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(Stroke. 1999;30:2174-2179.)
© 1999 American Heart Association, Inc.
Original Contributions |
Increased IL-1ß, IL-8, and IL-17 mRNA Expression in Blood Mononuclear Cells Observed in a Prospective Ischemic Stroke Study
From the Neuro-Angiological Research Center, Division of Neurology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Correspondence to Nikolaos Kostulas, Department of Neurology, Huddinge University Hospital, S-141 86 Huddinge, Sweden. E-mail Nikolakis{at}hotmail.com
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Ischemic brain injury secondary to arterial occlusion is characterized by acute local inflammation, which involves accumulation of polymorphonuclear neutrophils (PMN). Factors that influence the recruitment of PMN could represent new therapeutic targets in acute stroke. In this prospective study we evaluated numbers of peripheral blood mononuclear cells (PBMC) expressing mRNA for interleukin (IL)-1ß, IL-8, and IL-17 and macrophage inflammatory protein-1
(MIP-1) after ischemic stroke. Methods—Peripheral blood was obtained on days 1 to 3, 4 to 10, and 20 to 31 after onset of symptoms. In situ hybridization with radiolabeled synthetic oligonucleotide probes was adopted to measure cytokine mRNA expression in PBMC. Plasma and cerebrospinal fluid levels of IL-8 were measured by an enzyme-linked immunosorbent assay.
Results—Most patients with ischemic stroke had clearly
elevated numbers of IL-1ß, IL-8, and IL-17 mRNA expressing PBMC 1 to
3 days after onset of symptoms compared with healthy individuals
(P<0.0001 for all comparisons). At follow-up after 20
to 31 days, numbers of IL-8 mRNA expressing PBMC were lower than during
the acute stage (P<0.001), but only IL-1ß and IL-17
mRNA expression had returned to the level of the healthy individuals.
Numbers of MIP-1 mRNA expressing PBMC did not differ between
patients with ischemic stroke and healthy individuals at any
time point. A correlation was observed between numbers of IL-1ß,
IL-8, and IL-17 mRNA expressing PBMC and the degree of neurological
impairment as measured by the Scandinavian Stroke Scale 1 to 3 days
after onset of symptoms (r=0.5;
P<0.01 for all correlations).
Conclusions—A longitudinal study of patients with ischemic stroke revealed systemic increases of levels of IL-1ß, IL-8, and IL-17 that correlated with Scandinavian Stroke Scale scores. IL-8 levels were further increased in cerebrospinal fluid.
Key Words: chemokines • cytokines • inflammation • stroke, ischemic
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Stroke is a major cause of human suffering, hospitalization, chronic disability, and death. There is increasing evidence that ischemic brain injury secondary to arterial occlusion is characterized by acute local inflammation. During reperfusion after acute ischemia, polymorphonuclear neutrophils (PMN) are believed to exacerbate tissue damage by both physical obstruction of vessels and release of oxygen radicals, proinflammatory cytokines, and cytolytic enzymes.1 In animal models of cerebral ischemia, accumulation of PMN has been detected within the first 12 hours after induction of ischemia.2 Tissue damage due to ischemic stroke can be reduced in experimental animal models by blockage of leukocyte accumulation. For instance, in knockout mice lacking the intercellular adhesion molecule-1 (ICAM-1) gene, which results in less PMN infiltration, the infarct volume was significantly reduced after transient middle cerebral artery occlusion compared with control animals.3
Activated PMN produce cytokines, ie,
low-molecular-weight proteins that mediate and regulate immune and
inflammatory responses. Increased protein levels of proinflammatory
cytokines such as tumor necrosis factor- (TNF-) and
interferon-
(IFN-) have been demonstrated in brain autopsies from
patients after acute stroke compared with control brains from patients
with other neurological diseases.4 Increased
production of several cytokines, including interleukin
(IL)-1ß, IL-6, IL-8, IL-10, TNF-, and
granulocyte-macrophage colony-stimulating factor, has
been demonstrated intrathecally in patients with acute
ischemic stroke.5 6 7 Increased synthesis of
cytokines in acute stroke is, however, not restricted to the
central nervous system (CNS) but can also be detected
systemically.8 9 10 Such cytokine abnormalities are
of interest, because they may constitute a pathway for therapeutic
intervention into the CNS.
Chemokines constitute a subgroup of the cytokine family, which may play a pivotal role in the accumulation of leukocytes to ischemic areas of the brain.11
We have recently described that patients with acute ischemic
stroke have a clear increase systemically of IL-8 mRNA expressing PBMC,
as well as increased plasma levels of IL-8.9 To further
elucidate involvement of cytokines in ischemic stroke
and thereby identify substances that perhaps could be targeted in
future therapeutic studies, we examined mRNA expression by
peripheral blood mononuclear cells (PBMC) of the chemokine
macrophage inflammatory protein-1 (MIP-1), besides IL-8,
and of the proinflammatory cytokines IL-1ß and IL-17 over the
first month after ischemic stroke. IL-8 is a potent
chemoattractant for PMN both in vitro and in vivo, whereas MIP-1
mainly attracts mononuclear cells.11 12 13 14 IL-1ß and IL-17
induce the production of IL-8 in endothelial
and parenchymal cells, indicating an indirect role in PMN
recruitment.15 16 To study the temporal profile of
cytokine production after acute ischemic
stroke, a prospective longitudinal study with repetitive blood sampling
1 to 31 days after stroke onset was performed in 29 patients with
ischemic stroke. Cytokine mRNA expression was further
correlated to neurological impairment, as measured by the Scandinavian
Stroke Scale (SSS), at the acute stage (days 1 to 3 after onset of
symptoms) and during follow-up (days 20 to 31).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients
Twenty-nine consecutive patients with ischemic stroke, hospitalized at the Stroke Center of the Department of Neurology, Huddinge University Hospital (Huddinge, Sweden), were included in the study (Table 1
). Twenty-five
patients had completed ischemic stroke, defined as clinical
symptoms persisting for >24 hours, and 4 patients had 
1 transient
ischemic attacks (TIAs), defined as a complete recovery from
clinical symptoms within 24 hours.17 The diagnosis was
based on clinical history and neurological examination. Two of the
patients with ischemic stroke had symptoms confined to the
vertebrobasilar territory, and the remaining 27 patients had symptoms
from the carotid arterial territory. Brain CT was routinely
performed in all stroke patients within 24 hours after their admission
to the hospital. CT scans were normal in the patients with TIA.
Well-defined hypodense areas, indicating ischemic lesions, were
detected in all but 3 of the patients with completed ischemic
stroke. Patients with clinical evidence of an acute infection, as well
as patients with a history of malignancy, autoimmune disease, or
myocardial infarction, were excluded from the study to avoid other
potential sources of cytokine upregulation. Routine blood
variables were assessed in all patients. None of the patients had
increased blood leukocyte counts. From each patient,
peripheral blood was obtained at 3 time points, ie, on days
1 to 3, 4 to 10, and 20 to 31 after onset of symptoms. From 19 of the
stroke patients plasma and cerebrospinal fluid (CSF) were obtained on
days 1 to 3, and plasma only was obtained on days 20 to 31 after
stroke onset.
|
Peripheral blood was also obtained from 18 healthy
volunteers, consisting of staff from the department (Table 1
).
CSF and plasma samples were obtained from 17 patients with tension
headache (Table 1).
The study protocol was approved by the Ethics Committee of Karolinska Institutet at Huddinge University Hospital.
Preparation of Blood Mononuclear Cells
PBMC were obtained by density gradient
centrifugation on Lymphoprep (Nycomed). The
cells from the interphase were collected, washed twice with Dulbecco's
modification of Eagle medium (Gibco), ultimately washed once with PBS
and counted. Cell viability as measured by trypan blue exclusion always
exceeded 95%. Aliquots containing 1x105 PBMC
were dried onto electrically charged microscope slides
(SuperFrost/Plus, Menzel-Gläser). Slides were kept at -20°C
until hybridization.
In Situ Hybridization to Detect IL-8, IL-1ß, IL-17, and MIP-1
mRNA in PBMC
In situ hybridization (ISH) was performed as previously
described.18 A mixture of 3 to 4 different synthetic
oligonucleotide probes was used for each
cytokine in order to increase the sensitivity of the method.
The probes for IL-1ß, IL-8, and MIP-1 (R&D Systems)
were 30 bases long, and the probes for IL-17 (KEBO) contained 48 bases.
A constant guanine/cytosine ratio of approximately 60% was
used. Following ISH, slides were rinsed in SSC, dehydrated through
gradient ethanol, dipped in Kodak NTB2 emulsion, and exposed at 4°C
for 14 days. The emulsion-coated slides were developed in D19 (Kodak)
and fixed in Unifix (Kodak). As negative control probe, the sense
sequence to bases 4641 to 4688 of human IFN- was used in parallel,
without revealing any positive cells. Previous studies from our
laboratory have revealed no binding to the sense probes of IL-8,
IL-1ß, IL-17, and MIP-1, and were therefore not used. Coded slides
were examined by dark field microscopy for positive cells containing
>15 grains per cell in a starlike distribution. The intracellular
distribution of the grains was always checked by light microscopy at
higher magnification. The number of cells used for ISH was not equal to
the number of cells ultimately detected on the slides. To compensate
for cell losses, the total numbers of cells on the slides were counted.
Cell losses varied between 10% and 50% from cell application to cell
counting. The preferential loss of certain cell types is not ruled out.
Positive cells practically always contained >15 (usually 50 to 100)
grains in a starlike distribution, whereas negative cells contained no
or few grains, which were then scattered randomly over the cell and not
distributed in a starlike fashion. Consequently, it was easy to
differentiate between cytokine mRNA positive and negative
cells.
ELISA for the Determination of IL-8 Levels in
Peripheral Blood and CSF
Peripheral blood was collected in tubes containing
EDTA and centrifuged within 30 minutes at 1500g for
10 minutes at 4°C. Plasma and CSF supernatants were immediately
frozen at -20°C. The IL-8 ELISA was performed according to the
manufacturer's instructions (Biosource International). The detection
limit was 0.39 pg/mL. Plasma and CSF samples were examined in
duplicate.
Statistical Analysis
Friedman nonparametric repeated-measures test was
used to compare cytokine mRNA expression in stroke patients at
different time points. The nonparametric Mann-Whitney test
adjusted for multiple comparisons according to Bonferroni was used to
compare cytokine mRNA expression in stroke and healthy
individuals. Wilcoxon signed rank test for pairs were used for
2-group comparisons of the IL-8 levels in plasma and CSF. Correlations
between IL-8 mRNA expressing PBMC and IL-8 plasma levels and between
cytokine mRNA expressing PBMC and SSS scores were examined by
Spearman rank correlation test. Reported probability value are 2
tailed, and P<0.05 was considered statistically
significant. After adjustment to Bonferroni, P<0.01
was considered significant in the Mann-Whitney analysis.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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IL-8 mRNA Expressing PBMC
Most patients with ischemic stroke had high numbers of IL-8 mRNA expressing PBMC regardless of the time interval between onset of clinical symptoms and examination. When examined during the acute phase, ie, 1 to 3 days after onset of symptoms, 26 of 29 patients (90%) with ischemic stroke had elevated numbers of IL-8 mRNA expressing PBMC when defined as >(mean+2SD) of the numbers encountered in the healthy volunteers (P<0.0001). The highest numbers of IL-8 mRNA expressing PBMC were observed 1 to 3 days after onset of symptoms, with a tendency for lower numbers already at days 4 to 10 (Table 2
; Figure 1). During clinical follow-up 20 to 31
days after onset, the numbers of IL-8 mRNA expressing PBMC were
significantly lower than in the acute phase (P<0.001) but
still remained elevated compared with those in the group of healthy
volunteers (P<0.0001).
|
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IL-8 Concentrations in CSF and Plasma
Soluble IL-8 was detected in CSF and plasma 1 to 3 days after
onset of symptoms in all 19 examined patients with acute
ischemic stroke (Table 3). The
IL-8 concentrations were increased in both CSF (P<0.0001)
and plasma (P<0.001) in patients examined 1 to 3 days after
onset of stroke compared with concentrations in patients with tension
headache. Concentrations of IL-8 were higher in CSF than plasma in the
group of patients with ischemic stroke (P<0.0001)
as well as tension headache (P<0.001; Figure 2). At follow-up 20 to 31 days after
onset of ischemic stroke, IL-8 concentrations in plasma were
lower (P
0.01) than during the acute stage at days 1 to
3.
|
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A positive correlation between numbers of IL-8 mRNA expressing PBMC and plasma concentrations of IL-8 was observed in 19 patients with ischemic stroke from whom both blood and plasma samples were available (r=0.7; P<0.00001).
IL-1ßb and IL-17 mRNA Expressing PBMC
The temporal profiles of levels of IL-1ß and IL-17 mRNA
expressing PBMC after stroke onset were similar to that observed for
IL-8 mRNA–positive PBMC (Table 2). Thus, the highest numbers of
PBMC expressing IL-1ß and IL-17 mRNA were found 1 to 3 days after
onset of symptoms, followed by decreasing numbers during follow-up
(Table 2; Figure 1).
Twenty-three of 29 patients (79%) with ischemic stroke had
elevated numbers of IL-1ß mRNA expressing PBMC when defined as
>(mean+2SD) of the numbers encountered in the healthy subjects at days
1 to 3 (P<0.0001). At follow-up 20 to 31 days after stroke
onset, the numbers of IL-1ß mRNA were lower compared with those at 1
to 3 days after onset (P<0.0001), and no differences in
numbers of IL-1ß mRNA expressing PBMC could be detected between
patients with ischemic stroke examined 20 to 31 days after
onset and the group of healthy volunteers (Table 2).
Seventeen of 29 patients (59%) with ischemic stroke had
elevated numbers of IL-17 mRNA expressing PBMC defined as >(mean+2SD)
of the numbers encountered in the healthy subjects at days 1 to 3
(P<0.0001). Similarly to IL-1ß mRNA expression, numbers
of IL-17 mRNA expressing PBMC were at follow-up 20 to 31 days after
stroke onset lower compared with 1 to 3 days after onset
(P<0.0001), and no differences in numbers of IL-17 mRNA
expressing PBMC could be detected between patients with
ischemic stroke examined 20 to 31 days after onset and the
group of healthy volunteers (Table 2).
MIP-1 mRNA Expressing PBMC
No differences in numbers of MIP-1 mRNA expressing PBMC were
observed between the patients with ischemic stroke and the
group of healthy volunteers at any time point (Table 2). There
was a tendency for increasing numbers of MIP-1 mRNA expressing PBMC
during follow-up after ischemic stroke, but the differences
were small and did not reach statistical significance (Table 2;
Figure 1).
Correlation Between Neurological Impairment and Numbers of
Cytokine mRNA Expressing PBMC
The degree of neurological impairment was estimated in all
patients with ischemic stroke according to the SSS at inclusion
and follow-up 20 to 31 days after onset of symptoms.19 The
SSS scores ranged between 8 and 58 (median 28) at inclusion and between
12 and 58 (median 53) 20 to 31 days after onset of symptoms.
Ischemic stroke patients with a high degree of neurological
impairment (ie, a low SSS score) had high numbers of PBMC expressing
IL-8, IL-1ß, and IL-17 mRNA at inclusion (Figure 3). There was an inverse correlation
between SSS scores registered 1 to 3 days after onset of symptoms and
numbers of IL-8 (r=-0.5; P<0.01), IL-1ß
(r=-0.5; P<0.01), and IL-17
(r=-0.5; P<0.01) mRNA expressing PBMC.
|
For IL-8 and IL-1ß, the inverse correlation between numbers of
cytokine mRNA expressing PBMC and SSS scores still remained
significant (IL-8: r=-0.5, P<0.01; IL-1ß:
r=-0.4, P<0.05) at follow-up 20 to 31 days
after onset. The numbers of MIP-1 mRNA expressing PBMC did not
correlate to the degree of neurological impairment as measured by the
SSS at any of the time points examined.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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PMN infiltrating postischemic tissue are considered to contribute to disability after cerebral ischemia.20 Identification of factors involved in the selective recruitment and accumulation of inflammatory cells into ischemic brain tissue is likely to expand our understanding of the mechanisms that result in transient or permanent neurological deficits. The mechanisms behind the entry of leukocytes to sites of ischemia are incompletely understood. Locally produced proinflammatory cytokines such as TNF-
, IL-1ß, and IL-6
are thought to initiate the inflammatory process. TNF- and IL-1ß
mRNA and protein are, for instance, elevated in the brain after
experimental middle cerebral artery occlusion.21 22
Astrocytes and endothelial cells can respond in vitro
to such proinflammatory cytokines with enhanced expression of
chemokines, which results in the influx of leukocytes to areas of
inflammation.23 Increased concentrations of the CXC chemokine IL-8 can be detected intrathecally in patients with ischemic stroke.7 Enhanced synthesis of IL-8 is, however, not restricted to the CNS. We have previously demonstrated elevated levels of IL-8 mRNA expressing PBMC in patients with acute ischemic stroke,9 an observation confirmed in the present study. This upregulation of IL-8 mRNA expression occurred early, ie, already within the first few days after onset of symptoms, and remained elevated during the observation time of up to 1 month. IL-8 is a potent chemoattractant that has been demonstrated to recruit PMN in vivo.12 14 Besides attracting PMN, IL-8 can also stimulate the release of neutrophil granules and the respiratory burst of these cells.24 25 26 Degranulation of PMN is accompanied by upregulation of complement receptors and integrins on their cell membranes, facilitating cell adhesion.27 A recent study demonstrated that IL-8 can also delay PMN apoptosis, indicating that IL-8 can further prolong and amplify the effects of PMN.28
In the present study, we found that the proinflammatory cytokines IL-1ß and IL-17 were also elevated systemically after ischemic stroke. IL-17 induces the secretion of cytokines, including IL-8, and enhances the expression of ICAM-1 in cultures of stromal cells and human fibroblasts.15 29 IL-1ß may be indirectly involved in the recruitment of inflammatory cells through the induction of increased IL-8 production.16 Interestingly, administration of a human IL-1 receptor antagonist has been shown to reduce postischemic injury in murine studies of cerebral ischemia, as reflected by reduced numbers of necrotic neurons, and of leukocytes in the ischemic brain and a decreased area of pallor.30 31
Concentrations of IL-8 were higher in CSF compared with plasma in the
patients with ischemic stroke, indicating that IL-8 is
predominantly produced within the CNS, probably at the site of the
damaged tissue. In response to focal ischemia, a multitude of
genes show an increased expression. Activated brain
endothelial cells at the site of inflammation,
representing the front line of the blood-brain barrier,
secrete cytokines such as TNF-, IL-1ß, IL-6, and IL-8, and
express adhesion molecules such as ICAM-1, ELAM-1, and
P-selectin.32 These stimuli might activate PBMC
and result in the expression of cytokines and chemokines, as
observed in this study. After CNS injury the blood-brain barrier
becomes leaky, which facilitates the entry of activated
circulating immune cells into the CNS.33 34 35 It is,
however, still not clear whether resident cells in the CNS,
activated PBMC, or both are the main producers of
cytokines. A strong systemic response, as measured by increased
numbers of PBMC expressing mRNA for IL-8 as well as IL-1ß and
IL-17, may indicate a possible role for systemic cells
contributing to intrathecal production of
cytokines.
Increased expression of cytokines in PBMC may not necessarily contribute to CNS injury but may instead represent secondary epiphenomena to tissue damage. Alternatively, an inflammatory process distal from the CNS occurring in relation to the ischemic event, eg, concomitant infections, may result in increased activation of the PBMC. In this study, however, patients with clinical or laboratory evidence of any infection were excluded. Also, psychological stress may result in increased activation of the PBMC. The mechanism of stress-related increases in cytokine production remains unclear. Hypothetically, autonomic involvement, catecholamines, and neuropeptides may either alone or in combination play a role in activating PBMC.36
It is not clear whether affecting the production of cytokines by circulating PBMC reduces tissue damage. In a rabbit model of cerebral reperfusion injury, systemic administration of monoclonal antibodies against IL-8 at the initiation of reperfusion prevented PMN infiltration and reduced the size of brain edema at 6 hours and infarction at 12 hours after reperfusion.37 Further studies in the MCAO model will define a functional role for systemic therapeutic intervention with anticytokine monoclonal antibodies, receptor antagonists, or cytokine inducers in the treatment of stroke.
In conclusion, increased numbers of cells expressing IL-8, IL-1ß, and IL-17 mRNA were observed systemically in ischemic stroke patients, with highest levels within 1 to 3 days after onset of symptoms. IL-8 mRNA expression remained elevated at follow-up after 20 to 31 days, when levels of IL-1ß and IL-17 had returned to levels registered in healthy individuals. Numbers of IL-8 and IL-1ß mRNA expressing PBMC correlated with the severity of the ischemic event, as measured by the SSS. Systemic upregulation of cytokine expression may contribute to the pathogenesis of ischemic stroke through a potentiation of the secondary inflammatory process.
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Acknowledgments |
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This study was supported by the Swedish Medical Research Council, the Swedish Medical Association, the Swedish Society for Medical Research, and funds from Karolinska Institutet.
Received November 24, 1998; revision received July 2, 1999; accepted July 2, 1999.
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