, membranes can form because of tears in the retina, 29 but
this was not true of the rabbits used in these experiments. This may reflect anatomic differences between
rabbit and human eyes, especially with regard to the
vasculature. In humans, retinal blood vessels are abundant. In rabbits, the retinal vessels are restricted to
the medullary rays—a medullated nerve fiber layer
originating from the optic disk and extending nasally
and temporally in two broad white bands. 30 In the
present work, holes were created inferiorly to the medullated nerve fiber layer—an area devoid of retinal
blood vessels.
The process of membrane formation involves cellular proliferation and the production of a disorganized ECM containing constituents similar to Bruch's
membrane. It is likely that this ECM is produced and
remodeled by RPE and other cells that constitute the
epiretinal membrane. Among the enzymes involved
in these processes are the MMPs. Moreover, a variety
of studies have linked IL-1 production to MMP, induction and to membrane contraction, the most devastating event of pvR.21-31"33 It is therefore possible that
the effects of IL-1-/? in the presence of a retinal hole
are mediated by the synthesis of new MMPs; indeed,
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two predominant gelatinases (the 100-kd and the 65kd forms) were found in vitreous humor 24 hours
after the injection of IL-1-/?, whereas control vitreous
humor contained predominantly the 65-kd form. Samples taken 1 month after IL-1-/? administration showed
the vitreous humor had returned to the control state.
However, the additional presence of a retinal hole did
not affect the MMPs observed, and a retinal hole alone
did not affect MMP production. Thus, induction of
the 100-kd MMP by IL-1 cannot alone explain membrane formation in the model system used. Furthermore, both MMPs were present predominantly in a
latent form. It is likely that these enzymes exist as an
extracellular pool and become activated at specific
sites where membrane remodeling occurs, therefore
making detection of the patent enzyme difficult.
Our finding of IL-1 induction of MMP reflects
similar results with a cultured cell system. RPE cells
normally produce a 65-kd collagenase constitutively,
whereas IL-1-/? causes RPE cells to produce a 100-kd
collagenase.21 However, the situation in the eye may
be more complex, and it is possible that other ocular
cells types and infiltrating leukocytes contribute to the
MMP content of vitreous humor.
In mature animals, extracellular matrix remodeling is a continuous process for cells that form a basement membrane, and it is important in maintaining
the integrity of the basement membrane and cellextracellular matrix contacts. In disease states, the
precisely controlled events that result in the formation
of correct cellular interactions may go astray. For example, in metastatic neoplasia, cells produce an excess
of MMPs, which loosens cellular contacts with surrounding cells and the basement membrane, thus
allowing the invasion of other tissues.27 The presence
of retinal holes from trauma, in conjunction with the
abnormal production of cytokines (including IL-1-/?),
may under certain circumstances lead to a cascade of
events in the eye—including cell migration, proliferation, and matrix remodeling—similar to that seen in
neoplasia and, indeed, in normal wound healing.
Key Words
proliferative vitreoretinopathy, interleukin, retina, metalloproteinase, rabbit
Acknowledgment
The authors thank Dr. Jo H. Calkins for obtaining the IL1-/3 and for assistance with the thymocyte assay.
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