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(Investigative Ophthalmology and Visual Science. 2006;47:4926-4930.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-0340
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A Protective Role for IL-6 in Staphylococcal Microbial Keratitis

Emma B. H. Hume,1,2,3 Nerida Cole,2,4 Linda L. Garthwaite,1 Shamila Khan,2,3 and Mark D. P. Willcox1,2,3

1From the The School of Optometry and Vision Science, The University of New South Wales, Kensington, NSW, Australia; 2The Institute for Eye Research, Kensington, NSW, Australia; the 3Vision Cooperative Research Centre, Kensington, NSW, Australia; and the 4Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To determine whether interleukin-6 (IL-6) plays a protective role in Staphylococcus aureus keratitis in a gene knockout (gko) mouse model and to determine whether IL-6 may be used as a therapy to modulate host responses and control bacterial infection, thereby reducing scarring.

METHODS. The eyes of IL-6 gko mice and wild-type mice were challenged topically with S. aureus and examined at 24 hours after infection. Keratitis was examined clinically and histologically. Bacterial and polymorphonuclear leukocytes (PMNs) were enumerated, and cytokine and chemokine levels were determined by ELISA. Exogenous IL-6 was administered to both IL-6 gko and wild-type mice, and clinical parameters were determined.

RESULTS. IL-6 gko mice showed more severe disease, with increased bacterial counts and PMNs, than did wild-type mice. Changes in levels of chemokines and cytokines were also observed. Administration of exogenous IL-6 resulted in an improved outcome in IL-6 gko mice, with a threefold reduction in bacterial load.

CONCLUSIONS. The data suggest an important regulatory role for IL-6 in modulating excessive inflammatory responses and in controlling bacterial proliferation. IL-6 may play a role in the priming and activation of neutrophils. It could represent a broad-spectrum therapy to improve outcomes in patients who have these potentially blinding infections.

The pathogen Staphylococcus aureus is the leading cause of bacterial keratitis in humans.1 2 3 4 The incidence of this disease is higher in immunocompromised individuals such as those with HIV or diabetes, in aged persons, and in individuals who wear contact lenses. Staphylococcal keratitis is characterized by destruction of the cornea by exoproteins of the bacteria and by host-associated factors.5 Although antibiotic therapies may succeed in reducing or eliminating the bacterial load scarring, loss of visual acuity and even blindness still result.

The host inflammatory responses, which are orchestrated by cytokines and chemokines, are critical in determining the outcome of ocular infection.6 7 8 9 Interleukin (IL)-6 is a pleiotropic cytokine that plays an important role in the regulation of a variety of host immune responses, including inflammation, acute-phase responses, hematopoiesis, and differentiation of B-cells into antibody-producing plasma cells.10 IL-6 is often thought of as a protective factor in infectious disease,11 12 13 14 but also has been associated with a poor outcome in other diseases.15 Our studies have shown that IL-6 is important in protecting the cornea during Pseudomonas aeruginosa infection.6 Exogenous IL-6 administered to the eye at the time of Pseudomonas infection was found to decrease bacterial counts significantly in treated mice compared with untreated IL-6 gene knockout (gko) mice.16 Other studies, in which systemic administration of IL-6 in septic shock17 and listeriosis18 were used, also support the protective role of IL-6.

In recent studies, we have demonstrated that C57BL/6 mice are more resistant to infection than are BALB/c mice.19 In these studies a lack of ocular disease correlated with an upregulation of IL-6, -4, and -10.19 Our purpose was to determine whether IL-6 plays a protective role in S. aureus keratitis, by using a gko mouse model, and to determine whether IL-6 may be used as a therapy to control excessive inflammation and thereby reduce host scarring.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Bacteria
A clinical isolate from a human corneal ulcer (S. aureus 38) was used for this study. Stock cultures of S. aureus 38 were stored in 30% glycerol at –70°C. Bacteria were cultured onto chocolate blood agar and then grown overnight in tryptone soya broth (TSB; Oxoid, Basingstoke, UK) at 37°C and concentrated to approximately 4 x 1010 colony forming units (cfu)/mL.

Mice
All mice were treated and maintained in strict accordance with the tenets of the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Inbred 6- to 8-week-old IL-6 gko (B6:129 background) mice and their wild-type counterparts were used (Jackson Laboratories, Bar Harbor, ME). The mice were anesthetized with Avertin (125 mg/kg, intraperitoneally), and the corneal surfaces of both eyes were incised in a cross-shaped pattern with a sterile 27-gauge needle. Ten microliters of 5% acetyl cysteine (Sigma-Aldrich, St. Louis, MO) was pipetted onto the cornea, to break up the tear film, and then was removed with a sterile cotton swab. Ten microliters of the bacterial suspension (4.0 x 108 cfu) of strain S. aureus 38 was pipetted directly onto the wounded cornea. The left eye of each animal served as the control and was scratched but not infected. The animals were monitored during each experiment, and the Animal Care and Ethics Committee of The University of New South Wales, Australia, approved all protocols for animal use.

Slit Lamp Examination of Corneas
Mice were examined by slit lamp at 24 hours after infection by a masked observer. The animals were anesthetized for examination, as just described, and the corneas were examined at 48x magnification under white light with a slit lamp photograph biomicroscope (FS2; Topcon Corp., Tokyo, Japan). Three parameters (epithelial defect, corneal infiltrate, and corneal edema) were graded on a scale of 0 (none) to 4 (severe). The parameter grades were totaled to produce a single slit lamp examination score.

Histologic Examination of Corneas
Mice were killed at 24 hours after challenge. The eyes were immediately enucleated and fixed in neutral buffered formalin and embedded in paraffin. Five-micrometer sections were cut and stained with Whitlock’s hematoxylin and eosin for examination of pathologic changes.

Quantitation of Viable Bacteria
Corneas were removed at 24 hours after challenge and homogenized in 1 mL of sterile phosphate-buffered saline (PBS; pH 7.4) using a handheld dispersing tool (Ultra-Tarrax T-8; IKA, Rawang, Malaysia). To quantitate viable bacteria, a 100-µL aliquot was serially diluted 1:10 in sterile PBS. Triplicate aliquots (20 µL) of each dilution, including the original homogenate, were plated onto nutrient agar (Oxoid). Plates were incubated for 24 hours at 37°C before cfus were counted. Results are expressed as mean cfu per eye ± SEM.

Myeloperoxidase Assays
Myeloperoxidase activity, which is proportional to the number of polymorphonuclear neutrophils (PMNs) present, was determined as previously described.20 Briefly, corneas were removed from infected mice 24 hours after challenge and were individually homogenized in 1 mL of PBS, as described earlier. Hexadecyltrimethylammonium bromide was added to a final concentration of 0.5% wt/vol. Samples were sonicated (three times, 10 seconds each) on ice and subjected to three freeze–thaw cycles before centrifugation at 8000g for 20 minutes in a refrigerated microcentrifuge. The reaction was measured after adding O-dianisidine dihydrochloride and H2O2. The change in absorbance at 3 minutes was determined at 460 nm with a spectrophotometer and compared with a standard curve on the same plate. The standard curve was prepared as previously described from murine PMNs.20 Results are expressed as the average number of PMNs per cornea.

ELISAs
ELISAs for inflammatory mediators were performed as previously described.6 9 16 19 20 For macrophage inflammatory peptide (MIP)-2, KC (keratinocyte cytokine; a murine homologue of human GRO-{alpha}), IL-6, IL-10, IL-12 p40, IL-4, and interferon (IFN)-{gamma} ELISAs, eyes were homogenized in 1 mL of sterile PBS as described for the myeloperoxidase assay. MIP-2 and KC paired antibodies for ELISA were purchased from R & D Systems (Bioscientific, Sydney, Australia) and used according to the manufacturer’s directions, and the supplied standards were used to generate a standard curve. ELISAs for IL-10, IL-4, IL-12, IFN-{gamma}, and tumor necrosis factor (TNF)-{alpha} were performed (OptEIA ELISA kits; BD-PharMingen, Sydney, Australia) according to the manufacturer’s directions. Absorbances were converted to picograms per eye for each cytokine.

Administration of Recombinant IL-6
During the experiments involving administration of exogenous IL-6, the mice were challenged with S. aureus as described earlier. The mice were then subconjunctivally injected with 100 ng of recombinant IL-6 (R & D Systems, Inc., Minneapolis, MN) at the time of infection and then treated hourly with 25 ng of IL-6 suspended in eye ointment (PolyVisc; Alcon Laboratories, Fort Worth, TX) from either 4 to 9 hours or 10 to 15 hours after infection. Mice were killed at 1 hour after the last treatment, and the corneas were collected and assayed for bacterial and PMN counts, as described earlier.

Statistics
All data, except for slit lamp data, were examined by using two-way analysis of variance (ANOVA). Homogeneity of variance was tested using the Levene test. Variables that were significant between mouse strains were further analyzed for multiple comparisons using either the Bonferroni or Dunnett T3 correction based on the validity of ANOVA assumptions. In the presence of a significant interaction between mouse types, a one-way ANOVA was performed. P ≤ 0.05 was considered statistically significant. As slit lamp data is nonparametric, data were analyzed with the Mann-Whitney test, and P ≤ 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Slit Lamp Examination and Histopathology
A minimum of 47 mice per group were examined with the slit lamp. IL-6 gko mice, infected with S. aureus strain Staph 38, demonstrated more severe gross disease on all variables examined than did wild-type mice infected with the same strain (Fig. 1 ; P = 0.006). IL-6 gko corneas had more extensive infiltration and a greater extent of epithelial erosion than was observed in the wild-type mice.


Figure 1
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  		FIGURE 1. Wild-type (WT) and IL-6 gene knockout mice (gko) were infected with S. aureus strain 38 and examined by slit lamp at 24 hours after infection. Clinical presentation is represented by the slit lamp score ± SEM. A significant difference between the infected eyes of WT and gko mice was observed at 24 hours after infection (*P = 0.006; n = 47).

 
Figure 2 shows typical sections of wild-type and IL-6 gko corneas challenged with S. aureus. Histologic examination of the corneas correlated well with the slit lamp examination scores. C57BL/6 (wild-type) corneas showed less infiltration and epithelial damage (Fig. 2A) . IL-6 gko mouse eyes infected with strain Staph 38 showed more severe disease including marked infiltration (Fig. 2B) and corneal erosion, seen in this image overlying an abscess in the corneal stroma (Fig. 2B , inset).


Figure 2
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  		FIGURE 2. Histologic examination of mouse corneas infected with S. aureus. Histologic sections are stained with hematoxylin and eosin. (A) Wild-type mouse at 24 hours after challenge. Arrow: scratch site. (B) IL-6 gko mouse at 24 hours after challenge demonstrating marked infiltration of the corneal stroma by PMNs. Inset: an abscess filled with bacteria. Stromal infiltration and loss of epithelium can be seen in this section. Magnification: (A) x200; (B) x400.

 
Bacteria and PMNs
Significantly more bacteria were recovered from IL-6 gko mice than from wild-type mice in Staph 38–infected eyes (Fig. 3A ; P = 0.01). In IL-6 gko mice, there was approximately four times more bacteria than were isolated from wild-type mice. No bacteria were recovered from scratched control eyes.


Figure 3
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  		FIGURE 3. (A) Average number of viable S. aureus cfus in corneal tissue of wild-type and IL-6 gko mice at 24 hours after challenge, as determined by the direct-counting method. The mean number of cfus per cornea ± SEM is shown. (B) Number of PMNs per cornea ± SEM at 24 hours after challenge in wild-type and IL-6 gko mice. Data are shown for ({blacksquare}) wild-type mice and ({square}) IL-6 gko mice (*P < 0.05; n = 40).

 
There were significantly higher counts of PMNs in IL-6 gko corneas infected with S. aureus than in corneas of wild-type mice, as estimated by measurement of myeloperoxidase levels (Fig. 3B ; P = 0.004). IL-6 gko mice infected with the S. aureus had approximately two times higher levels of myeloperoxidase activity and PMNs per cornea than did wild-type mice infected with S. aureus. Infected corneas had more PMNs per cornea than the scratched control corneas (P < 0.0005).

Corneal Chemokines and Cytokines
There was a significant increase (at least 2.5-fold) in the production of the chemokine KC in the IL-6 gko mice compared with the wild-type mice (P ≤ 0.001; Fig. 4A ). MIP-2 showed a similar increase of twofold in the IL-6 gko mice compared with the wild-type mice (P ≤ 0.001; Fig. 4B ).


Figure 4
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  		FIGURE 4. (A) Average amount of KC (±SEM) produced by wild-type and IL-6 gko mice corneas infected with S. aureus. (B) Average amount of MIP-2 (±SEM) produced by wild-type and IL-6 gko mice corneas infected with S. aureus. Data are shown for ({blacksquare}) wild-type mice and ({square}) IL-6 gko mice (*P < 0.05; n = 40).

 
IL-6 was not detected in the IL-6 gko mice, as expected, but was upregulated in wild-type–infected mice compared with scratch control corneas (P < 0.05). Cytokines IL-4 and IL-10 were found in lower levels in IL-6 gko mice compared with wild-type mice. IL-10 levels were significantly lower (approximately threefold; P < 0.05; Table 1 ).


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  		TABLE 1. Cytokine Levels in Eyes 24 Hours after Challenge with S. aureus Strain 38

 
IL-1ß was significantly upregulated in IL-6 gko mice (P < 0.05). IL-1ß was approximately 2.5-fold higher in IL-6 gko mice. No differences in levels of IL-12 or IFN-{gamma} were detected between mouse types (Table 1) .

Administration of Exogenous IL-6
Application of recombinant IL-6 from 4 to 9 hours after infection did not result in any significant differences between treated or nontreated groups in either wild-type or IL-6 gko mice in all parameters measured. In contrast, evaluation of clinical scores and bacterial counts from mice treated from 10 to 15 hours after infection showed an improved outcome in the IL-6–treated mice (Figs. 5A 5B) . Clinical scores from wild-type and IL-6 gko mice were reduced significantly with administration of exogenous IL-6 from 10 to 15 hours when observed at 16 hours after infection (Fig. 5A ; P = 0.003 and P = 0.03 respectively). Bacterial counts were also significantly reduced (approximately threefold) in eyes from IL-6 gko mice treated with exogenous IL-6 on euthanasia at 16 hours after infection (Fig. 5B ; P = 0.02). Levels of bacteria in the wild-type mice treated with IL-6 were reduced by approximately 1.5-fold although this reduction was not significant (Fig. 5B) . In contrast, levels of PMNs were not different between treated and untreated groups in both types of mice (Fig. 5C) .


Figure 5
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  		FIGURE 5. (A) Wild-type (WT) and IL-6 gko mice were infected with S. aureus strain 38 and treated with recombinant IL-6 from 10 to 15 hours and examined by slit lamp at 16 hours after infection. Clinical presentation is represented by the slit lamp score ± SEM. A significant difference between the vehicle- and IL-6–treated eyes in mice was observed at 16 hours after infection (**P < 0.05). (B) The average S. aureus cfu in corneal tissue of wild-type and IL-6 gko mice treated with vehicle or recombinant IL-6 from 10 to 15 hours after infection and euthanatized at 16 hours after infection. The mean number of cfus per cornea ± SEM are shown (**P < 0.05). (C) Number of PMNs per cornea ± SEM at 24 hours after challenge in wild-type and IL-6 gko mice treated with recombinant IL-6 in (A). ({blacksquare}) Vehicle-treated eyes; (Figure 5) IL-6–treated eyes (n = 20).

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
These studies demonstrate that IL-6 is protective against S. aureus keratitis and may have use as a therapy to control infection. The absence of IL-6 results in more severe ocular disease, which correlates with an increase in bacterial and PMNs. These findings are consistent with other models in which the lack of IL-6 is associated with an increase in severity of disease20 and is consistent with our previous findings for staphylococcal keratitis.19

Our results demonstrated that a lack of IL-6 resulted in a concomitant increase in the chemokines KC and MIP-2 which correlated with an increase in PMN recruitment and bacterial load. The increase in MIP-2 and KC in the IL-6 gko mice is consistent with previous findings in the P. aeruginosa keratitis model20 and may be due to differential regulation of chemokines and neutrophil influx via the soluble IL-6 receptor.21 The increase in PMNs with the correlated increase in bacterial counts suggests that the PMNs were unable to kill the bacteria and requires further investigation. These findings imply that IL-6 may play a role in the activation of PMNs during staphylococcal infection. Increased levels of IL-6 correlate with neutrophil activation and have been previously reported.22 23 In addition, IL-6 has been shown to stimulate production of elastase and to prime neutrophils for the production of oxygen-free radicals.24 25 These data support our finding that, although larger numbers of PMNs are recruited into the cornea in the absence of IL-6, the number of bacteria are also significantly higher than those found in wild-type mice, indicating that the PMNs may not be primed or activated.

IL-4 and -10 were decreased in the IL-6 gko group in our study—probably because of IL-6’s providing the initial stimulation for IL-4 production during Th-2 differentiation and the subsequent production of Th-2 cytokines such as IL-10.26 We have shown in staphylococcal corneal infection that an increase in the production of IL-10 and -4 correlates with improved outcome, but the mechanism by which this occurs remains to be elucidated.19

IL-1ß was found to be significantly upregulated during S. aureus challenge in IL-6 gko mice (Table 1) . This result is expected, as IL-6 is known to downregulate IL-1 and TNF-{alpha} and to dampen the inflammatory response.10 The mutual regulation of these cytokines is further demonstrated by the abrogation of IL-1’s downregulating IL-6 expression in corneal cells.27 IL-1 has also been found to regulate the expression of chemokines in the cornea during P. aeruginosa infection,28 again correlating with the findings of increased expression of chemokines in IL-6 gko mice in this study.

The importance of IL-6 in controlling S. aureus ocular infection was further confirmed by treatment experiments. Of note, the time of treatment was crucial for the outcome of infection. Late-phase administration of IL-6 in IL-6 gko mice showed an improved clinical outcome with a decreased bacterial burden. However, early-phase IL-6 administration showed no improvement, which may reflect the kinetics of bacterial growth and recruitment of PMNs during infection. Exogenous administration of IL-6 has previously been shown to be protective during corneal infection with P. aeruginosa.16

Our study highlights the protective role of IL-6 during S. aureus infection and emphasizes the balance between IL-6 and IL-1ß in achieving bacterial control and maintaining the integrity of the cornea. It has been shown that high levels of IL-1ß are associated with corneal damage during P. aeruginosa infection of the cornea, and our data suggest an important regulatory role for IL-6 in modulating excessive inflammatory responses as well as in controlling bacterial proliferation. A possible mechanism for the control of the number of bacteria may be the regulation of the priming and activating neutrophils; however, this remains to be investigated. These effects are also seen in the exogenous treatment of P. aeruginosa corneal infection and, consequently, IL-6 may represent a broad-spectrum adjunct therapy to improve patient outcome from these potentially blinding infections.


   Acknowledgements
 
The authors thank Vivienne Reeve for the kind donation of the IL-6 gko mice, Karen Barnes and Elaine Chew for assistance with preparation of histologic specimens, Denise and Robyn Lawler for technical assistance, and Thomas John for assistance with statistics.


   Footnotes
 
Supported by a National Health Medical Research Council grant.

Submitted for publication March 28, 2006; revised May 9, 2006; accepted September 1, 2006.

Disclosure: E.B.H. Hume, None; N. Cole, None; L.L. Garthwaite, None; S. Khan, None; M.D.P. Willcox, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Emma B. H. Hume, Institute for Eye Research, Rupert Myers Building, University of New South Wales, NSW 2052, Kensington, Australia; e.hume{at}ier.org.au.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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