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Neuroimmunobiology and Host Defense Laboratory, and
Neurotrauma Research Laboratory, Minneapolis Medical Research Foundation, and
University of Minnesota Medical School, Minneapolis, MN 55404
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, which
also corresponded to elevated IL-8 mRNA levels by RT-PCR. Pretreatment
with IL-4, IL-10, or TGF-ß1 potently inhibited the stimulatory
effects of these proinflammatory agents. These findings indicate that
human microglia synthesize IL-8 in response to proinflammatory stimuli,
and that anti-inflammatory cytokines down-regulate the production
of this chemokine. These results may have important therapeutic
implications for certain central nervous system insults involving
inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bacteria induce the production of cytokines by many cell types
including leukocytes and endothelial cells (3) that form the vascular
component of the blood-brain barrier
(BBB).3 Additionally,
astrocytes, which are the predominant cell type on the brain side of
the BBB, and microglial cells (contributing up to 20% of the brain
cells of the BBB (4)) produce a wide variety of cytokines and
ß-chemokines (5, 6, 7) when activated. Cytokines appear to either play a
protective role or initiate an irreversible over-reaction of the immune
system ultimately leading to cell death (8). Both IL-1ß and TNF-
are produced during meningeal inflammation (9, 10, 11, 12, 13) and have been
implicated in cellular damage (14, 15, 16, 17, 18). Furthermore, they have been
found to initiate an inflammatory cascade (19) that includes the
release of IL-8 (20, 21).
IL-8, a member of the C-X-C () chemokine family, has been detected
in the cerebrospinal fluid (CSF) of patients with bacterial meningitis
(22, 23, 24, 25, 26, 27). Although the role of IL-8 and the specific cells that produce
it during meningeal inflammation are unknown, studies have shown that
IL-8 is a potent chemoattractant and activator of neutrophils (21, 28).
This activation may be exhibited by increased respiratory burst
activity, the production of bioactive lipids, and the release of
lysosomal enzymes, potentially contributing to tissue injury (29, 30).
IL-8 also regulates neutrophil adhesion to endothelial cells (31),
possibly mediating the large influx of these cells into the
subarachnoid space that is seen in patients with bacterial meningitis
(2). The release of IL-8 by cells comprising the BBB (specifically,
astrocytes and microglia) may be a key component in this influx.
Aloisi et al. reported that human astrocytes synthesize IL-8 in
response to IL-1ß and TNF- (32), but the production of IL-8 by
primary human microglia, which migrate to and proliferate at sites of
inflammation (33), has not been shown previously. Therefore, we
examined IL-8 production by microglia obtained from fetal and adult
human brain tissue in response to LPS, IL-1ß, and TNF-. We also
investigated the regulatory effects of anti-inflammatory cytokines
(IL-4, IL-10, and TGF-ß) on IL-8 production by microglial cells,
since the regulation of IL-8 seems critical to the control of the
inflammatory response in conditions such as meningitis. Finally, we
tested whether LPS or proinflammatory cytokines could induce astrocytes
to produce IL-8.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TNF-, IL-1ß, IL-4, IL-8, IL-10, TGF-ß1, and anti-IL-8
Abs were kindly provided by R&D Systems, Inc. (Minneapolis, MN).
Anti-goat horseradish peroxidase conjugate was obtained from Jackson
ImmunoResearch (West Grove, PA). LPS and Tween-20 were acquired from
Sigma Chemical Co. (St. Louis, MO).
Brain cell cultures
Human fetal brain tissues were obtained from 16- to 22-wk-old aborted fetuses under a protocol approved by the Human Subjects Research Committee at our institution. These cultures were prepared using a previously described technique (34). Briefly, brain tissues were dissociated after a 45-min trypsinization (0.125%) and were seeded into 75-cm2 Falcon culture flasks (Fisher Scientific, Pittsburgh, PA) in DMEM (Sigma) containing 10% heat-inactivated serum (Hyclone Laboratories, Logan, UT) and penicillin/streptomycin (Sigma). On day 10 to 12 of culture, harvested cells (microglia) were seeded into 96-well plates.
Adult brain specimen tissues (
0.01 g) were obtained from patients
(with informed consent) undergoing elective or emergency neurosurgical
procedures at Hennepin County Medical Center (Minneapolis, MN) and
prepared following a slightly modified protocol from that used for
processing fetal microglia. Following trypsinization, cells were
resuspended in 35.6 ml PBS, layered over a gradient containing 9.6 ml
of 100% Percoll (Sigma) and 4.8 ml of 1.25 M sucrose (Sigma), and
centrifuged at 14,000 rpm for 45 min. Collected cells were washed and
plated into 75-cm2 flasks. On day 14 of culture, microglia
(5 x 103 cells/well) were seeded into 96-well plates.
Purified fetal or adult microglia were composed of cell populations,
>99% of which stained with CD68 Abs (Dako, Carpenteria, CA), a
microglial cell marker, and <1% of which stained with Abs to glial
fibrillary acid protein (Dako), an astrocyte marker.
Fetal astrocytes were prepared as previously described (35). More than 99% of the cells were positive for glial fibrillary acid protein. Astrocytes were seeded into 96-well plates at a density of 5 x 103 cells/well.
Monocyte-derived macrophage (MDM) cultures
Whole blood was drawn from healthy laboratory donors and diluted with sterile PBS. This mixture was added to a Ficoll-Hypaque gradient (Lymphocyte Separation Medium, Organon Teknika Corp., Durham, NC) and centrifuged at 1400 rpm for 30 min. PBMC were collected from the gradient and washed three times in PBS. The cells were then resuspended in RPMI 1640 (Sigma) with antibiotics, and monocytes were allowed to adhere to the bottom of a 24-well plate for 2 to 3 h. Nonadherent cells were washed off vigorously several times, and RPMI 1640 containing 10% FBS and antibiotics was re-added. Monocytes were allowed to differentiate into MDMs for 5 days in a 5%-CO2 environment at 37°C.
Experimental protocol
In all experiments testing IL-8 protein production, cells were
washed once and treated the day after plating. Controls, which were
cells incubated in medium alone, were included in all experiments.
Supernatants were collected at 16 to 18 h and frozen at -20°C
to be tested later by ELISA. To evaluate the effects of LPS, IL-1ß,
and TNF- on IL-8 production by microglia, cells (5 x
103 per well) were treated with LPS, IL-1ß, or
TNF- at the indicated doses. Cytokine specificity was determined by
pretreating microglial cells (5 x 103 per well) with
10 µg/ml rabbit anti-human IL-1ß Ab (Genzyme, Cambridge, MA) or
anti-human TNF- Ab (R&D Systems) for 45 min followed by 16
h of stimulation with either IL-1ß (10 ng/ml) or TNF- (20 ng/ml),
respectively, and then measuring a decrease in IL-8 production in the
Ab-treated wells compared with the stimulated wells alone. The effects
of anti-inflammatory cytokines were tested by pretreating cells
with IL-4, IL-10, or TGF-ß1 for 6 h. Then LPS, IL-1ß, or
TNF- were added alone or in combination with IL-4, IL-10, or
TGF-ß1, and the cells were allowed to incubate overnight. Adult
microglia, MDM, and astrocytes (all at 5 x 103
cells/well) were treated with LPS, IL-1ß, or TNF- and compared
with fetal microglial cells treated in an identical manner.
RT-PCR
Total RNA was extracted from microglia using guanidinium isothiocyanate as previously described (36). Reverse transcription of 1.5 µg of RNA was performed with 50 µM oligo(dT)12–18 followed by the addition of a reaction mixture containing 5x first strand buffer (250 mM Tris-HCl (pH 8.3), 375 mM KCl, 15 mM MgCl2), 0.1 MDTT), SuperScript II RNase H- Reverse Transcriptase (Life Technologies, Gaithersburg, MD), and 10 mM deoxynucleoside triphosphates mix (10 mM each of dATP, dGTP, dCTP, and dHP (Pharmacia Biotech, Piscataway, NJ) in a final volume of 20 µl. The mixture was incubated at 42°C for 1 h followed by termination at 95°C for 5 min. Amplification of IL-8 or glyceraldehyde-3-phosphate dehydrogenase (GADPH) cDNA (as a control) was performed with an automatic thermocycler (Stratagene, La Jolla, CA) in a reaction mixture containing 10x PCR buffer (500 mM KCl, 100 mM Tris-HCl (pH 9.0 at 25°C), and 1% Triton X-100), 25 mM MgCl2, 10 mM deoxynucleoside triphosphates mixture, 5 U of Taq DNA polymerase (Promega, Madison, WI) per µl with 0.22 µg/µl TaqStart Ab (Clontech, Palo Alto, CA), 25 µM primer (sense and antisense), cDNA, and H2O. Amplification was set at 94°C for 45 s, 65°C for 45 s, and 72°C for 90 s followed by a 10-min extension at 72°C.
The IL-8 PCR product (289 bp) was amplified for 17 to 19 cycles and the GADPH (600 bp) for 22 cycles. Both PCR products were viewed under UV light after 2% agarose gel electrophoresis and staining in ethidium bromide. The IL-8 primer sets (Clontech) were 5'-ATG ACT TCC AAG CTG GCC GTG GCT-3' (sense) and 5'-TCT CAG CCC TCT TCA AAA ACT TCT C-3' (antisense). The GADPH primer sets (Stratagene) were 5'-ACC ACA GTC CAT GCC ATC AC-3' (sense) and 5'-TCC ACC ACC CTG TTG CTG TA-3' (antisense).
ELISA
IL-8 protein was detected by an ELISA developed in our laboratory. Briefly, 96-well culture plates were coated with 0.1 µg/ml mouse anti-human IL-8 mAb and stored overnight at 4°C. The following day, the plates were washed with 0.05% PBS/Tween-20 and nonspecific binding was blocked by treatment with 1% BSA for 1 h at 37°C. After washing, a standard series of diluted human rIL-8 was added to each plate along with supernatant samples and incubated for 2 h at 37°C. Next, goat anti-human IL-8 Ab (2 µg/ml) was added for 1.5 h at 37°C followed by anti-goat IgG horseradish peroxidase conjugate (1:20,000 in PBS) for 1 h. After extensive washing with PBS/Tween-20, K-Blue Substrate (Neogen Corporation, Lexington, KY) was added for 10 to 20 min at room temperature for color development, and then the development was stopped by the addition of 100 µl of 1 M H2SO4. OD was read at 450 nm and compared with standard values for quantification. The sensitivity of this assay is 10 pg/ml, and is specific for IL-8.
Statistical analysis
When appropriate, data were analyzed for comparison of multiple means using ANOVA followed by Scheffe’s F test. Statistical significance was determined at the level of 95% confidence.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After treatment with varying doses of LPS, IL-1ß, and TNF-,
fetal microglial cell culture supernatants were tested by ELISA
for IL-8 protein (Fig. 1
). LPS and
IL-1ß stimulated IL-8 in a dose-dependent manner
(ED50 = 20 pg and 2 ng, respectively) with a maximal
production of 180 ± 20 ng/ml and 161 ± 15 ng/ml,
respectively. TNF- also increased IL-8 production over the control
level (40 ± 1 ng/ml compared with 7 ± 1 ng/ml;
ED50 = 200 pg/ml) but the maximal stimulation of IL-8 by
TNF- was less than that observed with LPS and IL-1ß (Fig. 1). All
data points in Figure 1 were greater than control values
(p < 0.05) with the exception of the 0.01 and
0.1 ng/ml IL-1ß-stimulated and 0.01 ng/ml LPS-stimulated treatments.
IL-8 release induced by IL-1ß and TNF- was cytokine specific, as
mAbs against each cytokine inhibited IL-8 production by 75 ± 6%
and 92 ± 9%, respectively (data from two separate experiments).
These proinflammatory stimuli also increased IL-8 mRNA levels in human
fetal microglia (Fig. 2). A low level of
constitutive expression of IL-8 mRNA was seen in the control cells, but
only at higher amplification.
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) was
inhibited by IL-4, IL-10, and TGF-ß1 at levels of 59% to 86%
inhibition at maximal doses (Fig. 3,
A–C). These anti-inflammatory cytokines were
most effective in decreasing IL-1ß- and TNF--stimulated IL-8
production. IL-4, IL-10, or TGF-ß1 alone had a minimal effect on
constitutive expression relative to the amount of control production of
IL-8. All the data in Figure 3, A–C, were different
(p < 0.05) than the values obtained with the
stimulus alone (i.e., LPS, IL-1ß, or TNF-) with the exception of
the IL-4 (0.3 ng/ml)/TNF--stimulated and the IL-10 (0.1
ng/ml)/IL-1ß-stimulated points. When using RT-PCR at the
transcriptional level, microglial cells treated with LPS, IL-1ß, and
TNF- exhibited smaller bands when pretreated with IL-4 or IL-10
overnight (Fig. 4). TGF-ß1 appeared to
have no effect on LPS- and IL-1ß-induced IL-8 mRNA expression, but
potentially decreased IL-8 mRNA expression in the TNF--treated
cells. These observed decreases may have been due to differing
transcription rates and/or altered mRNA message stability, neither of
which were analyzed in the present study.
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). Compared with control
values at 16 h, LPS and IL-1ß increased IL-8 production
(p 
0.05), but the TNF--stimulated
increase was not significant. In sharp contrast to the mononuclear
phagocytes, astrocytes produced no IL-8 in response to LPS. However,
IL-1ß was a potent stimulus of IL-8 production by astrocytes (80
± 15 ng/ml), and TNF- elicited relatively low amounts of IL-8
(5 ± 1 ng/ml) (Table I).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, two cytokines that play a key role in the
initiation of an inflammatory response. This production appears to be
dose dependent in fetal microglia and is inhibited by the
anti-inflammatory cytokines IL-4, IL-10, and TGF-ß.
The role of chemokines such as IL-8 in CNS diseases is not understood
completely. Chemokines attract specific cell types (such as T
lymphocytes and monocytes) to the CNS, but how they help these cells
cross the BBB has not been fully delineated. However, chemokines
(including IL-8, macrophage inflammatory protein (MIP)-1ß, MIP-1,
monocyte chemoattractant protein (MCP)-1, RANTES, and IFN-inducible
protein-10) up-regulate cell adhesion molecules, potentially aiding
leukocyte trafficking across the BBB (37). Chemokines are regulated by
various cytokines, and a complete understanding of these interacting
pathways could give important insights into disease progression
(38).
IL-8 synthesis by human microglia adds further support to the
hypothesis that IL-8 is involved in the pathogenesis of acute bacterial
meningitis and other CNS diseases including Alzheimer’s disease (39, 40). The production of IL-8 during inflammation is fairly well
established (41, 42). Interestingly, the release of IL-8 and other
proinflammatory cytokines occurs before neutrophil influx during
meningitis (3, 12), suggesting that initial contact with LPS or other
bacterial products induces cells such as microglia and endothelial
cells to synthesize IL-8. Our results also show that LPS does not
stimulate astrocytes to make IL-8; however, IL-1ß is a potent
stimulus for astrocyte IL-8 production. Since LPS has been shown to
cause microglial cells to release IL-1ß (17), the potential exists
for astrocytes to synthesize IL-8 in response to this microglial source
of IL-1ß. Human microglia stimulated with LPS, IL-1ß, and TNF-
produce MIP-1, MIP-1ß, and MCP-1 (7), which also may contribute to
CNS pathogenesis.
IL-8 has been shown to induce neutrophil recruitment to the brain
parenchyma in vivo (43, 44). Once neutrophils have crossed the BBB,
IL-8 induces degranulation of neutrophils that are releasing
chemoattractants for T lymphocytes (45) and primes neutrophils for
superoxide production (46) along with other potentially neurotoxic
molecules. Thus, while the influx of neutrophils has been shown to
reduce the numbers of bacteria in experimental models of bacterial
meningitis, an excess of activated neutrophils may have a detrimental
effect. Regulation of IL-8 chemotactic and activating activity may be
beneficial in reducing the potentially negative effects of neutrophil
influx. However, other chemokines, including MIP-2 and IFN-inducible
protein-10, also induce neutrophil recruitment to the CNS (43)
complicating the milieu of factors to be regulated. Monocytic
chemoattraction into the CNS by chemokines such as MCP-1, MIP-1,
MIP-1ß, and RANTES may also contribute to cellular damage (38, 43),
and most of these chemokines have been found at elevated levels in the
CSF of patients with bacterial meningitis (47).
Additionally, these results show that while LPS, IL-1ß, and TNF-
up-regulate the production of IL-8 by microglial cells at a
transcriptional level, the anti-inflammatory cytokines IL-4 and
IL-10 may inhibit IL-8 synthesis at that same level. TGF-ß1 also
decreased IL-8 production by microglial cells in response to these
proinflammatory mediators but appeared not to function at the level of
transcription. These findings correspond with previous research
performed on endothelial cells (22, 48), neutrophils (49), and in vivo
models (50); however, our results could be due to altered message
stability or differing rates of transcription. Additionally, IL-10 and
TGF-ß1 have been found in the CSF of patients with bacterial
meningitis (51, 52, 53), suggesting these cytokines could modulate IL-8
production in vivo.
In conclusion, the interactions between microglia, IL-8, and
neutrophils appear important in understanding the pathogenesis of acute
bacterial meningitis and other CNS insults involving inflammation
including brain trauma (54, 55). Further studies to delineate the
mechanisms through which LPS, IL-1ß, and TNF- induce IL-8 and the
production of other chemokines and to determine whether microglia and
astrocytes produce IL-8 in vivo (leading to a migration of neutrophils
across the BBB or to further activation of neutrophils once they cross
the BBB) would contribute to greater knowledge and potential therapies
for brain insults involving inflammation.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Chun C. Chao, Minneapolis Medical Research Foundation, 914 South 8th St., D-3, Minneapolis, MN 55404. E-mail address:
3 Abbreviations used in this paper: BBB, blood-brain barrier; CNS, central nervous system; MDM, monocyte-derived macrophage; CSF, cerebrospinal fluid; GADPH, glyceraldehyde-3-phosphate dehydrogenase; MIP, macrophage inflammatory protein; MCP-1, monocyte chemoattractant protein-1.
Received for publication June 26, 1997. Accepted for publication October 31, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, interleukin 1, and interleukin 6 in meningococcal meningitis: relation to the inflammatory response. J. Exp. Med. 170:1859. (TNF) in cerebrospinal fluid from patients with meningitis of different etiologies: high levels of TNF indicate bacterial meningitis. J. Infect. Dis. 167:882.[Medline]
synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav. Immun. 9:355.[Medline]
. J. Immunol. 149:2358.[Abstract]
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