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* Department of Pediatrics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; Departments of
Experimental Internal Medicine and
Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1
mRNA and protein levels in the brain. The absence of an intact IL-1 signal was associated with a higher susceptibility to develop meningitis. Furthermore, the lack of IL-1 impaired bacterial clearance, as reflected by an increased number of CFU in cerebrospinal fluid of IL-1R-/- mice. The characteristic pleocytosis of meningitis was not significantly altered in IL-1R-/- mice, but meningitis was associated with lower brain levels of cytokines. The mortality was significantly higher and earlier in the course of the disease in IL-1R-/- mice. These results demonstrate that endogenous IL-1 is required for an adequate host defense in pneumococcal meningitis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-1 is a potent proinflammatory cytokine, consisting of two molecular species, IL-1 and IL-1, and two recently described other forms of IL-1, IL-1
and IL-1
(6). These molecules exert similar biological activity through IL-1R type I. Although a second receptor, IL-1R type II, has also been found, this receptor is not considered to be involved in signal transduction and functions as a regulatory decoy receptor (7, 8, 9). Another endogenous IL-1 inhibitor is IL-1R antagonist (IL-1Ra),2 which preferentially binds to the signaling-type I IL-1R without inducing any biological response (10). IL-1 initiates, in concert with other cytokines, the innate immune response. It has potent stimulatory effects on granulocytes, promotes the adhesion of neutrophils and monocytes to endothelial cells, is a strong chemoattractant for leukocytes, and induces the secretion of other inflammatory mediators such as arachidonic acid and cytokines such as TNF-, IL-6, and IFN- (10, 11, 12). IL-1 expression is induced early in the course of pneumococcal disease (13, 14, 15).
IL-1 is markedly elevated in the cerebrospinal fluid of patients with bacterial meningitis (16, 17, 18, 19) and correlates with concentrations of other inflammatory mediators, such as PGs (19) and TNF- (16).
At present no in vivo studies have been performed to explore the role of endogenous IL-1 in meningitis. Recently, we developed a murine bacterial meningitis model that is induced by intranasal inoculation of pneumococci with hyaluronidase, in which elevated levels of IL-1 and IL-1 are present in brain tissue during meningitis (20). In the present study we investigated the role of IL-1 in murine pneumococcal meningitis. Therefore, we induced pneumococcal meningitis in IL-1R type I-deficient (IL-1R-/-) mice and compared their immune response with that of wild-type mice. We found that host defense is impaired in the absence of an intact IL-1 signal.
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Materials and Methods |
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IL-1R-/- mice, backcrossed six times to a C57BL/6 background, were provided by Immunex (Seattle, WA). Sex-matched C57BL/6 wild-type mice (Harlan Sprague Dawley, Horst, The Netherlands) were used as controls. All mice were used at 3–4 wk of age. Each experimental group consisted of 14 or 15 mice/time point; 28 mice/group were inoculated for survival analysis. Homozygous IL-1R-/- mice are viable and fertile, and demonstrate no abnormalities in leukocyte subsets and no histopathologic abnormalities (21). The institutional animal care and use committee of Academic Medical Center (Amsterdam, The Netherlands) approved all experiments. All animal experimentation guidelines were followed in animal studies.
Bacteria and preparation of inoculum
S. pneumoniae (serotype 6A), isolated from a meningitis patient, was cultured overnight at 37°C in 80 ml of brain heart infusion broth. At midlogarithmic growth phase, 5 ml of this suspension was transferred to 25 ml of brain heart infusion broth. The bacterial suspensions were grown at 37°C until an OD of 1.0 at a wavelength of 620 nm was achieved. Subsequently, the suspension was washed twice in sterile, isotonic saline and resuspended in sterile isotonic saline to give a final concentration of 1.6 x 106 CFU/ml, and 3600 U of synthetic hyaluronidase (Sigma-Aldrich, St. Louis, MO) were added per milliliter of inoculum (20). The exact amount of CFU was determined retrospectively by growth of serial dilutions on blood agar plates.
Experimental meningitis
Meningitis was induced as described previously (20). Briefly, mice were lightly anesthetized by inhalation of isoflurane (Abott, Queensborough, U.K.), and 50 µl of the inoculum (8 x 104 CFU of S. pneumoniae and 180 U of hyaluronidase) was administered intranasally. Control mice were inoculated with isotonic saline. At 24, 48, or 72 h after inoculation mice were anesthetized with Hypnorm (Janssen Pharmaceutica, Beerse, Belgium) and midazolam (Roche, Mijdrecht, The Netherlands), after which blood was obtained through cardiac puncture, and cerebrospinal fluid was collected by puncture from the cisterna magna. White blood cells (WBC) in cerebrospinal fluid were counted immediately. Brains were removed, of which one-half was fixed in 10% buffered formalin for histopathologic study, while the other half was homogenized in sterile saline. Homogenized brain tissue was cultured (see below), and the remainder was subsequently incubated with lysis buffer (300 mM NaCl, 15 mM Tris, 2 mM MgCl2, 2 mM CaCl2, 2 mM Triton X-100, pepstatin A (20 ng/ml), leupeptin (20 ng/ml), and aprotinin (20 ng/ml), pH 7.4) for 30 min at 4°C and centrifuged for 15 min at 1500 x g. Supernatants of brain homogenates were stored at -20°C for cytokine measurements. Survival was monitored every 6 h during the first 3 days and then daily.
In a separate survival study IL-1R-/- (n = 6) and wild-type (n = 6) mice were inoculated and sacrificed in a terminal phase to determine the cause of death in these mice. Blood and cerebrospinal fluid were cultured, and the following organs were collected for histopathologic analysis: brain, lungs, spleen, and kidneys.
Quantification of bacterial outgrowth
Serial 10-fold dilutions in sterile isotonic saline were made of cerebrospinal fluid and blood and were plated onto blood agar plates. Plates were incubated for 18 h at 37°C, after which colonies were counted.
Histopathologic study
Brains were fixed in 10% buffered formalin, and after paraffin embedding, 4-µm sections were stained with H&E. All slides were coded and semiquantitatively scored by a pathologist without knowledge of the experimental group. For granulocyte staining, slides were deparaffinized, and endogenous peroxidase activity was quenched by a solution of methanol/0.03% H2O2 (Merck, Darmstadt, Germany). After digestion with a solution of 0.25% pepsin (Sigma-Aldrich) in 0.01 M HCl, the sections were incubated in 10% normal goat serum (DAKO, Glostrup, Denmark) and then exposed to FITC-labeled anti-mouse Ly-6-G mAb (BD PharMingen, San Diego, CA). Slides were then incubated with a rabbit anti-FITC Ab (DAKO), followed by a further incubation with a biotinylated swine anti-rabbit Ab (DAKO), rinsed again, incubated in a streptavidin-avidin-biotin complex solution (DAKO) and developed using 1% H2O2 and 3,3'-diaminobenzidine-tetra-hydrochloride (Sigma-Aldrich) in Tris-HCl. After light counterstaining with methyl green, sections were mounted in glycerin gelatin. For macrophage staining, after quenching endogenous peroxidase activity, slides were digested with a solution of trypsin 0.1% (Sigma-Aldrich) in PBS, then incubated in 10% normal goat serum (DAKO) and finally overnight exposed to rat anti-mouse F4/80 IgG2b mAb (Serotec, Breda, The Netherlands). Slides were then incubated with biotinylated rabbit anti-rat Ab (DAKO), rinsed again, incubated in a streptavidin-avidin-biotin complex solution (DAKO), and developed using 1% H2O2 and 3,3'-diaminobenzidine-tetra-hydrochloride (Sigma-Aldrich) in Tris-HCl. After light methylgreen counterstaining, sections were mounted in glycerin gelatin.
RT-PCR
For analysis of cytokine mRNA transcripts, total RNA was extracted from brain tissue. Brains from three mice per time point were pooled. Snap-frozen brain homogenates were homogenized in 1 ml of TRIzol reagent (Life Technologies, Grand Island, NY), and total RNA was isolated using chloroform extraction and isopropanolol precipitation. RNA was dissolved in diethylpyrocarbonate-treated water and quantified by spectrophotometry. cDNA was synthesized by mixing 2 µg of RNA with 0.5 µg oligo(dT) (Life Technologies) and by incubating the solution for 10 min at 72°C. Subsequently, 8 µg of a solution containing 5x first-strand buffer (Life Technologies), 1.25 mM each of dNTPs (Amersham Pharmacia Biotech, Little Chalfont, U.K.), 10 mM DTT (Life Technologies), and the Superscript preamplification system (Life Technologies) was added and then incubated for 60 min at 37°C. For RT-PCR, equivalent amounts of cDNA were amplified using a solution containing 4% DMSO (Merck, Munich, Germany), 12.5 µg of BSA (Biolabs, Northbrook, IL) 0, 1.25 mM of each dNTPs, 10x PCR buffer (0.67 M Tris-HCl (pH 8.8), 67 mM MgCl2, 0.1 M -ME, 67 µM EDTA, and 0.166 M (NH4)2SO4), 0.5 U of AmpliTaq DNA polymerase (PerkinElmer, Branchburg, NJ), and the forward and reverse primers (100 mM each). The PCR were conducted in an thermocycler GeneAmp PCR System 9700 (PerkinElmer, Norwalk, CT) using cycles including denaturation at 94°C, reannealing at 55°C, and primer extension at 72°C. Primer sequences and cycles (cycles were chosen within linear amplification rate) were: IL-1: forward, 5'-CTCTAGAGCACCATGCTACAGAC-3'; reverse, 5'-TGGAATCCAGGGGAAACACTG-3' (30 cycles); IL-1: forward, 5'-TCATGGGATGATGATAACCTGCT-3'; reverse, 5'-CCCATACTTTAGGAAGACACGGAT-3' (30 cycles); and -actin: forward, 5'-GTCAGAAGGACTCCTATGTG-3'; reverse, 5'-GCTCGTTGCCAATAGTGATG-3' (24 cycles). The PCR products were size fractionated by electrophoresis on 1.2% agarose gel containing ethidium bromide.
Measurement of cytokine concentrations
Levels of cytokines and chemokines were measured using commercially available ELISAs, according to the recommendations of the manufacturer (KC, macrophage inflammatory protein-2 (MIP-2), IL-1, IL-1, IL-1Ra, and TNF- (R&D Systems, Minneapolis, MN; IL-6 (BD PharMingen)).
Statistical analysis
Data are expressed as the mean ± SEM unless indicated otherwise. The Mann-Whitney U test was used to evaluate the statistical significance of the differences in cytokine levels, bacterial outgrowth, and leukocyte counts between the groups; the Kaplan-Meier test was used for survival analysis; and Pearson’s 
2 test was used to compare the proportions of mice that developed meningitis (p < 0.05 was considered significant).
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Results |
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, IL-1, and IL-1Ra during meningitis
Intranasal inoculation with 8 x 104 CFU of S. pneumoniae with hyaluronidase induced meningitis within 72 h in 64% of wild-type mice, confirming our previous results (20). To determine whether IL-1, IL-1, and IL-1Ra protein are up-regulated during pneumococcal meningitis, their concentrations were measured in brain homogenates by ELISA. The induction of pneumococcal meningitis was associated with an increase in IL-1, IL-1, and IL-1Ra brain concentrations (Fig. 1, A–C). IL-1 and IL-1 peaked 72 h after inoculation, whereas IL-1Ra concentrations reached a peak 48 h after inoculation. Neither mice without meningitis nor mice 24, 48, and 72 h after intranasal inoculation with sterile saline or hyaluronidase only had detectable IL-1 or IL-1Ra in brain homogenates; IL-1 was detectable in low concentrations in brain tissue of control mice.
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and IL-1 are locally produced within the central nervous system, RT-PCR was performed on brain tissue obtained from mice that developed meningitis and from mice that did not develop meningitis after intranasal inoculation with S. pneumoniae with hyaluronidase. RT-PCR demonstrated IL-1 and IL-1 mRNA expression in brain tissue of mice with meningitis, indicating local production of IL-1 and IL-1 by resident or recruited cells (Fig. 1D). Increased susceptibility to meningitis in IL-1R-/- mice
Meningitis was defined by pleocytosis of cerebrospinal fluid (>1 x 104 leukocytes/ml), positive cerebrospinal fluid culture, and meningeal inflammation on brain histology (20). Twenty-four hours after inoculation equal percentages of IL-1R-/- and wild-type mice had developed signs of meningitis; however, after 48 and 72 h more IL-1R-/- mice had meningitis compared with wild-type mice (p > 0.05; Fig. 2). In this model, after intranasal inoculation pneumococci gain access to the subarachnoid space via the circulation (20). Eighty-five percent of both IL-1R-/- mice and wild-type mice developed bacteremia, which occurred within 24 h after inoculation. These observations indicate that the difference between IL-1R-/- and wild-type mice in susceptibility to develop meningitis originates from a difference in blood-brain barrier passage by the bacteria, rather than from a difference in invasion of the bloodstream.
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To determine the role of IL-1 in early host defense against pneumococcal meningitis, we compared bacterial outgrowth in the brains of IL-1R-/- and wild-type mice 24, 48, and 72 h after intranasal inoculation with S. pneumoniae with hyaluronidase. The number of bacterial counts found in cerebrospinal fluid of IL-1R-/- mice was higher than that in wild-type mice at 24, 48, and 72 h after inoculation, indicating impaired bacterial clearance (Fig. 3A). In addition, bacterial outgrowth in blood was more profound in IL-1R-/- than in wild-type mice (Fig. 3B). These differences in early antibacterial defense are in line with the difference in survival rates among IL-1R-/- and wild-type mice. It should be noted that 48 h after inoculation three of 14 inoculated IL-1R-/- mice had died, compared with none of the wild-type mice; at 72 h after inoculation eight of 14 inoculated IL-1R-/- mice had died vs three of 14 inoculated wild-type mice. The dissimilarity between the experimentation groups that originated from the difference in survival might have biased the results at these time points. However, since these mice died from meningitis, this bias most likely leads to an underestimation of the difference.
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A marked increase in WBC in cerebrospinal fluid was found after induction of meningitis by inoculation with S. pneumoniae and hyaluronidase. No differences were found in WBC in cerebrospinal fluid between IL-1R-/- and wild-type mice 24, 48, or 72 h after inoculation (24 h, 2.0 ± 0.4 vs 1.5 ± 0.5 x 105 cells/ml, ns; 72 h, 1.5 ± 1.5 vs 1.6 ± 0.8 x 107 cells/ml; p = NS).
Histopathological analysis showed a more severe infiltration of leukocytes in wild-type mice (Fig. 4A) compared with IL-1R-/- mice (Fig. 4B). The inflammatory changes consisted mainly of granulocytes and monocytes and were primarily localized around the meninges.
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To determine whether alterations in the expression of cytokines or chemokines contributed to the impaired host defense in IL-1R-/- mice, their concentrations were measured in brain homogenates. Fig. 5 shows concentrations of proinflammatory cytokines (IL-6 and TNF-) and chemokines (KC and MIP-2) in IL-1R-/- compared with wild-type mice. A trend was visible 72 h after inoculation: all cytokines and chemokines were strongly up-regulated in wild-type mice, whereas in IL-1R-/- mice cytokine concentrations remained stable. However, due to the relatively large interindividual variation, the differences between IL-1R-/- and wild-type mice did not reach statistical significance.
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The survival of inoculated IL-1R-/- mice and wild-type mice was measured during 3 wk. IL-1R-/- succumbed significantly earlier than wild-type mice (p = 0.0024; Fig. 6). Mortality was early, with all deaths occurring within 5 days after inoculation in both IL-1R-/- mice and wild-type mice. Five days after inoculation 19 of 22 inoculated IL-1R-/- mice had died compared with eight of 22 inoculated wild-type mice.
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From these data we conclude that mortality is mainly due to meningitis in both IL-1R-/- and wild-type mice. In line with the results of other experiments, IL-1R-/- mice showed less pronounced inflammation and more bacterial growth compared with wild-type mice.
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Discussion |
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and IL-1 72 h after inoculation. The low levels of IL-1 in saline-injected control mice are in line with previous reports of constitutive IL-1 expression in brain tissue (24). The generation of IL-1R-/- mice enables comprehensive analysis of the function of IL-1 in vivo. In the present study we show that IL-1R-/- mice, lacking an intact IL-1 signal, are more susceptible to develop meningitis after intranasal infection and that meningitis is associated with higher mortality and enhanced growth of pneumococci in IL-1R-/- mice compared with wild-type mice.
Bacterial meningitis occurs when pathogenic organisms overcome host defense mechanisms and reach the subarachnoid space. At first, pathogens are believed to invade the circulation after nasopharyngeal colonization, whereafter sustained bacteremia is required before invasion of the meninges occurs (25). We report here that a greater percentage of IL-1R-/- mice develop meningitis after intranasal inoculation compared with wild-type mice, suggesting a protective role for IL-1 in the first-line defense against pathogens. No difference was found in the development of bacteremia, suggesting that IL-1 is needed to prevent the passage of bacteria through the blood-brain barrier. Once the bacterial pathogen enters the subarachnoid space, host defense mechanisms direct to control infection and bacterial replication. In the absence of an IL-1 response, significantly more pneumococci were recovered from the cerebrospinal fluid of IL-1R-/- mice than from that of wild-type mice at all time points measured. This and other studies (14) indicate that IL-1 plays an important role in bacterial clearance.
A major consequence of subarachnoid space inflammation during bacterial meningitis is cerebrospinal fluid pleocytosis, predominantly consisting of neutrophils. Leukocyte migration across the blood-brain barrier is believed to be a carefully controlled process for which the exact mechanisms are partly unknown. IL-1 participates in the recruitment of leukocytes to inflammatory sites by inducing adhesion molecules on endothelial and glial cells (26, 27, 28) and by the induction of chemokines, such as IL-8. However, no statistically significant difference in cerebrospinal fluid leukocyte counts was observed among IL-1R-/- and wild-type mice. Since bacterial products are chemotactic for neutrophils, higher bacterial counts in the cerebrospinal fluid of IL-1R-/- mice may compensate at least in part for the effect of the lack of an IL-1 response on chemotaxis. Secondly, it has been demonstrated previously that the net effect of inhibition of IL-1 (by IL-1Ra) on chemokine production and neutrophil accumulation is organ and chemokine dependent (29).
The absence of an intact IL-1 signal was furthermore associated with a less pronounced induction of several members of the cytokine cascade after the development of meningitis. Indeed, IL-1 is known to exert most of its effects indirectly by inducing a cascade of other inflammatory mediators (10). In accord, lower levels of TNF-, IL-6, KC, and MIP-2 after bacterial challenge in IL-1R-/- mice were demonstrated in previous studies (30, 31).
The increased bacterial outgrowth and the associated enhanced mortality indicate that IL-1 is needed in host defense during pneumococcal meningitis. Our observations are in line with the report by Saukkonen et al. (32), demonstrating that Abs against IL-1 reduced meningeal inflammation in rabbits after intracisternal challenge with pneumococci.
Our laboratory recently demonstrated that in a murine pneumococcal pneumonia model, IL-1R-/- mice show an impaired early host defense, but do not show a decrease in survival rate due to compensatory capacities of TNF- at a later phase (14). The role of TNF- in pneumococcal meningitis in the absence of IL-1 was not directly addressed in the present study. However, it is clear from the severely impaired survival of IL-1R-/- mice that TNF- is not capable of compensating for the function of IL-1 in this model. We speculate that this difference can be explained either by the even more acute and overwhelming nature of meningitis compared with pneumonia or by the local absence, due to the blood-brain barrier, of TNF--producing cells in the early phase of infection.
The interaction of IL-1 and IL-6 is complex; although synergism between IL-1 and IL-6 is a frequently reported phenomenon (10, 33), it has also been shown that IL-1 is able to suppress downstream effects of IL-6 at a transcriptional level (34, 35). As such, the cellular effect of IL-6 is not determined solely by the absolute level of expression, and the potency of IL-6 might be enhanced in the absence of an intact IL-1 signal. However, in this model IL-6 is not able to compensate for the absence of proinflammatory capacity of IL-1.
Although IL-1 is known to be involved in the induction of IFN- (10, 36, 37, 38), blocking IL-1 signaling either by using saturating concentrations of IL-1Ra or by a disruption in the IL-1R gene affects the induction of IFN- in some (39, 40), but not all (41, 42), models. Previous reports diverge on the role of IFN- in bacterial meningitis (43, 44, 45, 46); however, in our model IFN- levels are not up-regulated during meningitis. Therefore, we cannot speculate on the interaction between IL-1 and IFN-.
In conclusion, we here demonstrate that locally produced IL-1 is essential for host defense during meningitis caused by S. pneumoniae, as reflected by the impaired bacterial clearance and reduced survival of IL-1R-/- mice.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: IL-1Ra, IL-1R antagonist; MIP-2, macrophage inflammatory protein-2; WBC, white blood cells.
Received for publication May 3, 2002. Accepted for publication February 26, 2003.
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References |
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and IL-1
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interferon production by natural killer cells in scid mice: roles of tumor necrosis factor and bacterial stimuli. Infect. Immun. 59:1709.-converting enzyme (caspase-1) in intestinal inflammation. Proc. Natl. Acad. Sci. USA 98:13249., and tumor necrosis factor- in the production of interferon- induced by Candida albicans in human whole-blood cultures. J. Infect. Dis. 185:963.[Medline]
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) and wild-type (
) mice developed meningitis 24 h after intranasal inoculation with 8 x 104 CFU of S. pneumoniae and 180 U of hyaluronidase. However, IL-1R-/- mice were more susceptible to develop meningitis, determined 48 and 72 h after inoculation. Meningitis was defined as a positive cerebrospinal fluid culture, pleocytosis of cerebrospinal fluid, and histologic evidence of meningitis.
) and wild-type mice (•; n = 22 mice/group). The p value indicates the difference in survival by Kaplan-Meier test.