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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 258-265
Interleukin-6 Induces Monocyte Chemotactic Protein-1 in Peripheral
Blood Mononuclear Cells and in the U937 Cell Line
By
Priscilla Biswas,
Fanny Delfanti,
Sergio Bernasconi,
Manuela Mengozzi,
Manuela Cota,
Nadia Polentarutti,
Alberto Mantovani,
Adriano Lazzarin,
Silvano Sozzani, and
Guido Poli
From the AIDS Immunopathogenesis Unit, DIBIT, and the Division of
Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy;
the Department of Immunology and Cell Biology, "Mario Negri"
Institute for Pharmacological Research, Milan, Italy; and the
Department of Pathology, University of Brescia, Brescia, Italy.
 |
ABSTRACT |
Induction of chemokine gene expression from peripheral blood
mononuclear cells (PBMCs) stimulated by proinflammatory cytokines plays
an important role in both wound repair and response to infectious
agents. In the present study, we show that the proinflammatory cytokine
interleukin-6 (IL-6) potently induced mRNA expression and secretion of
the CC chemokine monocyte chemotactic protein 1 (MCP-1) in PBMCs. In
addition, because human immunodeficiency virus (HIV) infection in vivo
and in vitro has been shown to dysregulate the production of
and/or the response to cytokines, PBMCs from both healthy
uninfected and HIV-infected individuals were studied for their
constitutive and IL-6-induced expression of MCP-1. No substantial
differences were observed between the two groups of individuals. In
addition, IL-6 upregulated MCP-1 expression in the promonocytic cell
line U937 and in its chronically HIV-infected counterpart, U1. In these
cell lines, IL-6 selectively induced MCP-1 and not other chemokines,
including regulated upon activation normal T cells expressed and
secreted (RANTES), macrophage inflammatory protein-1 (MIP-1),
MIP-1 , and IL-8. IL-6 induction of MCP-1 was partially inhibited by
hydrocortisone in U1 cells. Thus, IL-6 activates PBMCs to secrete
MCP-1, a CC chemokine pivotal for monocyte recruitment in tissue and
organs in which important inflammatory events occur.
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INTRODUCTION |
MONOCYTE CHEMOTACTIC protein-1 (MCP-1)
belongs to the or CC family of chemotactic cytokines, or
chemokines,1 which stimulate the migration of monocytic
cells, whereas or CXC chemokines predominantly activate
polymorphonuclear leukocytes.2,3 The coordinated synthesis
and release of MCP-1 plays a central role in both acute and chronic
inflammatory processes by controlling the influx of phagocytic cells
and also their state of activation in concert with primary inflammatory
cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-
(TNF-), and IL-6.2,3 It is of interest that a selective
accumulation of MCP-1 in the cerebrospinal fluid (CSF) of AIDS patients
with cytomegalovirus (CMV) encephalitis, but not with other
opportunistic infections (OI) or primary lymphomas of the central
nervous system (CNS), has been recently described.4 In
addition, we have recently observed that a similar selective
accumulation of MCP-1 in the CSF occurred in patients with human
immunodeficiency virus (HIV) encephalitis (Cinque et al, manuscript
submitted). These findings suggest a potential role of
MCP-1 in monocyte recruitment to the brain in this acquired
immunodeficiency syndrome (AIDS)-related disease. It is conceivable
that the accumulation of MCP-1 in the CSF may be secondary to the known
ability of CMV to induce several proinflammatory cytokines, including
TNF-, IL-1, leukemia inhibitory factor (LIF), and
IL-6.5-8 All these cytokines, as well as IL-4 and
interferon- (IFN-), have been shown to induce MCP-1 expression in
human endothelial cells (ECs), mononuclear phagocytes, and
fibroblasts.9-15 Because both LIF and IL-6 share a common
gp130 transducing chain,16 the observation that LIF can
induce MCP-1 from human monocytes supports the hypothesis that IL-6 may
exert a similar regulatory effect in cells of monocytic lineage. In
support of this hypothesis, IL-6 has been reported to induce MCP-1 in
rat brain macrophages17 and also in mesenchymal cells such
as murine fibroblasts18 and human osteoblast cell
lines.19
IL-6 is a multifunctional cytokine that plays an important role in
several physiologic processes, including hematopoiesis, B-cell
proliferation, plasma cell differentiation, and hepatocyte
growth.16,20,21 Furthermore, IL-6 is a component of the
inflammatory cascade,22-25 and it is a critical factor for
triggering the acute-phase response.20,26,27 In addition to
inflammatory diseases, increased levels of IL-6 have been described in
the plasma and CSF of HIV-infected individuals.28-31
In the present study, we have investigated whether IL-6 could induce
MCP-1 expression in primary peripheral blood mononuclear cells (PBMCs)
obtained both from healthy HIV-seronegative individuals and from
HIV-infected individuals and in the promonocytic cell lines U937
(uninfected) and U1 (chronically HIV-infected).
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MATERIALS AND METHODS |
Patients.
The HIV-seropositive individuals who donated their blood for PBMC
studies were observed at the Division of Infectious Diseases of the San
Raffaele Scientific Institute (Milan, Italy). They had progressive
disease, with CD4+ counts of less than
200/µL, and were undergoing different therapeutic
regimens.
Cell cultures.
All cultures were maintained in RPMI 1640 supplemented with glutamine
(2 mmol/L), penicillin (100 U/mL), streptomycin (100 µg/mL;
Biowhittaker, Verviers, Belgium), and 10% fetal calf serum (Hyclone
Europe, Ltd, Cramlington, UK).
Cell lines.
U937 is a well-known human promonocytic cell line32 that
can be induced to differentiate into mature macrophages by several
agents, including phorbol 12-myristate 13-acetate (PMA). The
chronically infected U1 cell line was obtained by limiting dilution
cloning of U937 cells acutely infected with HIV-1 (IIIB/LAI
strain).33 Both U937 and U1 cells were seeded at the
initial concentration of 4 × 105 cells/mL in 48-well
polystirene culture plates (Falcon, Becton Dickinson Labware, Lincoln
Park, NJ), and culture supernatants were harvested at the indicated
time points and stored at  80°C until tested for the presence
of cytokines, chemokines, and, in the case of U1 cells, HIV.
Primary cells.
Whole venous blood and buffy coats donated by the transfusional center
of the San Raffaele Scientific Institute were obtained from
HIV-infected individuals and healthy donors, respectively. PBMCs, which
were isolated by centrifugation on a Ficoll-Hypaque (Pharmacia,
Uppsala, Sweden) density gradient, were cultured at the concentration
of 1.5 × 106 cells/mL in 24-well culture plates
(Falcon) in the absence and presence of IL-6 (10 ng/mL) or
lipopolysaccharide (LPS; 1 µg/mL), and supernatants were harvested at
the indicated time points.
Reagents.
LPS from Escherichia coli (serotype 055:B55) and PMA (Sigma
Chemical Corp, St Louis, MO) were used at the fixed final
concentrations of 1 µg/mL and 10 nmol/L, respectively. One hundred,
10, and 1 nmol/L final concentrations of hydrocortisone (Sigma) were
used in some experiments. Human recombinant TNF-, IL-6, and IFN-
were purchased from R&D Systems (Minneapolis, MN) and were used at the
concentrations of 0.02 nmol/L (1 ng/mL), 0.24 nmol/L (10 ng/mL), and
1.5 nmol/L (50 ng/mL), respectively.
Measurement of cytokine and chemokine contents.
All chemokines present in culture supernatants were measured using
enzyme-linked immunosorbent assay (ELISA). ELISA kits for RANTES,
MIP-1, and MIP-1 were purchased from R&D Systems, whereas
homemade assays were performed in the case of MCP-134 and
IL-8.4
Reverse transcriptase-polymerase chain reaction (RT-PCR) detection
of MCP-1 mRNA.
Total cellular RNA was isolated from 3 to 6 × 106
PBMCs with RNA-zol B (Duotech S.r.l., Milan, Italy), following the
manufacturer's protocol. RNA (1 µg) was reverse transcribed by
incubation at 42°C for 40 minutes and at 94°C for 5 minutes in
the presence of 1× RT buffer (GIBCO BRL, Life Technologies,
Paisley, UK), 800 mmol/L dNTPs (Pharmacia), 20 µg/mL random hexamers
(Promega, Madison, WI), 4 mmol/L dithiothreitol (GIBCO BRL), 12 U RNA
guard (Promega), and 400 U of Moloney murine leukemia virus
(M-MLV) RT (GIBCO BRL) in a 50-µL reaction. One
twentieth of the cDNA obtained from the RT reaction was amplified with
primers specific for MCP-1 (forward, 5 -CAATAGGAAGATCTCAGTGC;
reverse, 5-GTGTTCAAGTCTTCGGAGTT)35 in the presence
of 2.5 U of Taq polymerase (Ex Taq; Taqara Biomedical Europe S.A.,
Gennevilliers, France), following the instructions of the manufacturer.
To verify that equal amounts of cDNA were added in each PCR reaction,
the housekeeping gene GAPDH was amplified from 1/20 of the same cDNA,
using specific primers (forward,
5-CCATGGAGAAGGCTGGGG; reverse,
5-CAAAGTTGTCATGGATGACC).36 Amplification (30 seconds
of denaturation at 94°C, 45 seconds of annealing at 60°C, and
60 seconds of extension at 72°C) was performed for 32 cycles with
MCP-1 primers and for 28 cycles with GAPDH primers; amplifications were
preceded by a denaturation step (90 seconds at 94°C) and followed
by a final extension period (7 minutes at 72°C). PCR amplification
products were analyzed by 2% agarose gel electrophoresis and
visualized by ethidium bromide staining.
HIV-RT activity.
HIV expression, monitored as Mg2+-dependent RT activity
released into supernatants of chronically infected U1 cells, was
measured as previously described.37
Northern blot analyses.
A total of 107 U1 cells (4 × 105 cells/mL
in 25 mL per flask; Falcon) were seeded in culture for each condition
and time point. Northern blot analyses were performed according to
standard procedures.38 Briefly, 10 µg of total RNA was
isolated by the guanidium isothiocyanate method and analyzed by
electrophoresis through 1% agarose/formaldehyde gel, followed by
Northern blot transfer to Gene Screen Plus membranes (New England
Nuclear, Boston, MA). The probe, human MCP-1 cDNA (0.672-kb Pst
I-Pst I fragment)39 was labeled by Megaprime DNA
labeling system (Amersham, Buckinghamshire, UK) with
32P-dCTP (3,000 Ci/mmol; Amersham).
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RESULTS |
IL-6 induces MCP-1 expression in PBMCs of healthy seronegative and
HIV-infected individuals.
Basal levels of MCP-1 were detectable, with a mean of 0.7 ng/mL
(±0.8 standard deviation [SD]) and 0.5 ng/mL (±0.8 SD) for
healthy controls and HIV-seropositive individuals, respectively. IL-6
stimulation induced substantial levels of MCP-1 in PBMCs from both
groups of individuals, with a mean of 29 ng/mL (±26 SD) and 27.3
ng/mL (±14.3 SD) for uninfected and HIV-infected individuals,
respectively (Fig 1). These levels were
comparable to those induced by LPS in control individuals (mean, 28
ng/mL; ±10.1 SD) and were even higher, although not statistically
significant, than those induced by LPS in HIV-infected individuals
(mean, 14.9 ng/mL; ±16.9 SD).
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| Fig 1.
IL-6 and LPS induce MCP-1 secretion in healthy and
HIV-seropositive individuals. PBMCs from 6 healthy controls and 6
HIV-seropositive individuals were cultivated with medium alone
(Medium), IL-6 (0.24 nmol/L), or LPS (1 µg/mL). After 72 hours of
culture, supernatants were harvested and frozen at 80°C until
tested for MCP-1 content. Each symbol corresponds to a culture
established from a single individual. The lines indicate the mean MCP-1
concentrations: 0.7 (medium), 29 (IL-6), and 28 (LPS) ng/mL for healthy
controls and 0.5 (medium), 27.3 (IL-6), and 14.9 (LPS) ng/mL for
HIV-seropositive individuals, respectively. No statistical differences
in terms of MCP-1 production after stimulation with LPS were observed
between cultures established from HIV-negative and HIV-seropositive
individuals (P = .15, nonparametric Rank Sums test). A total
of 27 ng/mL of MCP-1 was produced from 1 patient ( ) after 8 days of
stimulation with LPS.
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IL-6 caused an increase of the levels of MCP-1 mRNA as detected at 24
hours (Fig 2A) in the very same cell
cultures in which the chemokine was simultaneously released in the
supernatants (Fig 2B).
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| Fig 2.
Induction of MCP-1 mRNA and protein by IL-6 and LPS in
PBMCs. One HIV-negative and one HIV-positive individual are shown.
PBMCs were cultivated for 24 hours with medium alone (control), IL-6
(0.24 nmol/L), or LPS (1 µg/mL). (A) The cells were pelletted and
frozen until processed for RT-PCR analysis of MCP-1 mRNA compared with
the levels of expression of the housekeeping gene GAPDH. (B) Cell
culture supernatants were harvested and frozen at 80°C until
tested for MCP-1 protein content by ELISA. Similar results were
obtained with PBMCs from two additional HIV-negative and two
HIV-seropositive individuals cultured under the same conditions for 24
hours. ( ) Unstimulated; ( ) IL-6 (0.24 nmol/L); ( ) LPS (1
µg/mL).
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Thus, no significant differences were observed between HIV-negative and
HIV-positive individuals, indicating that this viral infection does not
influence either basal production of MCP-1 or leukocyte responsiveness
to IL-6 and LPS, at least in the peripheral blood compartment. In
support of this interpretation, no substantial levels of MCP-1 were
detected in the plasma of AIDS patients with CMV encephalitis, which is
in sharp contrast to the substantial accumulation of this chemokine in
their CSF.4
IL-6 induces MCP-1 expression in U937 and in U937-derived chronically
HIV-infected U1 cell lines.
Among immune cells, monocytic cells are known to be the main producers
of MCP-1.13 Furthermore, the IL-6-related molecule LIF was
shown to induce MCP-1 in human monocytes.15 Therefore, we
tested whether IL-6 was capable of activating MCP-1 expression in the
promonocytic cell lines U937 and U1. IL-6 induced substantial levels of
MCP-1 in U937 cells; in addition, TNF- and IFN-, which were
previously described to upregulate MCP-1
expression,10-12,15,40-43 also induced secretion of this
chemokine (Fig 3). Basal expression of
MCP-1 was shown in HIV-infected U1 cells using Northern blot analysis
(Fig 4A), whereas stimulation with either
IL-6 or IFN- caused an increased accumulation of both mRNA (Fig 4A)
and release of MCP-1 in culture supernatants (Fig 4B), as observed in
uninfected U937 cells. In experiments in which different concentrations
of TNF- were compared, a dose-response of MCP-1 secretion from U1
cells was observed (with 0.3, 12.6, 23.9, and 27.7 ng/mL of MCP-1
secreted from cells that were unstimulated or were stimulated with
0.02, 0.2, or 2 nmol/L of TNF-, respectively; data not
shown).
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| Fig 3.
Kinetics of chemokine secretion by U937 cells. U937 cells
were cultivated with () medium alone, ( ) IL-6 (0.24 nmol/L),
() IFN- (1.5 nmol/L), or ( ) TNF- (0.02 nmol/L) for 72
hours. Supernatants were harvested daily, aliquoted, and frozen at
80°C until tested for the presence of MCP-1.
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| Fig 4.
Induction of MCP-1 expression by IL-6 and IFN- in
HIV-infected U1 cells. (A) Northern blot analysis of MCP-1 expression
after 4 and 18 hours of culture with medium alone, IL-6 (0.24 nmol/L),
or IFN- (1.5 nmol/L). The results of one representative experiment
of three independently performed are shown. Intermediate (11 hours) and
later (36 hours) time points were evaluated in the additional two
experiments, showing that baseline and cytokine-induced MCP-1 message
decreases after 36 hours of culture. Ethidium bromide staining of the
18S and 28S ribosomal RNA is shown as a control for RNA loading. (B)
MCP-1 secretion in supernatants harvested after 4 and 18 hours of
culture from the same cells of the experiment shown in (A). Low, but
detectable levels of MCP-1 were already present in the supernatants 4
hours after stimulation.
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IL-6 induced a twofold upregulation of MCP-1 secretion over low but
detectable constitutive levels also in the myelomonocytic cell line
HL-60 (data not shown).
Selective MCP-1 induction by IL-6 and TNF- in U1 cells.
Stimulation of U937 and U1 cells with PMA resulted in the increased
expression of the CC chemokines MCP-1, RANTES, MIP-1, and MIP-1
and of the CXC chemokine IL-8 (data not shown). In contrast, both IL-6
and TNF- induced MCP-1 but not the other tested chemokines in U937
(data not shown) and U1 cells (Fig 5). In
this latter cell line, IL-6 and TNF- also induced comparable levels
of virus production in culture supernatants (Table
1), as previously reported.37
Therefore, we attempted to investigate whether endogenous MCP-1 played
a role in cytokine-induced virus expression from U1 cells by adding the
anti-MCP-1 monoclonal antibody 5D3-F734 to both
unstimulated and stimulated U1 cells. Overall results were
inconclusive, although a partial (up to 50%) inhibition of HIV
production was observed in some experiments (data not shown). Because
this as well as other anti-MCP-1 monoclonal antibodies can only
partially neutralize the biologic effects of the chemokine, the
possibility that MCP-1 may influence HIV replication remains to be
thoroughly investigated.
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| Fig 5.
Patterns of chemokine secretion by HIV-infected U1 cells
in unstimulated conditions and in response to TNF- and IL-6. U1
cells were cultured with medium alone, TNF- (0.02 nmol/L), or IL-6
(0.24 nmol/L) for 72 hours; supernatants were harvested daily and
stored at 80°C until tested. The data shown are from one
representative experiment of four independently performed. Four CC
chemokines (MCP-1, RANTES, MIP-1, and MIP-1) and one CXC
chemokine (IL-8) were measured in the supernatants of unstimulated and
stimulated cultures. Low (MCP-1, RANTES, and IL-8) to undetectable
(MIP-1 and MIP-1) levels of chemokines were present in
supernatants of unstimulated U1 cells. Both IL-6 and TNF-
upregulated MCP-1 secretion; a modest enhancement of IL-8 production
was also noted in U1 cells stimulated with TNF- and IL-6.
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Hydrocortisone inhibition of IL-6-induced MCP-1 in U1 cells.
It has been reported that induction of MCP-1 by stimuli other than IL-6
can be inhibited by anti-inflammatory agents such as glucocorticoid
hormones.44 On the other hand, glucocorticoids potentiate
certain IL-6-mediated effects on hepatocytes and other cell
types,45-47 including HIV expression in U1
cells.48 We therefore tested whether hydrocortisone could
modulate IL-6-dependent MCP-1 secretion in this cell line. A
concentration-dependent inhibition of MCP-1 secretion was observed when
hydrocortisone was added simultaneously (cotreatment) to U1 cell
cultures stimulated with PMA, IL-6, or IFN- (Fig
6). One hour of pretreatment or
posttreatment with hydrocortisone (10 nmol/L) versus the time of
addition of the stimuli showed no significant differences in terms of
inhibition of MCP-1 secretion as compared with cultures that were
cotreated with the hormone (data not shown).
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| Fig 6.
Concentration-dependent inhibitory effect of
hydrocortisone (HC) on MCP-1 secretion from U1 cells stimulated by
different agents. Cells cultivated with medium alone, PMA (10 nmol/L),
IL-6 (0.24 nmol/L), and IFN- (1.5 nmol/L) were coincubated with
decreasing concentrations (ranging from 100 to 1 nmol/L) of
hydrocortisone. After 72 hours, culture supernatants were harvested and
stored at 80°C until tested for MCP-1 content. Mean values of
duplicate cultures from one of three independent experiments are shown.
Intersample variability was  10%.
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DISCUSSION |
In the present study, we have observed that IL-6 is a potent inducer of
MCP-1 expression and secretion in primary PBMCs obtained from both
healthy seronegative and HIV-seropositive individuals. Further, IL-6
selectively induced MCP-1, but not other chemokines, including RANTES,
MIP-1, MIP-1, or IL-8 in the U937 cell line and in its
HIV-infected counterpart, U1. Finally, hydrocortisone partially
inhibited MCP-1 expression induced by IL-6, IFN-, or PMA in U1
cells.
MCP-1, which is predominantly produced by monocytes, EC, and
fibroblasts,9-15,49 is an important molecule in the
regulation of leukocyte trafficking by eliciting the directional
migration of mononuclear phagocytes.1-3 Several
proinflammatory and immunoregulatory cytokines, including IL-1,
TNF-, IFN-, and IL-4, have been shown to induce synthesis and
secretion of MCP-1 by human EC.9-12,13,41 In this regard,
it has recently been shown that soluble IL-6 receptor together with
exogenous IL-6 is required for induction of MCP-1 expression from ECs
that constitutively express the gp130 transducing chain in
IL-6 / mice.50 The IL-6-related
molecule LIF induced both MCP-1 and IL-815 in purified
human monocytes, suggesting that the ability of inducing chemokines may
be a common feature among cytokines using gp130 as the common
transducer for signaling.16
In vivo, a selective increase in MCP-1 has recently been found in the
CSF of AIDS patients with CMV encephalitis, but not in HIV seronegative
controls without neurologic symptoms or in AIDS patients with other OI
of the CNS.4 CMV has been reported to induce IL-6 from
macrophages and microglial cells in the CNS,5 suggesting
the possibility that a concomitant expression of IL-6 and/or
TNF- and MCP-1 may occur in the CNS of AIDS patients, a hypothesis
that we are currently investigating in our laboratory. It is of
interest that CMV encodes a homologue of a CC chemokine receptor gene
(US28) that is capable of binding MCP-1.51 The observation
that this chemokine accumulates in the CSF of individuals with CMV
encephalitis suggests that autocrine/paracrine pathways may be
triggered by CMV aimed at recruiting monocytes from the bloodstream to
the brain, which may affect the ability of the virus to persist and
replicate in this organ. Furthermore, MCP-1 has also been shown to
induce expression of cytokines, including IL-6, in human
monocytes,52 suggesting an alternative or complementary
loop of amplification of inflammatory responses. It is of interest that
we have also recently observed a concomitant accumulation of MCP-1 and
HIV in the CSF of AIDS patients with HIV encephalitis (Cinque et al,
manuscript submitted), suggesting the possibility that, in
addition to CMV, HIV can also induce MCP-1 expression. However, in the
present study, we have failed to show substantial differences between
uninfected and chronically HIV-infected U937 cells in the expression of
several chemokines, including MCP-1. Whether acute HIV replication in
vitro may affect the expression of MCP-1 or other chemokines is under
investigation in our laboratory.
Increased levels of mRNA of two other CC chemokines, MIP-1 and
MIP-1, have also been found expressed by microglia and astrocytes in
brain tissues from HIV-infected patients with dementia.53
Thus, the localized overexpression of certain chemokines in the CNS or
other tissues and organs may play an important pathogenetic role via
leukocyte recruitment and either their direct activation or their
priming to the regulatory effects of proinflammatory cytokines.
IL-6 is a multifunctional cytokine that acts on B cells, T cells,
hematopoietic progenitor cells, and hepatocytes, thus influencing the
regulation of the immune response and of hematopoiesis, contributing to
the inflammatory process, and triggering the acute-phase
reaction.16,20-27 In this regard, IL-6-deficient mice have
shown impaired immune and acute-phase responses.25-27
Increased levels of IL-6 are found together with those of IL-1 and
TNF- during sepsis and septic shock,22-24 although IL-6
accumulation usually occurs later than that of other proinflammatory
cytokines, and its increase may be prevented by antibodies neutralizing
TNF-.24 Elevated levels of IL-6 have also been found in
the plasma/serum or CSF of some HIV-infected
individuals,28-31 whereas this cytokine can induce HIV
replication in primary monocyte-derived macrophages and
activation of virus expression from latently infected U1
cells.37 Whether endogenous MCP-1 is a mediator of the
upregulating effect of IL-6 or other inflammatory cytokines on HIV
replication remains to be further investigated.
IL-6 and IL-6-induced MCP-1 may also play a potential pathogenetic
role in Kaposi's sarcoma (KS), a pathologic process characterized by a
prominent leukocyte infiltrate54-56 and in B-cell
lymphomas.56 In this regard, both IL-6 and Oncostatin M
(also belonging to the family of gp130-related cytokines16)
have been early recognized as growth factors for KS cells and lymphoma
cells.54-56 Later, expression of MCP-1 has been observed in
KS cells both in vitro and in vivo,57 whereas a new human
herpesvirus, KSHV or HHV-8, has been recently involved in the
etiopathogenesis of both endemic and AIDS-associated KS and
body cavity lymphomas (BCL).58-60 Of particular interest is
the fact that KSHV encodes viral homologues of a constitutively active
chemokine receptor, an IFN-response gene, and IL-6
(v-IL-6).61 Thus, it is conceivable that v-IL-6 may
directly induce MCP-1 expression and monocyte recruitment during the
development and growth of KS and BCL.
In conclusion, the novel finding that IL-6 is a strong inducer of MCP-1
in PBMCs adds another important property to this multifunctional
cytokine in terms of regulation of monocyte extravasation and tissue
infiltration occurring during viral, inflammatory, and neoplastic
diseases.
| |
FOOTNOTES |
Submitted May 12, 1997;
accepted September 5, 1997.
Supported entirely by grants of the 1996 AIDS Project of the Istituto
Superiore di Sanità, Rome, Italy.
Address reprint requests to Priscilla Biswas, PhD, P2-P3 Laboratories,
DIBIT, Via Olgettina n. 58, 20132, Milan, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Dr Elisa Vicenzi for helpful discussions and critical
reading of the manuscript, Dr Fabrizio Veglia for statistical analyses,
and Pietro Transidico for MCP-1 determinations.
| |
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I. S. Leal, B. Smedegard, P. Andersen, and R. Appelberg
Interleukin-6 and Interleukin-12 Participate in Induction of a Type 1 Protective T-Cell Response during Vaccination with a Tuberculosis Subunit Vaccine
Infect. Immun.,
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[Abstract]
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S. Vlahopoulos, I. Boldogh, A. Casola, and A. R. Brasier
Nuclear Factor-kappa B-Dependent Induction of Interleukin-8 Gene Expression by Tumor Necrosis Factor alpha : Evidence for an Antioxidant Sensitive Activating Pathway Distinct From Nuclear Translocation
Blood,
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[Abstract]
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B. Sporri, K. M. Muller, U. Wiesmann, and M. Bickel
Soluble IL-6 receptor induces calcium flux and selectively modulates chemokine expression in human dermal fibroblasts
Int. Immunol.,
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[Abstract]
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A. Aiuti, L. Turchetto, M. Cota, A. Cipponi, A. Brambilla, C. Arcelloni, R. Paroni, E. Vicenzi, C. Bordignon, and G. Poli
Human CD34+ Cells Express CXCR4 and Its Ligand Stromal Cell-Derived Factor-1. Implications for Infection by T-Cell Tropic Human Immunodeficiency Virus
Blood,
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[Abstract]
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M. Mengozzi, C. De Filippi, P. Transidico, P. Biswas, M. Cota, S. Ghezzi, E. Vicenzi, A. Mantovani, S. Sozzani, and G. Poli
Human Immunodeficiency Virus Replication Induces Monocyte Chemotactic Protein-1 in Human Macrophages and U937 Promonocytic Cells
Blood,
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[Abstract]
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J.-W. Oh, N. J. Van Wagoner, S. Rose-John, and E. N. Benveniste
Role of IL-6 and the Soluble IL-6 Receptor in Inhibition of VCAM-1 Gene Expression
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D. A. Sukovich, K. Kauser, F. D. Shirley, V. DelVecchio, M. Halks-Miller, and G. M. Rubanyi
Expression of Interleukin-6 in Atherosclerotic Lesions of Male ApoE-Knockout Mice : Inhibition by 17ß-Estradiol
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Abstract
Introduction
Abstract