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and MIP-1ß in Human Fetal Microglia1
Departments of
*
Pathology, and
Microbiology, Immunology, and
Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, MIP-1ß, MCP-1, and RANTES in
human fetal microglial cultures. Unstimulated microglia expressed
minimal levels of MIP-1, MIP-1ß, and MCP-1, while RANTES was
undetectable. In response to LPS, TNF-, or IL-1ß, both MIP-1
and MIP-1ß were induced at the mRNA and protein levels in a dose- and
time-dependent manner. IFN-
did not significantly induce chemokine
expression. MCP-1 was detectable in LPS- and cytokine-treated
microglia. TGF-ß, a cytokine with down-modulatory effects on other
cell types, had little effect on chemokine expression in microglia when
used concomitantly before or during treatment with LPS. These results
illustrate the ability of certain inflammatory stimuli to induce
expression of MIP-1, MIP-1ß, and MCP-1 by human fetal microglia.
The expression of these chemoattractants may function to recruit
inflammatory cells into the CNS during the course of neuroimmunologic
diseases and may modulate the ability of HIV to infect the CNS. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemokines are low m.w. chemotactic cytokines that have been shown to
recruit leukocytes. MIP-1, MIP-1ß, MCP-1, and RANTES are
all members of the C-C chemokine family, named for the distinct
cysteine-cysteine motif found near the N termini of all members. These
chemokines are characterized by their ability to attract monocytes and
T cells and may be necessary for the recruitment of inflammatory cells
to sites of injury (11). During the course of neuroimmunologic
diseases, cells endogenous to the CNS must produce chemotactic factors
that can recruit mononuclear cells across the blood-brain barrier to
sites of injury. There is evidence both in vitro and in vivo for the
production of chemokines in the CNS (12, 13). Hayashi et al. (12)
showed that murine microglia secrete MIP-1 after stimulation with
LPS, and MIP-1 has been shown by Miyagishi et al. (13) to be present
in the cerebrospinal fluid of MS patients. Karpus et al. (14)
demonstrated that blocking Ab to MIP-1 prevented development of both
acute and relapsing experimental autoimmune encephalomyelitis (EAE)
while also preventing the infiltration of mononuclear cells. Also,
MCP-1 has been shown to increase in the CNS of mice with EAE, an animal
model of MS (15, 16, 17, 18). Despite these reports on chemokine expression in
the CNS of rodent models of inflammation, little is known about
chemokine expression in the human CNS.
Schmidtmayerova et al. (19) showed that MIP-1 and MIP-1ß mRNA are
up-regulated in the brain tissue of patients with AIDS dementia. In
addition, MIP-1, MIP-1ß, and RANTES have recently been shown to be
suppressive factors for HIV, and their receptors are cofactors for HIV
entry into cells (20, 21, 22). The role of these chemokines in HIV
infection of cells of the CNS provides potential new therapeutic
targets for the treatment and prevention of HIV infection in the CNS
and in AIDS-related dementia.
The cellular sources and regulation of chemokines have not been
definitively shown in cells of the human CNS. In this study, we
analyzed the kinetics of expression of the C-C chemokines MIP-1,
MIP-1ß, RANTES, and MCP-1 in human fetal microglia. The
proinflammatory cytokines IL-1ß, TNF-, and IFN-, in addition to
LPS, were used to activate microglia, and analyses were performed for
RNA and protein expression of the various chemokines.
TGF-ß is a pleiotropic cytokine that has been shown to be protective
in EAE and to regulate expression of some cytokines, as well as nitric
oxide, in murine microglia (23, 24). Previous data by Maltman et al.
(25) showed that TGF-ß is a potent down-regulator of MIP-1 and
MIP-1ß mRNA and protein in murine bone marrow macrophages. Thus, we
also analyzed the effects of TGF-ß on the expression of MIP-1 and
MIP-1ß.
Here, we present the first comprehensive study of the expression of
chemokines in human microglia. Our data show that human primary fetal
microglia can differentially express MIP-1, MIP-1ß, and MCP-1
under inflammatory conditions, and that the LPS-induced expression of
MIP-1 and MIP-1ß is not significantly down-modulated by TGF-ß.
These findings differ from what is seen in monocytes and macrophages
from other human tissues, as well as in murine cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human fetal CNS tissue (20–23 wk) was obtained at the time of
elective termination of intrauterine pregnancy from otherwise normal
healthy females. Informed consent was obtained from all participants.
This tissue was used as part of an ongoing research protocol that has
been approved by the Albert Einstein College of Medicine Committee on
Clinical Investigation and the City of New York Health and Hospitals
Corporation. The tissue was prepared similarly to that previously
described by Lee et al. (26). Briefly, tissue was dissociated and
incubated for 45 min at 37°C in 1x HBSS (Life Technologies, Grand
Island, NY), 1x trypsin (Life Technologies), and DNase I (Boehringer
Mannheim, Indianapolis, IN). Tissue fragments were then passed through
250- and 150-µM nylon mesh (Tetko, Inc., Briarcliff Manor, NY). Cells
were washed, resuspended in complete DMEM (25 mM HEPES, 10% FCS, 1%
nonessential amino acids, and 1% penicillin-streptomycin), and
rewashed. Cells were seeded at 1.2 x 108 per
150-cm2 tissue culture flask (Falcon, Becton Dickinson,
Franklin Lakes, NJ) and cultured for 12 days. Microglial cells were
then removed from the mixed culture by shaking 30 min at 4°C and
plated in complete DMEM at a concentration of 1 x 106
cells per 100 x 20-mm tissue culture plate (Falcon). Cells were
analyzed for the purity of the culture and shown to be 
95% HAM56 (a
microglial marker) positive. Cells were treated with between 1 ng/ml
and 1 µg/ml of LPS (serotype 0111:B4) from Sigma Chemical Co. (St.
Louis, MO), 10 U/ml of human rIL-1ß (a gift from the National Cancer
Institute, Biological Resources Branch, Frederick, MD), IL-4 (10
ng/ml), IL-10 (10 ng/ml), IFN- (200 U/ml), and MCP-1 (10 ng/ml)
(Genzyme Co., Cambridge, MA). Cells were also treated with 10 ng/ml of
TGF-ß and 100 U/ml of TNF- (R&D Systems, Minneapolis,
MN).
Immunofluorescence
Adherent cells were washed twice with PBS, fixed with ice-cold methanol, and blocked in 1% BSA for 1 h. The primary Ab, either HAM56 (specific for fixed macrophages and used at a dilution of 1:50, Enzo Diagnostics, Farmingdale, NY), glial fibrillary acidic protein (GFAP) (an astrocyte-specific marker used at a dilution of 1:50, Boehringer Mannheim), or mouse myeloma IgG1 or IgM (used at a dilution of 1:100, Cappel Research Products, Durham, NC) was incubated overnight at 4°C. Cells were then washed and incubated with fluorescently labeled isotype-specific secondary Abs for 1 h. The cells were photographed at x10 magnification using an inverted Olympus IMT-2 microscope with an Olympus 35-mm camera (Olympus Corporation, Lake Success, NY). The pictures were taken with Kodak Elite II 35-mm color film for slides and then developed. After developing, the slides were captured and processed with Adobe Photoshop (Adobe Systems Inc., Mountain View, CA).
RNA extraction and Northern blot analysis
Total RNA was extracted from microglial cultures using
Tri-Reagent (Molecular Research Center, Cincinnati, OH). RNA was
electrophoresed through a 1% agarose gel and transferred to Hybond
nylon membrane (Amersham, Cleveland, OH). Membranes were then
prehybridized for 1 h at 65°C and hybridized overnight at 65°C
with [-32P]-labeled cDNA inserts as probes
(Random Primer Labeling Kit, Amersham). Prehybridization and
hybridization were performed in a buffer consisting of 25% 20x SSPE,
10% 50x Denhardt’s solution, 2.5% and 20% SDS, and salmon sperm
DNA. Hybridization was conducted using the following cDNA inserts as
probes: MIP-1, MIP-1ß (courtesy of Dr. Barbara Sherry, Picower
Institute for Medical Research, Manhasset, NY) (27, 28), MCP-1
(courtesy of Dr. Detlef Schlondorff, Albert Einstein College of
Medicine, Bronx, NY) (29), and 18S (30). The MIP-1 and MIP-1ß
probes have been shown to be specific for the individual chemokine.
After hybridization, blots were washed twice at room temperature with
wash buffer (2x SSC, 0.1% SDS, 0.005% NaP inorganic phosphate), once
at 55°C in buffer at a 1:2 dilution, and once at 65°C in wash
buffer at a 1:2 dilution. Blots were then exposed to x-ray film
(Fisher, Springfield, NJ) at -70°C. Densitometry was performed on
multiple film exposures using a computing densitometer
(Molecular Dynamics, Sunnyvale, CA).
Chemokine ELISA
Supernatants from microglial cell cultures were analyzed for
chemokine proteins. ELISA kits for MIP-1, MIP-1ß, MCP-1, and
RANTES were purchased from R&D Systems and used according to the
manufacturer’s instructions.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human CNS tissue was cultured and microglia were obtained from a
mixed culture of CNS cells. Figure 1
shows the morphology and purity of the microglial cell cultures that
were used throughout this study. More than 95% of the cells were
positive for HAM56, a microglial marker, as determined by
immunofluorescence. Occasionally, some astrocytes were detected by GFAP
reactivity, but those detected represented <5% of the cells.
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and MIP-1ß in human fetal microglia
Highly purified human fetal microglial cultures were analyzed for
their ability to express chemokines under different treatment
conditions. LPS, a potent activator of cells of the monocyte/macrophage
cell lineage, was used to activate microglia, and these cultures were
then analyzed for mRNA and protein expression of MIP-1 or MIP-1ß.
Northern blot analysis of cultures stimulated with increasing doses of
LPS showed potent induction of both MIP-1 and MIP-1ß mRNA (Fig. 2A). There is a similar
induction of these chemokines at all doses after 8 h of treatment.
Cell supernatants were analyzed by ELISA for protein expression of both
MIP-1 and MIP-1ß (Fig. 2B). Both chemokines were
strongly induced at all doses of LPS tested.
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A
illustrating a time-dependent response for MIP-1 and MIP-1ß
expression. The densitometric analysis of these data showed that
MIP-1 and MIP-1ß mRNA were induced after 8 h of treatment
with LPS, increased after 12 h, declined over the next 24 h,
and returned to almost untreated levels by 48 h after treatment
(Fig. 3B). Figure 3C shows pooled protein
data from ELISA analyses of cell culture supernatants. The protein
expression induced by LPS continued to increase over all time points
examined, with similar induction of MIP-1 and MIP-1ß.
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or MIP-1ß induction by LPS
TGF-ß, a cytokine with anti-inflammatory properties, can
significantly down-modulate MIP-1 and MIP-1ß expression in murine
bone marrow macrophages (25). In addition, Suzumura et al. have shown
that TGF-ß suppresses cytokine-induced activation of murine microglia
(31). We have previously shown that TGF-ß down-modulates LPS-induced
IL-1 expression in human fetal microglia (data not shown). However, we
have also found that in human fetal microglia, TGF-ß was unable to
modulate chemokine expression. Figure 4
shows a representative experiment of TGF-ß pretreatment before 8
h of treatment with LPS. As can be seen in Figure 4A, mRNA
expression was increased after LPS treatment alone; pretreatment with
TGF-ß did not alter this expression. The protein data follow what is
seen with mRNA expression in that there was no significant modulation
by TGF-ß. Cotreatment of microglia with TGF-ß and LPS for 20 h
had no significant effect on mRNA or protein expression of MIP-1 or
MIP-1ß as compared with treatment with LPS alone (data not shown).
Pretreatment of microglia with TGF-ß for 16 h before 4 h of
treatment with LPS (data not shown) also had no significant effect on
mRNA or protein expression of MIP-1 or MIP-1ß.
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and MIP-1ß expression
in human fetal microglia
The proinflammatory cytokines TNF-, IL-1ß, and IFN- were
tested for their ability to induce MIP-1 or MIP-1ß at the mRNA and
protein levels. These cytokines are all made by cells endogenous to the
CNS (5, 6, 3, 2) and have been shown to play a role in CNS
inflammatory diseases (9, 33). TNF- induced MIP-1 mRNA as shown
in Figure 5A. TNF-
induction was similar to that of LPS in that it followed the same
kinetics. Induction was observed at 8 h, increased at 12 h,
and then decreased to basal level by 48 h. Protein expression
shows that TNF- potently induced both MIP-1 and MIP-1ß to
similar levels. The amount of protein expressed continued to increase
up to the last time point analyzed, which was 48 h.
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and MIP-1ß expression as shown by the
graph of protein in Figure 6A.
Over time, MIP- was not induced as potently by IL-1ß as compared
with MIP-1ß. MIP-1ß protein increased over time up to 48 h,
and MIP-1 increased only until 24 h and then remained at a
similar level up to 48 h. Figure 6B shows that IFN-
could not induce either MIP-1 or MIP-1ß protein at any time points
analyzed. It is important to note that astrocytes, a possible
contaminating cell type in our cultures, do not produce either MIP-1
or MIP-1ß in response to these factors (data not shown).
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or MIP-1ß. We found that IL-4 and IL-10, as
well as MCP-1, could not significantly induce expression of either
chemokine at the mRNA or protein level (data not shown).
Comparison of the kinetics of MIP-1 and MIP-1ß protein
expression induced by LPS and cytokine treatment of human fetal
microglia
MIP-1 and MIP-1ß were significantly induced by LPS over a
time course of 48 h. Comparison of their expression from pooled
data of several experiments (n 4) shows that
MIP-1 and MIP-1ß had similar kinetics as well as levels of
induction following treatment with LPS (Fig. 3
C).
Figure 7 shows a comparison of cytokine
treatments for pooled protein data from several experiments
(n 4). TNF- was an effective inducer of
MIP-1, and this induction was similar to that of LPS. IL-1ß was a
weaker inducer of MIP-1, and IFN- did not induce this chemokine
at any time. MIP-1ß expression differed from MIP-1 in that TNF-
and IL-1ß were similar inducers of MIP-1ß over time, whereas
IL-1ß was only a weak inducer for MIP-1. Similar to MIP-1,
IFN- did not induce MIP-1ß. Although IL-1ß and TNF- are
inducers of MIP-1 and MIP-1ß, their potencies of induction were
not as strong as LPS. These results reflect the differential expression
of these chemokines in response to various inflammatory factors.
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MCP-1 is another member of the C-C chemokine family that is known
to correlate with the course of disease in EAE (15). Human fetal
microglia, as shown in Figure 8,
expressed significant levels of MCP-1 mRNA after treatment with LPS.
This expression continued to increase over time to up 48 h, the
last time point assayed. These kinetics differ from what was seen with
MIP-1 and MIP-1ß, both of which had an earlier peak of mRNA
expression at 12 to 24 h. MCP-1 protein was also detected in the
cell supernatants of these cultures after LPS and cytokine treatment
(data not shown).
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Untreated cells, as well as LPS-, TNF--, IL-1ß-, or
IFN--treated cells, were analyzed for RANTES mRNA or protein
expression. RANTES was undetectable under all conditions by both
Northern blot analysis and ELISA analysis (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and MIP-1ß in response to LPS, TNF-, and
IL-1ß and did not respond to IFN-. LPS treatment also elicited
MCP-1 expression. These responses were dose and time dependent. TGF-ß
did not significantly modulate LPS-induced expression of MIP-1 or
MIP-1ß. We also showed that human fetal microglia were not induced to
express these chemokines after treatment with IL-4, IL-10, or MCP-1.
The expression of these chemokines from cells endogenous to the CNS,
particularly the human CNS, has not been extensively studied. This is
the first report of MIP-1 and MIP-1ß mRNA and protein expression
as well as MCP-1 expression from human primary microglial cells.
Chemokines, or chemotactic cytokines, are characterized by their
ability to induce migration of leukocytes. The C-C chemokine family,
MIP-1, MIP-1ß, MCP-1, RANTES, etc., is characterized by its
ability to recruit monocytes and T cells (11). A hallmark of CNS
inflammation is the infiltration of monocytes/macrophages and T cells
across the blood-brain barrier to sites of injury. This is seen in MS
and EAE as well as in AIDS encephalitis (9, 34). Thus, the release of
chemokines by cells endogenous to the CNS could play a role in
recruiting inflammatory cells into the CNS and therefore could be
crucial to the pathogenesis of CNS inflammatory disease. Several groups
have shown that chemokines are expressed in the CNS of animal models of
inflammation (14, 15, 16, 17, 18). We have shown previously that MCP-1 may be an
important mediator of CNS inflammation, using a rat model of EAE. MCP-1
was detected at the onset of inflammation and its levels increased and
decreased according to the course of disease activity (15). Godiska et
al. and others demonstrated that many chemokines including MIP-1,
MIP-1ß, JE (MCP-1), and RANTES were induced during the course of EAE
in mice (15, 16, 17, 18). Karpus et al. (14) illustrated a distinct role for
one chemokine, MIP-1, in murine EAE. This group showed that Abs to
MIP-1 blocked the development of EAE as well as leukocyte
infiltration into the CNS. All of these findings point to an important
role for chemokines in CNS inflammation.
We found that the Th1-associated cytokines TNF- and IL-1ß induced
expression of MIP-1 and MIP-1ß from human fetal microglia. In
contrast, we found that Th2-associated cytokines did not induce this
expression. These data are consistent with recent findings by Schrum et
al. (35) implicating MIP-1 and MIP-1ß in type 1 cytokine-mediated
inflammation. EAE, a Th1-mediated disease, can be abrogated by blocking
Abs to MIP-1 (14), a Th1-associated chemokine, but not MCP-1 (14), a
Th2-associated factor (36). Thus, current data on chemokines may be
better understood when analyzed in the context of Th1 and Th2
responses.
The recent findings indicating that MIP-1, MIP-1ß, and
RANTES act as suppressive factors for HIV and that their
receptors play a role as cofactors for HIV entry into host cells also
propose new roles for these chemokines and raise interesting questions,
especially in the context of HIV infection of the CNS (20, 21, 22).
Schmidtmayerova et al. (19) showed that HIV-1-infected monocytes
produced MIP-1 and MIP-1ß chemokine messages and that mRNA levels
of these chemokines were elevated in the brains of patients with HIV
encephalitis. They also indicated that cells with cytologic features of
microglia/macrophages and astrocytes were expressing this message.
Sasseville et al. (37) showed that there was increased expression of
MIP-1 and MIP-1ß protein in the brains of macaque monkeys with
SIV-induced AIDS encephalitis and that cells with the morphology of
monocytes/microglia appeared to be expressing these chemokines. Recent
data by He et al. show that human microglia express CD4 as well as CCR3
and CCR5, chemokine receptors that function as cofactors for HIV-1
infection (38). It is of interest that MIP-1 and MIP-1ß are
ligands for CCR5 and may be important as suppressive factors that
compete with HIV for this receptor to block infection of microglial
cells. Future studies on the regulation of receptor expression on
microglia in response to HIV infection as well as proinflammatory
stimuli will help clarify the role of chemokines in CNS disease. It
will be important to determine chemokine and chemokine receptor
expression by cells in the CNS to understand the mechanism by which HIV
infects these cells and how it then mediates damage resulting in
encephalitis and dementia. We are currently pursuing these studies.
The data presented here illustrate both some distinct differences and
some similarities between human microglial chemokine expression and
chemokine expression by similar cell types, monocytes, and macrophages
in both humans and rodents. Our data are consistent with Hayashi et al.
(12), who showed that LPS induces MIP-1 from murine microglial cells
as well as from other groups showing LPS induction of MIP-1 and
MIP-1ß from human PBMCs and alveolar macrophages (39, 40).
However, Hayashi et al. (12) also demonstrated that murine microglia do
not express MCP-1 in response to LPS, whereas we found that human
microglia are potently induced by LPS to express MCP-1. Similarly,
previous studies have shown that IL-1ß induces MIP-1 in human
PBMCs and alveolar macrophages, and although we found that IL-1ß was
a potent inducer of MIP-1ß, it only weakly induced MIP-1 in our
studies (39). TNF- and IFN- do not induce MIP-1 in human PBMCs
or alveolar macrophages (39). Human fetal microglia are also not
induced by IFN- to produce MIP-1 or MIP-1ß. In our studies,
TNF- potently induced MIP-1 and MIP-1ß expression. This differs
from what was reported by Berkman et al. (39) and Martin et al., whose
studies demonstrated no induction of these chemokines by TNF- in
human or murine macrophages (41). Another major difference between our
studies and those of others is the inability of TGF-ß to modulate
MIP-1 or MIP-1ß expression in human fetal microglia, whereas it
strongly down-regulates their expression in murine bone marrow
macrophages (25). These differences illustrate the complexity of
cytokine/chemokine interaction and emphasize how this interplay varies
between cells of similar lineage as well as between the same cells of
different species. This also highlights the differences between the CNS
and other organs and tissues.
Our results show for the first time that human primary fetal microglia
can be induced to express MIP-1, MIP-1ß, and MCP-1 mRNA and
protein in response to various proinflammatory stimuli including LPS.
An understanding of the different profiles of chemokine expression from
cells endogenous to the CNS and from cells that can infiltrate into the
CNS during inflammation will be important in the development of novel
therapeutic strategies to treat neuroimmunologic diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joan W. Berman, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.
3 Abbreviations used in this paper: CNS, central nervous system; MS, multiple sclerosis; MIP, macrophage inflammatory protein; MCP, monocyte chemoattractant protein; EAE, experimental autoimmune encephalitis; GFAP, glial fibrillary acidic protein.
Received for publication March 31, 1997. Accepted for publication October 17, 1997.
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References |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases. J. Neuroimmunol. 129:223.
in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J. Immunol. 155:5003.[Abstract]
- and ß-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am. J. Pathol. 150:617.[Abstract]
, and MIP-1ß as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811.. J. Immunol. 156:1566.[Abstract]
and conservation of potential regulatory sequences with a human homolog, LD78. J. Immunol. 146:4031.[Abstract]
, MIP-1ß, and RANTES is associated with a type 1 immune response. J. Immunol. 157:3598.[Abstract]
in human monocytes and alveolar macrophages. Am. J. Physiol. 269:L443.This article has been cited by other articles:
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|
 |
|
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A. V. Andjelkovic, D. Kerkovich, and J. S. Pachter Monocyte:astrocyte interactions regulate MCP-1 expression in both cell types J. Leukoc. Biol., October 1, 2000; 68(4): 545 - 552. [Abstract] [Full Text]
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 O. Kutsch, J.-W. Oh, A. Nath, and E. N. Benveniste Induction of the Chemokines Interleukin-8 and IP-10 by Human Immunodeficiency Virus Type 1 Tat in Astrocytes J. Virol., October 1, 2000; 74(19): 9214 - 9221. [Abstract] [Full Text]
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Y. Persidsky, J. Zheng, D. Miller, and H. E. Gendelman Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia J. Leukoc. Biol., September 1, 2000; 68(3): 413 - 422. [Abstract] [Full Text] [PDF]
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 S. Hu, C. C. Chao, C. C. Hegg, S. Thayer, and P. K. Peterson Morphine inhibits human microglial cell production of, and migration towards, RANTES J Psychopharmacol, May 1, 2000; 14(3): 238 - 243. [Abstract] [PDF]
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C. M. McManus, K. Weidenheim, S. E. Woodman, J. Nunez, J. Hesselgesser, A. Nath, and J. W. Berman Chemokine and Chemokine-Receptor Expression in Human Glial Elements : Induction by the HIV Protein, Tat, and Chemokine Autoregulation Am. J. Pathol., April 1, 2000; 156(4): 1441 - 1453. [Abstract] [Full Text] [PDF]
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M. C. Bosco, A. Rapisarda, S. Massazza, G. Melillo, H. Young, and L. Varesio The Tryptophan Catabolite Picolinic Acid Selectively Induces the Chemokines Macrophage Inflammatory Protein-1{alpha} and -1{beta} in Macrophages J. Immunol., March 15, 2000; 164(6): 3283 - 3291. [Abstract] [Full Text] [PDF]
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N. Tong, S. W. Perry, Q. Zhang, H. J. James, H. Guo, A. Brooks, H. Bal, S. A. Kinnear, S. Fine, L. G. Epstein, et al. Neuronal Fractalkine Expression in HIV-1 Encephalitis: Roles for Macrophage Recruitment and Neuroprotection in the Central Nervous System J. Immunol., February 1, 2000; 164(3): 1333 - 1339. [Abstract] [Full Text] [PDF]
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 L. L. Reznikov, B. D. Shames, H. A. Barton, C. H. Selzman, G. Fantuzzi, S.-H. Kim, S. M. Johnson, and C. A. Dinarello Interleukin-1beta deficiency results in reduced NF-kappa B levels in pregnant mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R263 - R270. [Abstract] [Full Text] [PDF]
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B. R. Lane, D. M. Markovitz, N. L. Woodford, R. Rochford, R. M. Strieter, and M. J. Coffey TNF-{alpha} Inhibits HIV-1 Replication in Peripheral Blood Monocytes and Alveolar Macrophages by Inducing the Production of RANTES and Decreasing C-C Chemokine Receptor 5 (CCR5) Expression J. Immunol., October 1, 1999; 163(7): 3653 - 3661. [Abstract] [Full Text] [PDF]
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J. M. Weiss, A. Nath, E. O. Major, and J. W. Berman HIV-1 Tat Induces Monocyte Chemoattractant Protein-1-Mediated Monocyte Transmigration Across a Model of the Human Blood-Brain Barrier and Up-Regulates CCR5 Expression on Human Monocytes J. Immunol., September 1, 1999; 163(5): 2953 - 2959. [Abstract] [Full Text] [PDF]
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R. S. Klein, K. C. Williams, X. Alvarez-Hernandez, S. Westmoreland, T. Force, A. A. Lackner, and A. D. Luster Chemokine Receptor Expression and Signaling in Macaque and Human Fetal Neurons and Astrocytes: Implications for the Neuropathogenesis of AIDS J. Immunol., August 1, 1999; 163(3): 1636 - 1646. [Abstract] [Full Text] [PDF]
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N. Janabi, I. Hau, and M. Tardieu Negative Feedback Between Prostaglandin and {alpha}- and {beta}-Chemokine Synthesis in Human Microglial Cells and Astrocytes J. Immunol., February 1, 1999; 162(3): 1701 - 1706. [Abstract] [Full Text] [PDF]
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J. M. Weiss, S. A. Downie, W. D. Lyman, and J. W. Berman Astrocyte-Derived Monocyte-Chemoattractant Protein-1 Directs the Transmigration of Leukocytes Across a Model of the Human Blood-Brain Barrier J. Immunol., December 15, 1998; 161(12): 6896 - 6903. [Abstract] [Full Text] [PDF]
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J. M. Galasso, J. K. Harrison, and F. S. Silverstein Excitotoxic Brain Injury Stimulates Expression of the Chemokine Receptor CCR5 in Neonatal Rats Am. J. Pathol., November 1, 1998; 153(5): 1631 - 1640. [Abstract] [Full Text] [PDF]
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A. K. Stalder, M. J. Carson, A. Pagenstecher, V. C. Asensio, C. Kincaid, M. Benedict, H. C. Powell, E. Masliah, and I. L. Campbell Late-Onset Chronic Inflammatory Encephalopathy in Immune-Competent and Severe Combined Immune-Deficient (SCID) Mice with Astrocyte-Targeted Expression of Tumor Necrosis Factor Am. J. Pathol., September 1, 1998; 153(3): 767 - 783. [Abstract] [Full Text] [PDF]
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J. S. H. Liu, T. D. Amaral, C. F. Brosnan, and S. C. Lee IFNs Are Critical Regulators of IL-1 Receptor Antagonist and IL-1 Expression in Human Microglia J. Immunol., August 15, 1998; 161(4): 1989 - 1996. [Abstract] [Full Text] [PDF]
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