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and Interleukin-6 mRNA Expression by Interleukin-13
1 From the INSERM U450, Development, Aging and Pathology of the Retina, Paris, France; and 2 Department of Ophthalmology, University of Nantes, France.
Abstract
PURPOSE. To investigate the effect of systemic injections of interleukin (IL)-13 on the development of endotoxin-induced uveitis (EIU) in the rat.
METHODS. EIU was induced in Lewis rats by a single footpad injection of lipopolysaccharide (LPS; 350 µg/kg) from Salmonella typhimurium. Rats were treated with a subcutaneous injection in the back of recombinant human IL-13 (50 µg/kg in 0.2 ml of saline) performed 30 minutes before LPS injection and 6 and 10 hours afterward. At 23 hours after LPS injection, EIU was evaluated by slit-lamp examination and by counts of inflammatory cells on cryostat sections after specific immunostaining. The expression of nitric oxide synthase (NOS)–II in ocular tissues was determined by dual immunofluorescent staining and the release of nitrite in aqueous humor by Griess reaction. Cytokine gene expression in the iris/ciliary body, choroid, and retina was evaluated by reverse transcription–polymerase chain reaction.
RESULTS. At 24 hours after LPS injection, significant clinical inhibition of
ocular inflammation and fibrin deposition in the eye was observed in
IL-13–treated rats. Quantitative analysis of ocular tissues revealed a
significant decrease of OX-42+ cells (microglia, activated macrophages,
dendritic cells, and polymorphonuclear leukocytes) and ED-1+ cells
(monocytes/macrophages and dendritic cells). No effect on ED2+ cells
(resident tissue macrophages) was found. Treatment with IL-13 decreased
nitrite levels in aqueous humor and enhanced the expression of tumor
necrosis factor-
(TNF-) and IL-6 mRNA in ocular tissues.
CONCLUSIONS. Interleukin-13 treatment inhibits LPS-induced ocular inflammation with inhibition of nitrite release and increased TNF and IL-6 production in the eye. These results confirm the role of the NO pathway in the pathogenesis of EIU and suggest the involvement of TNF and IL-6 in the downregulation of ocular inflammation.
A single injection of endotoxin, the lipopolysaccharide (LPS)
component of Gram-negative bacterial cell walls, induces an acute,
bilateral, and self-limited uveitis in the rat1
2
without
involvement of other organs.3
This disease, known as
endotoxin-induced uveitis (EIU), is a useful model for human uveitis
that appears in Reiter’s syndrome and ankylosing
spondylarthritis.1
4
The ocular inflammation is
characterized by a breakdown of the blood-ocular
barriers,5
with inflammatory cell infiltration affecting
the anterior segment of the eye (iris, ciliary body, cornea, and
aqueous humor 2
6
7
) and also the posterior segment
(choroid, retina, and vitreous 8
9
10
). Inflammatory cell
infiltration, which starts at 4 hours, is maximal at 18 to 24 hours and
disappears at 96 hours.10
During EIU, the LPS stimulates
inflammatory cells to produce different cytokines (interleukin
[IL]-1–ß, IL-6, interferon [IFN]-
, and tumor necrosis factor
[TNF]-) and chemokines.11
12
13
14
15
In humans, different
cytokines including IL-2 and IFN- have been detected in inflamed
uvea and retina.4
16
Nitric oxide (NO), produced in large
amounts in infiltrating inflammatory cells by the inducible form of NO
synthase (NOS-II), is an important mediator that participates in the
pathogenesis of EIU.17
18
19
20
Interleukin-13 is a cytokine produced by activated T cells, particularly Th2 lymphocytes.21 This interleukin is recognized to share many but not all of its biological activities with IL-4.22 Interleukin-13 inhibits the synthesis of proinflammatory cytokines and chemokines by LPS-activated monocytes.23 24 25 26 Moreover, IL-13 enhances the production of IL-1 receptor antagonist by monocytes.27 It also suppresses the production of NO by macrophages.23 Interestingly, IL-13 downregulates the expression of CD14, which functions as a receptor for the LPS/LPS-binding protein complex.24 Recently, IL-13 has been shown to modulate natural killer cells (NK) and T-cell activation through a regulation of the Janus kinase–STAT pathway.28
The treatment with IL-13 has been shown to be effective in Th1-induced autoimmune diseases such as experimental autoimmune encephalomyelitis in rats,29 collagen-induced arthritis in mice,30 and LPS-induced endotoxemia.31 Recently, treatment with recombinant human IL-13 injections was reported to induce a clinical amelioration in Th1-induced experimental autoimmune uveoretinitis in monkeys.32 Although biological effects of IL-13 are not fully known, the main role of IL-13 is the suppression of inflammatory functions of monocytes/macrophages.21 Interestingly, macrophages play a critical role in EIU as selective elimination of macrophages by intravenous injection of liposomes containing dichloromethylene diphosphonate (CL2MDP) was effective in reducing ED1+ monocytes/macrophages and decreasing pathologic and biological manifestations of EIU.33 These data prompted us to determine the effects of IL-13 injection on clinical and histopathologic EIU. In addition, we monitored the effect of IL-13 on cytokines synthesis and NOS-2 expression in ocular media and tissues from IL-13–treated rats.
Materials and Methods
Animals
Inbred male adult 8-week-old Lewis rats (Jean-Pierre Ravaut,
Institut National de la Recherche Agronomique, Nouzilly, France) were
used. Animals were maintained in a 12-hour light/12-hour dark cycle.
Food and water were supplied ad libitum. Animals were cared for in
accordance with the ARVO Statement for the Use of Animals in Ophthalmic
and Vision Research. The tenets of the Declaration of Helsinki were
followed in all experiments described below.
Induction of EIU
Rats were injected in one footpad with 350 µg/kg34
of LPS from Salmonella typhimurium (Sigma Chemical, St.
Louis, MO) in 0.1 ml of sterile pyrogen-free saline. This dose of LPS
takes into account the weight of the animals and corresponds
approximately to the dose of 100 to 200 µg of LPS currently used to
induce EIU in rats.
Treatment with IL-13
Treatment with a subcutaneous injection (in the back) of 50
µg/kg human recombinant IL-13 (R&D, Abingdon, UK)31
in
0. 2 ml of sterile pyrogen-free saline was performed 30 minutes before
LPS injection and 6 and 10 hours after.
The timing of IL-13 injections was chosen according to the time course of cytokine mRNA expression during the development of EIU13 14 ; the kinetics of the inflammatory cell infiltrate in ocular tissues6 10 ; and the kinetics of expression of inducible NO synthase (NOS-II) in the eye.19 20 It has to noted that our experiment was of too short a duration (24 hours) to generate an immune response against the cytokine of human origin.
The level of endotoxin contamination in these preparations was less than 0.1 ng for 1 µg of cytokine recombinant human (rh) IL-13 as tested by Limulus amebocyte lysate assay (according to manufacturers instructions, R&D).
Slit-Lamp Examination and Clinical Score of EIU
The intensity of intraocular inflammation was graded from 0
to 5, 23 hours after LPS injection, by a masked investigator, as
previously defined18
: 0, no inflammatory reaction; 1,
discrete inflammation of the iris and conjunctival vessels; 2,
intermediate inflammation; 3, intense iridal hyperhemia with flare
in the anterior chamber; 4, same clinical signs as 3 plus presence
of fibrinoid exudation in the pupillary area; and 5, same
signs as 4 plus hypopyon. Clinical EIU was considered
positive when 
1.
Histopathologic Evaluation
At the time of sacrifice (i.e., 24 hours after LPS injection),
rats were anesthetized with pentobarbital (40 mg/kg; Sanofi Santé
Animale, Libourne, France) and perfused with 2%
paraformaldehyde. Eyes were enucleated and postfixed for 1 hour in 2%
paraformaldehyde at room temperature. The eyes were rinsed in 5%
sucrose for 5 hours at 4°C. Then a scleral incision was made, and the
eyes were incubated overnight in 15% sucrose at 4°C and then stored
at -20°C. The eyes were included in OCT (Tissue-Tek; Miles,
Diagnostic Division, Elkhart, IN), and 10-µm-thick frozen
anteroposterior sections were performed at the optic nerve level, on
gelatin-coated slides for immunohistochemical analysis. Sections were
washed with phosphate-buffered saline (PBS) and incubated for 1 hour
with PBS containing 5% skimmed milk, to block nonspecific binding. The
sections were then incubated with mouse monoclonal antibody ED1
(Serotec, Oxford, UK; recognizing a cytoplasmic antigen in rat
monocytes, macrophages, and dendritic cells), mouse monoclonal antibody
OX42 (Serotec; marker of rat C3Bi receptor, b-chain CD11a, a protein
present on macrophage subset, microglia, dendritic cells and
polymorphonuclear leukocytes). Each antibody was used at dilution 1/50
in PBS-1% skimmed milk. After washing, sections were incubated for 1
hour with biotinylated sheep anti-mouse immunoglobulin G (1/50 in PBS)
and then for 1 hour with fluorescein-conjugated streptavidin (1/50;
Amersham, Little Chalfont, UK). Sections were observed using a Nikon
microphot-FXA-photomicroscope. To quantify EIU, all immunopositive
cells were counted on the whole ocular section, and the cell number was
expressed as mean ± SD of total cell
number/animal.33
To investigate the production and cell source of inducible NOS-II, double immunofluorescence staining was used. After permeabilization and blocking of the nonspecific sites, cryostat sections were incubated sequentially with polyclonal rabbit anti–NOS-II (1/50; Transduction Laboratories, Lexinton, NY) followed by biotinylated donkey anti-rabbit Ig (1/50; Amersham), and ExtrAvidin TRITC conjugate (1/50; Sigma Chemical Co., Saint Quentin Fallavier, France) followed by mouse monoclonal antibody OX42, as described above. Sections were viewed with appropriate filters of a Nikon Optiphot-2 photomicroscope. Photographs were taken using a triple exposure of the image with TRITC (XF39, Omega, Nikon), fluorescein (X1623, Omega), and fluorescein–propidium iodide (Chroma, Nikon) filters to detect the NOS-II/Extravidin/TRITC and the OX42/FITC staining.
RNA Isolation and Reverse Transcriptase
Total RNA from freshly enucleated eyes was isolated by the acid
guanidinium thiocyanate–phenol–chloroform method.35
Four
micrograms of RNA was reverse-transcribed for 1 hour at 42°C with 200
U of Superscript Moloney Murine Leukemia virus reverse transcriptase
(RT; GIBCO-BRL, Life Technologies, Cergy Pontoise, France), using
random hexamers (15 mM) in RT buffer (250 mM Tris-HCl pH 8.3, 375 mM
KCl, 15 mM MgCl2). The reaction was terminated by
heating to 70°C for 5 minutes, and 2 µl of cDNA was added to each
polymerase chain reaction (PCR). PCR mixes contained the PCR buffer
(100 mM Tris–HCl [pH 9], 500 mM KCl, 1% Triton X-100 + 25 mM
MgCl2), 200 mM of each deoxynucleotide
triphosphate, 30 pmol of each primer, and 2.5 U Taq DNA
polymerase; Promega, Charbonnieres, France) in a total volume of 25
µl. Each sample was incubated in a DNA thermal cycler (Appligene,
Illkirch, France), and amplification was performed as follows: 93°C
for 1 minute, 60°C for 2 minutes, 72°C for 3 minutes, 25 cycles for
ß-actin and 35 cycles for TNF- (OligoExpress, Paris, France), and
94°C for 1 minute, 55°C for 1 minute, 72°C for 1 minute, 35
cycles for IL-6 (OligoExpress, Paris, France), and then 72°C for 7
minutes, 1 cycle. Non–reverse-transcribed RNA was also submitted to
the PCR amplification steps as a negative control for DNA
contamination. The PCR fragments were analyzed by 3% agarose gel
electrophoresis and visualized by ethidium bromide staining. Ethidium
bromide–stained gels were visualized under UV light.
To verify that equal amounts of RNA were added in each PCR within an experiment and to verify a uniform amplification process, ß-actin mRNA was also transcribed and amplified for each sample. The relative band intensity was calculated in comparison to that for ß-actin.
Primers used were as follows: TNF- sense primer,
5'-ATGAGCACAGAAAGCATGATCCGC-3'; TNF- anti-sense primer,
5'-CCAAAGTAGACCTGCCCGGACTC-3'; IL-6 sense primer, 5'-AAA ATC TGC TCT
GGT CTT CTG G-3'; IL-6 anti-sense primer, 5'-GGT TTG CCG AGT AGA CCT
CA-3'; ß-actin sense-primer, 5'-CTG GAG AAG AGC TAT GAG CTG-3'; and
ß-actin anti-sense primer, 5'-AAT CTC CTT CTG CAT CCT GTC-3'. These
primers were designed to specifically amplify cDNA fragments
representing mature mRNA transcripts of 244 bp for ß-actin, 446 bp
for TNF-, and 290 bp for IL-6.
Protein Determination in Aqueous Humor
At the time the animals were killed, 24 hours after LPS injection,
aqueous humor was collected in microcapillaries by an anterior chamber
puncture under a stereomicroscope using a 30-gauge
needle.9
Aqueous humors from both eyes of each animal were
pooled. After centrifugation for 5 minutes, protein concentration was
determined by Bradford assay with gamma globulin as a standard (Biorad,
les Ulis, France) using 3 µl of the aqueous humor of each sample.
Nitrite Evaluation
Because nitrite and nitrate are stable end products of NO
metabolism, NO synthesis was determined with nitrite release using a
spectrophotometric assay based on the Griess reaction.18
Aqueous humor samples were collected by anterior puncture of both eyes
of each animal and were pooled. After centrifugation, nitrite levels
were determined in the supernatant. Briefly, 50 µl of cell free
aqueous humor was mixed with 50 µl of Griess reaction solution (1%
sulfanilamide, 0.1% naphthyl-ethylenediamine). After 10 minutes, the
absorbance was read at 540 nm and compared with nitric standards.
Statistical Analysis
Results were expressed as mean ± SEM and were analyzed
statistically by using the Mann–Whitney U test or the unpaired
Student’s t-test (clinical and histologic score of EIU).
Each mouse (average of both eyes) was studied as one statistical event.
P < 0.05 was considered significant.
Results
Suppression of Development of Clinical EIU by IL-13 Treatment
The clinical inflammatory score, which was determined 23 hours
after LPS induction, was significantly lower in the IL-13 group
(P = 0.0001) compared with nontreated controls. Animals
treated with IL-13 that developed EIU presented a disease of lower
intensity than controls. Indeed, 17 IL-13–treated rats developed a
disease with a mean intensity of 2 ± 0.2 versus 3.3 ± 0.2
in the 20 control rats (P = 0.0002). No inflammation
was detected in 3 of 20 treated animals, whereas all control rats
developed EIU. In addition, although 75% of control rats presented a
major inflammatory reaction with fibrinous deposits in the pupillary
area, only 25% of IL-13–treated rats showed fibrin in the anterior
chamber. This clinical result was confirmed in four separate
experiments (Fig. 1)
.
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|
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Downregulation of NO Production in Aqueous Humor by IL-13
To test whether the inhibitory effect of IL-13 on EIU was
related to an effect on NO production, we measured the nitrite release
in aqueous humor from control and treated rats. High levels of nitrite
were detected in the aqueous humor from control rats. In contrast,
IL-13 significantly inhibited the increase in nitrite levels in treated
animals with low ocular inflammation. These data confirm previous
observations,18
which showed a correlation between the
level of nitrite in the aqueous humor and the intensity of clinical
manifestations of EIU (Fig. 4)
.
|
Upregulation of Ocular mRNA Expression of TNF- and IL-6 by IL-13
The effect of IL-13 treatment on the expression of different
cytokines implicated in ocular inflammation was investigated by
semiquantitative reverse transcription–PCR 24 hours after LPS
injection. By comparison, there was no detectable difference in
IL-1ß, IL-10, or MCP-1 mRNA expression between control and
IL-13–treated rats (data not shown). In contrast, an upregulation of
TNF- and IL-6 over levels in uveitic control eyes was detected in
the iris/ciliary body and the retina from IL-13–treated rats with
inhibited EIU (Fig. 5)
.
|
The present study demonstrates that systemic administration of IL-13 inhibited ocular inflammation in EIU at clinical and histologic levels. Indeed, at slit-lamp examination, compared with controls, less severe cellular infiltration of the eyes was detected in IL-13–treated rats together with a decrease of hypopyon formation in the anterior chamber of the eye. Correlatively to the beneficial clinical effect of IL-13 injection, we show that the treatment inhibited very efficiently the infiltration of OX42+ cells (mainly polymorphonuclear cells and microglia) into tissues from anterior and posterior segments of the eye at 24 hours after LPS injection. A significant inhibition of ED1+ cell infiltrates (monocytes/macrophages, dendritic cells) was noted in the uveal tissues: iris/ciliary body and choroid but not in the retina and the vitreous. This incomplete effect on ED1+ cells could be related to a difference in the kinetics of ED1+ and OX42+ infiltration in ocular tissues and from differences in the kinetics of uveal and retinal cellular infiltration.3 6 7 8 9 10 In addition, low numbers of ED1+ and OX42+ cells are detected in normal tissue sections.33 After LPS injection, rats presenting EIU show a low number of ED1+ cells in the retina and the vitreous, which could explain why the difference between control and treated rats is not significant. The density of ED2+ resident tissue macrophages, which remains unchanged during the course of EIU,6 was not modified by IL-13 treatment.
To try to explain the inhibitory effect of IL-13 on ocular inflammation, we have analyzed NO and cytokine production in ocular tissues from control and treated rats. Nitric oxide has been shown to be strongly involved in the pathogenesis of EIU. Indeed, an expression of NOS-II was found in inflammatory cells and resident ocular cells from susceptible rats and mice,18 19 20 36 37 38 and administration of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) allowed to inhibit ocular inflammation induced by LPS injection.7 18 34 The cytokine IL-13 has an important inhibitory effect on the global release of NO through a decrease of the in vitro production of NO by activated macrophages23 and microglial cells.29 In vivo, IL-13 injection allowed inhibition of experimental autoimmune encephalomyelitis in rats by inactivating macrophages and microglia.29 In the present study, the reduction of the ocular inflammatory response by IL-13 was related to decreased NOS-II expression in the eye. This inhibitory effect of IL-13 could result from a downregulation of the activation of monocytes/macrophages lineage, from a local inhibition of NO synthesis by the ocular resident cells, or both. However, although IL-13 clearly reduced ocular inflammatory manifestations of EIU, no effect on protein exudation could be noted. A similar dissociation was reported after IL-6 injection of rats made tolerant to LPS in which leakage of plasma proteins was detected but no influx of inflammatory cells.2 A similar finding was described during the treatment of EIU by systemic administration of IL-10.39 It could be suggested that IL-13 (although effective on NO level in the aqueous humor through an effect on the inducible NOS-II) would be less effective on the constitutive form of NOS, which is more involved in the regulation of the blood-ocular barriers.
We investigated then the effect of IL-13 treatment on cytokine
production. The expression of IL-1ß, MCP-1, and IL-10 mRNA in ocular
tissues from IL-13–treated rats was not different from controls (data
not shown). In contrast, an upregulation of mRNA of TNF- and IL-6
was detected in the iris/ciliary body and the retina from
IL-13–treated rats. This would suggest a protective role for TNF-
and IL-6 during ocular inflammation. However, further experiments are
needed to determine whether corresponding proteins are synthesized and
to detect the exact cellular source of these cytokines. The
contribution of TNF- and IL-6 to EIU is pleiotropic. On one hand
both cytokines appear to be proinflammatory: injection of IL-6 and
TNF- into the vitreous of rats produced severe intraocular
inflammation in animals2
40
and the susceptibility of rats
to develop ocular inflammation seemed to be related to the intraocular
synthesis of both cytokines14
; numerous cytokines
including IL-6 and TNF- were detected in the serum and the eye from
rats developing EIU11
12
13
14
15
; TNF was involved in the
blood-retinal barrier breakdown by opening tight junctions of retinal
vascular endothelial cells5
and retinal pigmented
epithelial cells.41
TNF has been shown to mediate
leukocyte trafficking in the retina.42
On the contrary, a
protective role for these two cytokines is suggested by the following
data: retinal Müller glial cells isolated from EIU-resistant
strains of mice expressed TNF- and IL-6 under in vitro stimulation
with LPS and IFN-, whereas cells from susceptible strains do
not37
38
; mice carrying a targeted disruption of the gene
encoding TNF (TNF-/-) developed experimental autoimmune uveoretinitis
of increased severity compared with controls TNF+/+43
; and
rats and mice injected with anti–TNF- antibody demonstrated an
exacerbation of EIU compared with controls.43
44
It is
interesting to note that anti–TNF- antibody treatment protected
against the systemic effects of LPS, while it exacerbated EIU,
suggesting that a distinct ocular milieu of cytokines and mediators is
induced by the inflammation compared with the systemic inflammatory
process.44
45
The precise mechanisms at the origin of the antiinflammatory effect of
TNF- and IL-6 in the eye are unknown. TNF upregulated in the
intraocular media during EIU is expressed together with nerve growth
factor by ocular resident cells, retinal Müller glial cells, and
retinal pigmented epithelial cells.46
47
TNF is
functionally related to Fas ligand (Fas L, CD95L), a comember of the
TNF/nerve growth factor family, which when expressed in cells of the
eye contributes to the ocular immune privilege.48
Fas–Fas
L interaction has been shown to induce apoptosis in inflammatory
infiltrating cells after viral infection,49
and Fas L
expression on vascular endothelial cells is regulated by
TNF-.50
Taken together, these data suggest that TNF
could be at the origin of immunosuppressive and immunostimulatory
effects depending on the time and the site of its expression. The
results of the present study suggest that IL-13 (by increasing the
intraocular levels of TNF- and IL-6 and inhibiting NO synthesis)
could have an important role in the limitation of ocular inflammation
and could be an interesting agent for the treatment of human uveitis.
Footnotes
Supported by INSERM (Institut National de la Santé et de la Recherche Médicale) and Retina France Funds.
Submitted for publication January 13, 1999; revised April 2, 1999; accepted May 2, 1999.
Proprietary interest category: N.
Corresponding author: Yvonne de Kozak, Laboratoire d’Immunopathologie de l’Oeil, INSERM U450, Centre Biomédical des Cordeliers, 15, rue de l’Ecole de Médecine, 75270, Paris, Cedex 06, France. E-mail: ydekozak@ccr.jussieu.fr
References
, and interleukin-1ß-mediated breakdown J Neurosci Res 49,268-280[Medline][Order article via Infotrieve]
, interleukin-1ß, and tumor necrosis factor gene expression in endotoxin-induced uveitis Invest Ophthalmol Vis Sci 35,1107-1113 secretion in normal human monocytes J Immunol 155,3145-3151[Abstract]
) in endotoxin-induced uveitis Invest Ophthalmol Vis Sci 34,2911-2917 regulation of fas ligand expression on the vascular endothelium modulates leukocyte extravasation Nat Med 4,414-420
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