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From the Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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METHODS. Bacterial lipopolysaccharide (LPS) was injected into hind footpads of
C3H/HeN mice; and AqH, collected at 6, 12, 24, and 48 hours, was
evaluated for content of transforming growth factor (TGF)-ß, tumor
necrosis factor (TNF)-
, interleukin (IL)-1ß, IL-6, and interferon
(IFN)-
and capacity to suppress anti-CD3–driven T-cell
proliferation. Cytokine mRNA expression in iris–ciliary body (I/CB)
was analyzed by RNase protection assays.
RESULTS. During 6 to 24 hours after LPS injection, total TGF-ß levels in AqH increased even though the fluid lost its capacity to suppress T-cell activation. At this time, AqH contained high levels of IL-6, and I/CB contained high levels of IL-6 mRNA. When IL-6 was neutralized with specific antibodies, inflamed AqH reacquired its capacity to suppress T-cell activation, which correlated with high levels of TGF-ß. Coinjection of IL-6 plus antigen into the anterior chamber of the eye of normal mice prevented antigen-specific anterior chamber–associated immune deviation (ACAID).
CONCLUSIONS. LPS-induced intraocular inflammation is associated with local production of IL-6, which robs AqH of its immunosuppressive activity, perhaps by antagonizing TGF-ß. The fact that IL-6 antagonized ACAID induction in normal eyes suggests that strategies to suppress the intraocular synthesis of IL-6 may reduce inflammation and restore ocular immune privilege.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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-melanocyte–stimulating hormone (-MSH), vasoactive intestinal
peptide (VIP), calcitonin gene–related peptide (CGRP), and macrophage
migration inhibitory factor (MIF).3
4
5
6
7
8
Normal AqH has been
shown to inhibit T-cell activation, leading to proliferation and
cytokine production.2
4
5
Among the factors found in AqH,
TGF-ß2 has been thought to be the most important agent responsible
for inhibiting T-cell responses in vitro. TGF-ß is produced locally
within the eye, and explants if iris–ciliary body (I/CB) has been
found to produce immunosuppressive factors, including
TGF-ß.9
10
11
12 Ocular immune privilege is believed to serve the purpose of limiting the extent to which innate and adaptive immune responses lead to intraocular inflammation. By limiting intraocular inflammation, immune privilege preserves the integrity of the visual axis and thereby prevents blindness. Ocular inflammation, whether expressed within the cornea or within the uveal tract, is a frequent cause of visual impairment. A variety of experimental models have been developed in laboratory animals as a means of studying the pathogenesis of ocular inflammation.13 14 Yet, virtually nothing is known about the extent to which ocular inflammation interferes with ocular immune privilege. For this reason, and because we wish to understand the critical factors that contribute to the existence of ocular immune privilege, we examined the so-called immune privileged status of eyes of mice in which intraocular inflammation had been induced experimentally.
In this study, we used one popular murine model of ocular inflammation
called endotoxin-induced uveitis (EIU). EIU is generated by injecting
lipopolysaccharide (LPS) into the footpads of susceptible mice and
rats. Shortly after injection, an acute inflammatory response emerges
in the anterior segment of the eyes.13
EIU is considered
to represent a number of sight-threatening human inflammatory eye
diseases, such as Behçet’s disease, Crohn’s disease, Reiter’s
disease, and ulcerative colitis. A variety of inflammatory factors have
been suspected of contributing to the development of EIU. Upregulation
of tumor necrosis factor (TNF)-, interleukin (IL)-1ß, and IL-6
mRNAs within ocular tissues during EIU has been
reported,15
16
17
and these cytokines have been detected
directly in AqH of rat eyes displaying EIU.18
19
Although de Boer et al.20 reported that TGF-ß levels were decreased in AqH obtained from human eyes with uveitis, no consensus exists concerning changes in TGF-ß levels in the AqH of rodent eyes with experimental uveitis.15 21 22 More important, no data are available concerning the extent to which TGF-ß in the AqH from eyes of mice with uveitis is active or latent. In normal AqH, the vast majority of TGF-ß is latent.4 5 Unless activated, latent TGF-ß has little if any immunosuppressive properties. Thus, we are interested not only in whether the absolute levels of TGF-ß in AqH change during acute intraocular inflammation but whether the TGF-ß present is in its active or latent form.
Using the model system of EIU, we previously reported that when the blood–ocular barrier was breached, AqH lost its immunosuppressive properties and acquired the novel capacity to stimulate T-cell proliferation in vitro.23 In the current experiment, breakdown of the blood–ocular barrier has been correlated with enhanced levels of TGF-ß in AqH and, more important, with the presence of IL-6, which appeared to be produced locally. When this cytokine was neutralized with specific antibodies, the underlying immunosuppressive properties of AqH (probably due to active TGF-ß) were revealed. Finally, coinjection of IL-6 with antigen into the anterior chamber of normal eyes prevented the induction of anterior chamber–associated immune deviation (ACAID), implying that IL-6 is a major threat to ocular immune privilege.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Induction of Uveitis
To generate EIU, C3H/HeN mice received a footpad injection of 200
µg of LPS from Salmonella typhimurium (Difco, Detroit, MI)
in 100 µl of phosphate-buffered saline solution (PBS).
Aqueous Humor Collection and Analysis
AqH was obtained from eyes of C3H/HeN mice for in vitro analysis
at 0, 6, 12, 24, and 48 hours after LPS injection. AqH was obtained
immediately from both eyes after rats were euthanatized, using a
30-gauge needle and 10-µl micropipets (Fisher Scientific, Pittsburgh,
PA) by capillary attraction, and multiple samples were pooled into a
siliconized microcentrifuge tube (Fisher Scientific). Pooled AqH
samples from panels of at least five mice (10 eyes) were centrifuged at
3000 rpm for 3 minutes, and the cell-free supernatant was frozen
immediately at -70°C. On average, a total of 6 µl of AqH was
obtained from the two eyes of each mouse. Every experiment was repeated
at least three times with similar results.
Determination of Cytokine Production
TGF-ß1 and -ß2 levels in stocked AqH were assessed with a
commercially available human enzyme-linked immunosorbent assay (ELISA)
kit (Promega, Madison, WI). This immunoassay detects biologically
active TGF-ß2. Cross-reactivity with other TGF-ß isoforms is less
than or equal to 5%, according to manufacturer’s manual. Interferon
(IFN)- and IL-2 levels in AqH were also measured using anti-mouse
monoclonal antibody (mAb) pairs: Rat IgG1, 18181D and IgG1, 18112D and
Rat IgG2a, 18161D and IgG2b, 18172D, respectively (PharMingen, San
Diego, CA). IL- ß, IL-6, and TNF- were also estimated using an
ELISA kit from R&D Systems (Minneapolis, MN) according to the
manufacturer’s instructions.
TGF-ß Bioassay
To measure total TGF-ß, AqH was added to Mv1Lu cells (CCL-64;
American Type Culture Collection, Rockville, MD) as described
previously.22
In brief, 1 x
105 Mv1Lu cells in 200 µl with AqH diluted with
Eagle’s Minimum Essential Medium (EMEM; BioWhitaker,
Walkersville, MD) were incubated for 20 hours at 37°C, 5%
CO2. To each well, 20 µl of 50 Ci/ml
3H-thymidine (New England Nuclear–DuPont) was
added, and the plate was incubated for an additional 4 hours. After
incubation, the media was discarded and 50 µl of 10x trypsin–EDTA
(BioWhitaker) solution was added to each well, then the plate
was incubated for 15 minutes at 37°C. The cells were recovered using
a Harvester 96 (Tomtec, Orange, CT), and
[3H]thymidine incorporation was measured in
counts per minute (cpm), using a 1205 Betaplate Liquid Scintillation
Counter (Wallac, Gaithersburg, MD). Cultures of known amounts of pure
TGF-ß1 (R&D Systems) were prepared in the same plates as the assayed
samples. A standard curve of TGF-ß concentration (20 ng/ml to 2
pg/ml) versus counts per minute was used to measure TGF-ß in AqH from
eyes with EIU. Each 15 µl of AqH was diluted to 100 µl with assay
medium. To convert all TGF-ß from the latent to active form, 1N HCl
was added to these samples. After incubation for 1 hour at 4°C, the
acid was neutralized with a 1:1 mixture of 1N NaOH/1 M HEPES.
Assay of T-Cell Proliferation
Spleens were removed from naive BALB/c mice and pressed through
nylon mesh to produce single cell suspensions. Red blood cells were
lysed with Tris–NH4Cl. T cells were subsequently
purified by passage through a T-cell enrichment column (R&D Systems)
according to manufacturer’s directions. The enriched, naive T cells
(>95% Thy 1+ cells as measured by flow
cytometry) were suspended in serum-free medium. Serum-free medium was
composed of RPMI 1640 medium, 10 mM HEPES, 0.1 mM nonessential amino
acids, 1 mM sodium pyruvate, 100 U/ml penicillin, 100 µg/ml
streptomycin (all from BioWhitaker) and 1 x
10-5 M 2-ME
(Sigma, St. Louis, MO) and supplemented with 0.1% bovine serum
albumin (Sigma), insulin, transferrin, selenium (ITS) + culture
supplement [1 µg/ml iron-free transferrin, 10 ng/ml linoleic acid,
0.3 ng/ml Na2Se, and 0.2 µg/ml
Fe(NO3)3; Collaborative
Biomedical Products, Bedford, MA]. The proliferation assay used was a
modification of one described previously.7
24
To
individual wells of a 96-well V-shaped bottom plate (Corning, Corning,
NY) we added 2.0 to 2.5 x 104 enriched T
cells, hamster anti-mouse CD3e IgG (2C11; final concentration is 1.0
µg/ml; PharMingen, San Diego, CA), and 5 µl of AqH or PBS as 20%
vol/vol. Total reaction volume was kept constant at 25 µl. The cells
were pulsed with 2.5 µl of 20 µCi/ml
[3H]thymidine for the final 8 hours of the
48-hour incubation (37°C, 5% CO2/95%
humidified air mixture). Then, the cells were recovered and
[3H]thymidine incorporation was measured in
counts per minute. Each sample was cultured in triplicate. In some
assays, samples of AqH were neutralized with Ab against TGF-ß2 (R&D
Systems) or control polyclonal IgG (ICN Biochemicals, Lisle, IL), or
anti-murine IL-6 (PharMingen) or control monoclonal IgG Ab
(PharMingen). To study the potential interacting effects of TGF-ß and
proinflammatory cytokines, serially diluted cytokine recombinant
porcine TGF-ß2, murine IL-6, murine IL-1ß, murine TNF-, and
murine IFN- (R&D Systems) were added to the T-cell proliferation
assay instead of AqH. All proliferation experiments were performed at
least three times with similar results.
RNA Preparation and RNase Protection Assay
Total RNA was extracted by the single-step method using
RNA-STAT-60 (Tel-Test, Friendswood, TX). I/CBs were dissected from
eyes, homogenized, and centrifuged to remove cellular debris. The RNA
pellet obtained from 20 eyes was resuspended in nuclease-free water and
processed together as a group. Detection and quantification of murine
cytokine mRNAs were accomplished with a multiprobe RNase protection
assay system (PharMingen) as recommended by the supplier. Briefly, a
mixture of [(-32P] UTP-labeled antisense riboprobes was generated
from the mCK-3b Multi-Probe Template Set (PharMingen). This set
contains anti-sense RNA probes that can hybridize with target mouse
mRNAs encoding TNF-ß, lymphotoxin (LT)-ß, TNF-, IL-6,
IFN-, IFN-ß, TGF-ß1, TGF-ß2, TGF-ß3, and MIF as well as two
housekeeping gene products, L32 and glyceraldehyde-3-phosphate
dehydrogenase (GAPDH). Five µg of total RNA was used in each sample.
Total RNA was hybridized overnight at 56°C with 300 pg of the
32P–anti-sense riboprobe mixture.
Nuclease-protected RNA fragments were purified by ethanol
precipitation. After purification, the samples were resolved on 5%
polyacrylamide sequencing gels. The gels were dried and subjected to
autoradiography. Protected bands were observed after exposure of gels
to x-ray film. Specific bands were identified on the basis of their
individual migration patterns in comparison with the undigested probes.
The bands were quantitated by densitometric analysis (NIH Image) and
were normalized to GAPDH.
Induction and Assay of Delayed Hypersensitivity and ACAID
To induce delayed hypersensitivity, mice were immunized
subcutaneously with 100 µg of ovalbumin (OVA) emulsified 1:1 in
complete Freund’s adjuvant (CFA) in a total volume of 100 µl. To
induce ACAID, OVA was injected (50 µg/3 µl PBS) into the AC of one
eye of recipient mice. To examine the effects of IL-6 in ACAID, OVA was
mixed with 20 ng/ml of recombinant murine IL-6 and then injected
intracamerally. One week later these mice were immunized with OVA/CFA
into the nape of neck. After 7 days, OVA (200 µg/10 µl) was
injected into the right ear pinna, and ear swelling responses were
assessed 24 and 48 hours later using an engineer’s micrometer
(Mitutoyo; MTI Corporation, Paramus, NJ). Ear swelling was expressed as
follows: specific ear swelling = (24-hour measurement of right
ear - 0-hour measurement of right ear) - (24-hour
measurement of left ear - 0-hour measurement of left ear) x
10-3 mm. Ear swelling
responses of groups of mice are presented as mean ± SEM.
Statistical Evaluations
Data were subjected to analysis by ANOVA and the Scheffé
test. A value of P < 0.05 was deemed to be
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Eyes of mice afflicted with EIU were also enucleated periodically during the course of their disease and subjected to histologic analysis. Within 6 hours of footpad injection of endotoxin, the AC of recipient eyes contained an eosin-staining amorphous substance. Rare leukocytes were detected on the surface of ciliary body epithelium and iris at this time, and vessels within the stromae of ciliary body and iris were dilated. By 12 hours, these changes were exaggerated, and significant numbers of leukocytes were attached to the corneal endothelium, and to the epithelial surfaces of I/CB. Vasodilatation was particularly intense at 24 hours post-LPS injection, and leukocytes were found to be adjacent to dilated vessels in I/CB. A small number of leukocytes was also found in the posterior vitreous body. Otherwise, the posterior compartment of the eyes of endotoxin-treated C3H/HeN mice was unchanged from that of untreated C3H/HeN mice.
TGF-ß2 Levels in AqH from Inflamed Eyes and Its Influence on
Capacity to Suppress T-Cell Activation
Samples from normal and inflamed AqHs were collected as described
above, acid-activated, and assayed for total TGF-ß (latent plus
active forms) concentration using the mink lung epithelial cell
bioassay. This assay measures all isoforms of TGF-ß1, -ß2, and
-ß3. As revealed in Figure 1
, total TGF-ß levels increased by 6 hours after LPS injection and
peaked at 12 and 24 hours. Thus, development of intraocular
inflammation in EIU correlated with a rise, not a fall, in total
TGF-ß levels in the AqH.
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, IL-1ß,
and IL-6 as proinflammatory cytokines, and IL-2 and IFN- as
activated lymphocyte-derived inflammatory cytokines. AqH samples were
collected as above and subjected to ELISA assay. The results of these
experiments are summarized in Figure 3
. Within 6 hours of LPS injection, AqH contained high levels of TNF-,
IL-6, and IFN- and low levels of IL-1ß. No evidence of IL-2 was
found. The absolute levels of IL-6 were particularly high (>10 ng/ml),
compared with the other cytokines (in the range of 1.5 ng/ml or less).
Moreover, IL-6 continued to be present in AqH throughout the
experiment; at 48 hours the amount of IL-6 was in the 100 pg/ml range.
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, and IFN- in inflamed AqH, we next inquired whether these
factors were produced locally by parenchymal ocular cells or were
elevated because the blood–ocular barrier had been breached. I/CBs
were harvested from normal eyes and from eyes with EIU at the
stipulated times post–LPS injection. These tissues were analyzed for
mRNA content using a RPA. The results are presented in Figure 6
. An autoradiograph of I/CB mRNA samples displayed in Figure 6A
reveals
that IL-6 mRNA is virtually nondetectable in normal tissues but is
massively upregulated at 6 (especially), 12, and 24 hours after LPS
injection. Similar, though quantitatively much fewer, changes were
observed for TNF-, IFN-, and TGF-ß1 mRNAs. No significant
increase was observed in mRNA for TGF-ß2. Densitometric evaluations
of this autoradiograph are presented in Figures 6B
and 6C
. The rise in
IL-6 mRNA from normal to 6-hour samples is approximately 30-fold. An
approximate threefold rise for TGF-ß1 mRNA was observed in the same
interval. These results suggest that the remarkable rise in intraocular
IL-6 early in EIU is due to production locally. Because this rise was
so much greater than the elevations observed with TNF- and IFN-,
we infer that the production arises from ocular parenchymal cells
rather than infiltrating leukocytes.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Using the murine EIU model, we recently reported that, on the one
hand, AqH from inflamed eyes transiently loses its immunosuppressive
properties (capacity to suppress T-cell activation in vitro), and that,
on the other hand, inflamed AqH displays the capacity to activate T
cells (in the absence of a cognate ligand for the T-cell receptor for
antigen). The results of experiments reported here provide a molecular
explanation for these attributes of AqH from EIU-inflamed eyes. TGF-ß
has been known to be one of the important immunosuppressive factors in
normal AqH.4
5
However, in normal AqH virtually all the
TGF-ß is present in the latent, rather than active (i.e.,
immunosuppressive) form. Previous reports of AqH displaying T-cell
inhibitory activity in vitro have been performed after the AqH had been
acid activated.5
This procedure not only activates latent
TGF-ß but it also destroys the numerous immunomodulatory
neuropeptides that are normally present in this ocular fluid. By
contrast, when fresh (not acid-activated) AqH is examined for its
immunosuppressive properties, TGF-ß contributes very little. Instead,
other factors such as VIP and -MSH are the major immunosuppressive
agents. Our results showing only small amounts of active TGF-ß in AqH
removed directly from eyes of normal mice are consistent with this
concept. Our experimental results indicate that total TGF-ß levels
(both 1 and 2 isoforms) were increased as early as 6 hours after EIU
induction and remained elevated through 24 hours (i.e., during the peak
interval of inflammation). Unlike in normal AqH, much of this TGF-ß
was "active." By RPA of I/CB from inflamed eyes, we found that
TGF-ß1 mRNA levels rose modestly, whereas there was little if any
change in mRNA for TGF-ß2. Similar results were reported for EIU in
rats.15
17
We infer that, because the rise in intraocular
TGF-ß levels correlated with a rise in AqH protein levels (reflecting
a breakdown in the blood–ocular barrier), increased TGF-ß in AqH was
probably delivered from blood plasma rather than the eye itself. The
paradox is that AqH displayed increased levels of a potent and active
immunosuppressive factor (TGF-ß) at the same time the eye was
experiencing the development of inflammation in the anterior segment.
Our suspicion that this paradox might be resolved by determining the factor responsible for inflamed AqH’s mitogenic activity proved to be correct. Although we assayed inflamed AqH for several cytokines known to be associated with inflammation, IL-6 turned out to be the factor responsible for enabling T-cell proliferation in vitro. Not only was IL-6 present in inflamed eyes at extremely high levels, but IL-6 mRNA levels in I/CB removed from inflamed eyes was 30-fold higher than IL-6 mRNA levels in similar tissues from untreated eyes. Moreover, inflamed AqH treated with anti–IL-6 antibodies was able to express a potent capacity to suppress anti-CD3–derived T-cell activation in vitro. Our evidence suggests that IL-6 is a potent proinflammatory factor in inflamed AqH. In fact, IL-6 may be a major mediator of uveitis. Although there is general agreement that normal AqH is devoid of this cytokine, IL-6 has been detected in ocular fluids of patients with uveitis31 32 and in rodents with EIU.18 However, IL-6 is not necessary for the development of uveitis subsequent to intravitreal injection of endotoxin in mice.33
To the best of our knowledge, there is no prior evidence to suggest
that IL-6, on its own, is mitogenic for T cells. However, evidence does
exist to implicate IL-6 in the induction of IL-2 receptor expression,
and in differentiation, and proliferation of T cells after stimulation
through the T-cell receptor for antigen.34
Indeed, IL-6 is
more active in this regard than either IL-1 or TNF-.35
It is pertinent to this consideration that Kogiso et al.36
have reported that CD4+ T lymphocytes are
required for the expression of EIU in mice, even though it is not
usually thought of as a T cell–mediated disorder. With regard to the
simultaneous presence of IL-6 and elevated levels of TGF-ß in
inflamed AqH, Reinhold et al.37
have reported that IL-6
and IL-2 are capable of abolishing the effect of TGF-ß1 on DNA
synthesis by T cells. In light of this varied evidence, we conclude
that IL-6 is a potent antagonist of TGF-ß, and we infer that the
presence of IL-6 in inflamed AqH abolishes the potential
immunosuppression that would otherwise be mediated by the elevated
levels of active TGF-ß.
Our studies suggest, but do not prove, that the IL-6 found in inflamed
AqH is derived from ocular parenchymal cells. Many cells have the
potential to secrete IL-6, and macrophages that infiltrate inflammation
sites, such as the anterior segment in EIU, clearly have the capacity
to secrete IL-6. Typically, the synthesis and secretion of IL-6 by
macrophages is coordinated with synthesis and secretion of IL-1 and
TNF-. We have reasoned that if the bulk of the IL-6 found in
inflamed AqH was macrophage-derived, then similarly high levels of IL-1
and TNF- should have also been found. Instead, IL-1 and TNF-
levels were only modestly elevated. Moreover, RPA revealed that
upregulation of IL-6 mRNA in I/CB tissues removed from EIU eyes was
10-fold higher (or greater). Therefore, our current view is that the
extremely high levels of IL-6 in inflamed AqH in EIU are produced by
ocular parenchymal cells. Although the stimulus for ocular production
of IL-6 in EIU is unknown, LPS itself can be detected in AqH samples
from mice that receive footpad injections of this
substance.23
In our experiments, coinjection of soluble antigen injection with IL-6
into the AC of BALB/c mice impaired ACAID induction. Several other
proinflammatory cytokines, such as IL-2,38
IL-1,39
TNF-, and IFN-40
have been
shown similarly to prevent ACAID induction. We suspect, but have no
direct evidence, that these cytokines act by altering the functional
properties of indigenous antigen-presenting cells that, under the
influence of TGF-ß, are responsible for preparing and delivering an
ACAID-inducing signal to the spleen. The ability of IL-6 to interfere
with ACAID induction implies that eyes experiencing LPS-induced
anterior uveitis have lost immune privilege. It will be important to
determine whether loss of immune privilege renders the transiently
inflamed eye vulnerable to other immunopathogenic disorders that may
have the potential to produce chronic inflammation, and therefore
blindness.
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Acknowledgements |
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Footnotes |
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Submitted for publication September 27, 1999; revised December 20, 1999 and March 14, 2000; accepted March 17, 2000.
Commercial relationships policy: N.
Corresponding author: J. Wayne Streilein, Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114-0115. waynes{at}vision.eri.harvard.edu
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References |
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, interleukin-1ß, and tumor necrosis factor gene expression in endotoxin-induced uveitis Invest Ophthalmol Vis Sci 35,1107-1113This article has been cited by other articles:
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  L. J. Dawes, M. A. Sleeman, I. K. Anderson, J. R. Reddan, and I. M. Wormstone TGF{beta}/Smad4-Dependent and -Independent Regulation of Human Lens Epithelial Cells Invest. Ophthalmol. Vis. Sci., November 1, 2009; 50(11): 5318 - 5327. [Abstract] [Full Text] [PDF]
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S. J. Curnow, K. Wloka, J. M. Faint, N. Amft, C. M. G. Cheung, V. Savant, J. Lord, A. N. Akbar, C. D. Buckley, P. I. Murray, et al. Topical Glucocorticoid Therapy Directly Induces Up-Regulation of Functional CXCR4 on Primed T Lymphocytes in the Aqueous Humor of Patients with Uveitis J. Immunol., June 1, 2004; 172(11): 7154 - 7161. [Abstract] [Full Text] [PDF]
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S. Yamagami, S. Yokoo, T. Mimura, and S. Amano Effects of TGF-{beta}2 on Immune Response-Related Gene Expression Profiles in the Human Corneal Endothelium Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 515 - 521. [Abstract] [Full Text] [PDF]
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Y.-W. Hsiao, K.-W. Liao, S.-W. Hung, and R.-M. Chu Tumor-Infiltrating Lymphocyte Secretion of IL-6 Antagonizes Tumor-Derived TGF-{beta}1 and Restores the Lymphokine-Activated Killing Activity J. Immunol., February 1, 2004; 172(3): 1508 - 1514. [Abstract] [Full Text] [PDF]
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D A Carter and A D Dick Lipopolysaccharide/interferon-{gamma} and not transforming growth factor {beta} inhibits retinal microglial migration from retinal explant Br J Ophthalmol, April 1, 2003; 87(4): 481 - 487. [Abstract] [Full Text] [PDF]
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H. Yamagami, S. Yamagami, T. Inoki, S. Amano, and K. Miyata The Effects of Proinflammatory Cytokines on Cytokine-Chemokine Gene Expression Profiles in the Human Corneal Endothelium Invest. Ophthalmol. Vis. Sci., February 1, 2003; 44(2): 514 - 520. [Abstract] [Full Text] [PDF]
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 T. Reinhard, H. Bonig, S. Mayweg, D. Bohringer, U. Gobel, and R. Sundmacher Soluble Fas Ligand and Transforming Growth Factor {beta}2 in the Aqueous Humor of Patients With Endothelial Immune Reactions After Penetrating Keratoplasty Arch Ophthalmol, December 1, 2002; 120(12): 1630 - 1635. [Abstract] [Full Text] [PDF]
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C. S. Brissette-Storkus, S. M. Reynolds, A. J. Lepisto, and R. L. Hendricks Identification of a Novel Macrophage Population in the Normal Mouse Corneal Stroma Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2264 - 2271. [Abstract] [Full Text] [PDF]
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I. M. Wormstone, S. Tamiya, I. Anderson, and G. Duncan TGF-{beta}2-Induced Matrix Modification and Cell Transdifferentiation in the Human Lens Capsular Bag Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2301 - 2308. [Abstract] [Full Text] [PDF]
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M Huhtinen, H Repo, K Laasila, S-E Jansson, H Kautiainen, A Karma, and M Leirisalo-Repo Systemic inflammation and innate immune response in patients with previous anterior uveitis Br J Ophthalmol, April 1, 2002; 86(4): 412 - 417. [Abstract] [Full Text] [PDF]
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R. R. Fenton, S. Molesworth-Kenyon, J. E. Oakes, and R. N. Lausch Linkage of IL-6 with Neutrophil Chemoattractant Expression in Virus-Induced Ocular Inflammation Invest. Ophthalmol. Vis. Sci., March 1, 2002; 43(3): 737 - 743. [Abstract] [Full Text] [PDF]
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