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Previous Article | Next Article 
Infection and Immunity, May 1999, p. 2071-2074, Vol. 67, No. 5
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Effects of Polysaccharide Fucoidin on Cerebrospinal
Fluid Interleukin-1 and Tumor Necrosis Factor Alpha in Pneumococcal
Meningitis in the Rabbit
Carl
Granert,1,*
Johan
Raud,2,
Anders
Waage,3 and
Lars
Lindquist1
Department of Infectious Diseases, Huddinge
Hospital, S-141 86 Huddinge,1 and
Department of Physiology and Pharmacology, Karolinska
Institutet, S-171 77 Stockholm,2 Sweden, and
Section of Hematology, University Hospital of Trondheim, N-7006
Trondheim, Norway3
Received 14 September 1998/Returned for modification 24 November
1998/Accepted 2 February 1999
 |
ABSTRACT |
The inflammatory response in bacterial meningitis is mediated by
cytokines, such as tumor necrosis factor alpha (TNF-
) and interleukin-1 (IL-1), which are produced in the subarachnoid space by
different cells, e.g., leukocytes, astrocytes, and microglia. The
recruitment of leukocytes into the cerebrospinal fluid (CSF) has been
shown to contribute to the neurological damage in this disease, a
process which could be enhanced by treatment with antibiotics. In this
study, we have used a rabbit meningitis model for two sets of
experiments with intracisternal (i.c.) injections of
Streptococcus pneumoniae. First, pneumococcal cell wall
(PCW) components were injected i.c., inducing an inflammatory response
with pleocytosis and increased levels of CSF TNF-) and IL-1 at 6 and
12 h after PCW injection. Treatment with fucoidin, known to
inhibit leukocyte rolling, abolished pleocytosis and inhibited the
release of TNF- and IL-1. In the second experiment, live
pneumococcal bacteria were injected i.c. and treatment with one dose of
ampicillin (40 mg/kg of body weight intravenously) was given 16 h
after induction of meningitis, causing a sevenfold increase in CSF
leukocytes over a 4-h period. CSF IL-1 levels at 16 h were high
but did not increase further at 20 h. Also, CSF TNF- levels
were high at 16 h and tended to increase at 20 h. Fucoidin
treatment prevented the antibiotic-induced increase of CSF leukocytes
but had no effect on the TNF- and IL-1 levels. Taken together,
fucoidin reduced CSF TNF- and IL-1 levels in acute bacterial
meningitis induced by PCW fragments but had no effect later in the
course of the disease, when live bacteria were used and an inflammatory
increase was caused by a dose of antibiotics.
| |
INTRODUCTION |
In bacterial meningitis, the
meningeal inflammatory reaction most likely contributes to the central
nervous system (CNS) injury associated with this disease, and one part
of this process is the deleterious effects of the cerebrospinal fluid
(CSF) leukocytes and their cytotoxic products (19).
Consequently, inhibition of leukocyte recruitment into the subarachnoid
space has been shown to reduce mortality in experimental meningitis
(16, 20). The process of inflammatory leukocyte recruitment
involves several sequential steps: margination and rolling of
leukocytes along vascular endothelium, firm adhesion to the endothelial
cells, and subsequent diapedesis through the vessel wall
(2). Leukocyte rolling is mediated by adhesion molecules of
the selectin family (2), while stationary leukocyte adhesion
is critically dependent on leukocytic integrins, such as CD11 and CD18
(2). Accordingly, the polysaccharide fucoidin, which blocks
L- and P-selectin function, inhibits leukocyte rolling (9,
23), and monoclonal antibodies directed against CD11 and CD18
block firm leukocyte adhesion (1). With regard to bacterial
meningitis, we have recently shown that fucoidin treatment is an
effective way to attenuate meningeal inflammation induced by
pneumcoccal cell wall (PCW) fragments (6) and furthermore,
it prevents antibiotic-induced CSF leukocyte accumulation in rabbits
inoculated with live pneumococcal bacteria (7).
During the onset of meningitis caused by both gram-negative and
gram-positive bacteria, the proinflammatory cytokines tumor necrosis
factor alpha (TNF-) and interleukin-1 (IL-1) are present in the CSF
(18, 24). These cytokines can be produced by different cells, including leukocytes and cells within the CNS, such as astrocytes and microglia (22). The cytokines play an
important role in the pathophysiology of bacterial meningitis. Thus,
TNF- contributes to the accumulation of leukocytes in the CSF, brain edema (17), blood-brain barrier damage (18), and
damage of cells within the CNS (22). IL-1 also contributes
to disruption of the blood-brain barrier and CSF leukocyte recruitment
and stimulates the production of other cytokines, such as IL-6 and
TNF- (22). Moreover, in patients with bacterial
meningitis, high CSF IL-1 levels correlate with neurological
complications (22). There is also evidence that treatment of
bacterial meningitis with antibiotics has the capability to increase
CSF cytokine concentrations, most likely because antibiotic-induced
bacterial lysis liberates large amounts of harmful bacterial products
in the CSF (13). For example, in experimental pneumococcal
meningitis, Tuomanen et al. have demonstrated an increase in meningeal
inflammation after ampicillin treatment, characterized by a massive
influx of leukocytes and elevated levels of protein and lactate in the
CSF (20, 21). In the same type of model with pneumococcal
bacteria, others have demonstrated elevated CSF TNF- levels after
antibiotic treatment (14). Similar effects of antibiotics
have also been demonstrated in experimental Haemophilus
influenzae meningitis (13, 16). However, the cellular
source of the cytokines (blood leukocytes or stationary CNS cells) is
still unclear.
In the present study, we examined whether inhibition of CSF leukocyte
recruitment with fucoidin has the capacity to inhibit the production of
CSF TNF- and IL-1 in rabbits with meningitis induced by PCW
fragments and in animals inoculated with live pneumococcal bacteria and
then treated with ampicillin.
| |
MATERIALS AND METHODS |
Bacterial strain.
Streptococcus pneumoniae III, type
III, a gift from Elaine Tuomanen, was cultured on blood agar plates and
suspended in pyrogen-free saline before injection.
Preparation of pneumococcal antigen.
An unencapsulated
strain (CSR-SCS-2 clone 1) of S. pneumoniae ("Cesam
strain," from the Department of Bacteriology, Karolinska Institutet)
was cultured overnight on blood agar plates, suspended in pyrogen-free
saline, and heat inactivated by being boiled for 10 min. The optical
density of the final antigen solution was adjusted to a viable count of
106 CFU/ml.
Experimental meningitis model with PCW.
A previously
described meningitis model in female New Zealand White rabbits (3.5 to
4.5 kg) was used (10). Briefly, 0.25 ml of CSF was collected
from the cisterna magna, after which an equal volume of the
pneumococcal antigen suspension was injected. Subsequent CSF samples
(0.25 ml) were taken after 6 and 12 h. In a group of five rabbits,
fucoidin (10 mg/kg of body weight; Sigma Chemical Co., St. Louis, Mo.)
was administered intravenously (i.v.) at 
5 min and at 2 and 4 h
relative to the intracisternal (i.c.) introduction of antigen. A
control group of six rabbits received an i.c. injection of antigen and
i.v. treatment with a vehicle. Fucoidin was dissolved in sterile
phosphate-buffered saline (10 mg/ml at pH 7.3) and passed through a
0.2-µm-pore-size sterile filter prior to i.v. administration.
Fucoidin has been found to block leukocyte rolling in a dose-dependent
manner, without interfering with the process of firm leukocyte adhesion
per se (9). Our choice of dose and regimen are based on
previous studies (6).
Experimental meningitis model with live pneumococcal
bacteria.
In the same model described above, a 0.25-ml saline
suspension containing an inoculum of live pneumococci (105
CFU/ml) was injected i.c. in 15 rabbits. Sixteen hours after inoculation of the bacterial, 10 animals received an i.v. injection of
ampicillin (40 mg/kg) (Doktacillin; Astra AB, Södertälje, Sweden). Five of these rabbits received ampicillin only, and five rabbits were treated with fucoidin (10 mg/kg i.v.), given 5 min before
the ampicillin dose and 2 h thereafter. Five rabbits served as
controls, i.e., they were inoculated with bacteria but did not receive
any treatment. In all animals, aliquots of CSF were obtained just
before inoculation with pneumococci and at 16 and 20 h thereafter.
The rationale for choosing these time points was based on previous
studies (7).
In both sets of experiments, total and differential leukocyte counts of
CSF were done immediately after collection. The remaining CSF was
centrifuged (1,200 × g; 10 min), and the supernatants were stored at 70°C until they were assayed for TNF- and IL-1.
During each cisternal puncture, the animals were anesthetized with 0.25 ml of fluanison-fentanyl (Hypnorm Vet 10; 0.2 mg/ml) (Janssen
Pharmaceutica, Beerse, Belgium)/kg and 0.25 ml of diazepam (Stesolid; 5 mg/ml) (Dumex, Kabi Pharmacia, Sweden)/kg intramuscularly. The
experiments were approved by an animal ethics committee at Södra
Roslags Court House. All animals were euthanized within 24 h after
inoculation with bacterial.
Assays for TNF- and IL-1.
TNF- was measured by its
cytotoxic effect on the mouse fibrosarcoma cell line WEHI 164 clone 13 (3). Cell viability was measured after 20 h by a
colorimetric MTT (tetrazolium) assay (11). Human recombinant
TNF- (Genentech Inc., South San Francisco, Calif.) was used as a
standard. CSF was assayed in duplicate in serial dilutions from 1:8 to
1:528. The detection limit was 15 pg of TNF- per ml of CSF.
IL-1 was measured in a two-stage assay with the IL-1-responsive mouse
T-cell line EL-4 6.1 clone NOB-I (5) and the IL-2-dependent mouse T-cell line HT-2 (12). The EL-4 cells produce IL-2 in response to IL-1 stimulation, and IL-2 production is measured by the
proliferation of the IL-2-dependent HT-2 cells. The medium used was
RPMI 1640 supplemented with L-glutamine (0.1 mg/ml), gentamicin (40 µg/ml), 10% fetal calf serum, and 2-mercaptoethanol (25 µmol/liter). Serial dilutions of CSF were added in duplicate to
flat-bottom 96-well microtiter plates, and the volume was adjusted with
medium to 100 µl per well. The EL-4 cells were washed once in Hanks'
balanced salt solution, resuspended in medium, and incubated at 2 × 105 per well, producing a final volume of 200 µl per
well. After 24 h of incubation, 100 µl of supernatant was
transferred from each well into a replicate microtiter plate. The HT-2
cells were washed three times in Hanks' balanced salt solution,
resuspended in medium, and distributed in the microtiter plates at a
concentration of 0.15 × 105 per well, giving a final
volume of 200 µl per well. After 20 h of incubation, the cell
growth was measured by the colorimetric MTT assay. Human recombinant
IL-1 (Glaxo, Geneva, Switzerland) was included as a standard. CSF
was assayed in dilutions from 1:4 to 1:256. The detection limit was 8 pg of IL-1 per ml of CSF. Some samples containing IL-1 activity were
retested in the HT-2 assay to ascertain if the activity could be caused
by the presence of IL-2 in the sample.
Statistical analysis.
Results were analyzed by the Wilcoxon
signed-rank test or the Mann-Whitney rank sum test. Differences were
considered significant when P was less than 0.05. Data are
expressed as mean ± standard error.
| |
RESULTS |
Experimental meningitis with PCW.
In the experiment with i.c.
injection of PCW fragments, the mean CSF leukocyte counts in the
control animals increased substantially at both 6 and 12 h (Table
1). In the group of rabbits treated with
fucoidin (10 mg/kg, given 5 min before and 2 and 4 h after antigen
challenge), the corresponding mean CSF leukocyte counts were very low
at 6 h and slightly raised at 12 h (i.e., 8 h after the
end of fucoidin treatment) (Table 1).
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|
TABLE 1.
Mean CSF leukocyte counts and CSF IL-1 and TNF-
concentrations in rabbits injected i.c. with PCW fragments, with and
without fucoidin treatmenta
|
|
In the control group, PCW injection increased the mean CSF IL-1
concentration at 6 and 12 h (Table 1). In the animals treated with
fucoidin, the mean CSF IL-1 values were significantly reduced at 6 h and tended to be reduced at 12 h (Table 1). IL-1 was detected in
the CSF of all rabbits after PCW injection.
PCW challenge also increased the mean CSF TNF- levels in control
rabbits at 6 and 12 h. Fucoidin treatment tended to reduce the
mean CSF TNF- levels at 6 h (not significant), while the reduction was significant at 12 h (Table 1). However, TNF- was detected in only two animals in the treatment group, both at 6 h.
In contrast, the control group had detectable TNF- in all samples at
both time points after PCW injection.
Experimental meningitis with live pneumococcal bacteria.
In
the second set of experiments, where live pneumococci were injected
i.c., an i.v. dose of ampicillin (40 mg/kg 16 h after inoculation
with bacteria elicited a sevenfold increase of the mean CSF leukocyte
count 4 h later. If a dose of fucoidin was given i.v. 5 min before
the ampicillin and 2 h thereafter, the CSF leukocyte influx was
prevented and the 20-h value was even lower than the 16-h value (Table
2). In the five animals serving as
controls (inoculated with bacteria without treatment with ampicillin or
fucoidin), the CSF leukocyte counts were 0, 960 × 106 ± 326 × 106, and 662 × 106 ± 160 × 106/ml at 0, 16, and 20 h, respectively
(data not shown).
View this table:
[in this window]
[in a new window]
|
TABLE 2.
Mean CSF leukocyte counts and CSF IL-1 and TNF-
concentrations in rabbits injected i.c. with live pneumococci and
treated with ampicillin or ampicillin
and fucoidina
|
|
The CSF IL-1 concentration at 16 h after inoculation with bacteria
was increased in all 10 animals. Treatment with ampicillin at the 16-h
time point did not elevate the IL-1 levels as measured 4 h later.
Moreover, treatment with fucoidin had no effect on the CSF IL-1 levels
(Table 2). The individual values for each animal at 16 and 20 h
are presented in Fig. 1, showing the
narrow range of values in both treatment groups at both time points.
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|
FIG. 1.
CSF IL-1 and TNF- concentrations in rabbits injected
i.c. with live pneumococci and treated with a dose of ampicillin (40 mg/kg i.v.) after 16 h. One group (Control) received ampicillin
only, and the other group received treatment with fucoidin (10 mg/kg
i.v.). The values for each animal are shown; n = 5 in
each group.
|
|
The mean CSF TNF- concentration 4 h after ampicillin treatment
only tended to be increased in both treatment groups, and fucoidin
treatment did not affect the TNF- levels (Table 2). However, one
fucoidin-treated animal had a pronounced CSF TNF- activity (30,700 pg/liter) in the 20-h sample, causing the substantially increased mean
value. The individual values for each animal at 16 and 20 h are
presented in Fig. 1, showing the wide range of TNF- values,
particularly in the control group. All rabbits except one (16-h sample)
had detectable TNF- levels in all samples after inoculation with bacteria.
| |
DISCUSSION |
In this study, as in a previous one (6), we found that
pretreatment with fucoidin prevented the accumulation of leukocytes in
the subarachnoid space during the first 6 h of experimental meningitis induced with PCW components. In parallel, fucoidin treatment
significantly attenuated the increased CSF levels of the
proinflammatory cytokine IL-1 while only tending to reduce TNF-
levels. At 12 h, however, fucoidin treatment abolished TNF- release in all animals. In the second part of this study, where meningitis was established with live pneumococci, a sevenfold increase
in CSF leukocytosis occurred after a dose of ampicillin. This increased
leukocyte influx was also prevented with fucoidin treatment, consistent
with our previous results (7). In these experiments the mean
TNF- level increased fourfold, although not significantly, while the
mean IL-1 activity remained unchanged 4 h after the dose of ampicillin.
In the first set of experiments with PCW fragments, the reduced levels
of CSF TNF- and IL-1 appeared to correlate with the inhibition of
CSF leukocyte accumulation, indicating that leukocytes (directly or
indirectly) were involved in the production of these inflammatory
cytokines. In contrast, no such correlation could be demonstrated in
the second set of experiments with live pneumococci. Thus, despite a
significant inhibition of CSF leukocyte influx after a dose of
ampicillin in fucoidin-treated animals, no significant inhibition of
CSF cytokines was observed, suggesting that leukocytes might be less
important for cytokine production in this later phase of meningitis.
This is in line with a meningitis study by Saéz-Llorens et al.
(16) showing that treatment with an anti-CD18 monoclonal
antibody of rabbits inoculated with H. influenzae and treated with antibiotics did not inhibit CSF TNF- formation, despite
significant attenuation of the CSF inflammatory burst, including
pleocytosis (16).
It is not clear why leukocyte blocking with fucoidin partially
inhibited TNF- and IL-1 production in our experiments with PCW but
not in the experiments with live bacteria. However, it is clear that
several types of cells possibly involved in the pathophysiological
process in bacterial meningitis can produce TNF- and/or IL-1 upon
stimulation with, e.g., pneumococci. For example, it has been
demonstrated that both monocytes and CNS cells (astrocytes and
microglia) produce IL-1
and TNF- in response to PCW components
and other stimuli (4, 8, 15, 22). Moreover, in studies of
experimental pneumococcal meningitis in rabbits, it has been shown that
systemic monocyte depletion reduced CSF IL-1 levels whereas CSF
TNF- concentrations were not different from those of controls
(25). Thus, one explanation for the different effects of
fucoidin in our acute experiment with PCW and the prolonged experiments
with live bacteria could be that the major source of these cytokines in
the acute phase of meningitis is leukocytes and that other cells, like
astrocytes and microglia, reach full cytokine production later in the
course of pneumococcal meningitis. However, further studies are needed
to elucidate the exact cellular sources and release kinetics of
cytokines in both experimental and clinical meningitis.
In summary, we have documented that blocking of CSF leukocyte
accumulation with the polysaccharide fucoidin has the capacity to
inhibit CSF levels of TNF- and IL-1 in experimental meningitis induced with PCW fragments. However, fucoidin treatment had no significant effect on TNF- or IL-1 levels after a dose of
antibiotics 16 h after the induction of meningitis with live
pneumococci, although the burst of pleocytosis was prevented.
| |
ACKNOWLEDGMENTS |
We thank Gudmundur Axelsson for valuable help with statistics.
This study was supported by the Swedish Society for Medical Research,
the Swedish Medical Research Council (14X-4342), the Swedish Foundation
for Health Care Sciences and Allergy Research (A95093), and Clas
Groschinski's Memorial Foundation.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Infectious Diseases, Huddinge Hospital, S-141 86 Huddinge, Sweden.
Phone: 46-8-585 80000. Fax: 46-8-585 81916.
Present address: Astra Pain Control AB, Discovery Division, S-141
57 Huddinge, Sweden.
Editor:
E. I. Tuomanen
| |
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Infection and Immunity, May 1999, p. 2071-2074, Vol. 67, No. 5
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
