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*
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Department of Cell Biology and Immunology, Free University, Amsterdam, The Netherlands;
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducible protein (IP-10), macrophage inflammatory protein
(MIP)-2, and KC) and CC (JE/monocyte chemoattractant protein (MCP)-1,
MCP-5, MIP-1
, MIP-1
, and RANTES) chemokine genes evaluated were
sensitive to stimulation by LPS in vitro and in vivo. While IL-10
suppressed the expression of all LPS-induced chemokine genes evaluated
in vitro, treatment with IFN- selectively induced IP-10 and MCP-5
mRNAs, but inhibited LPS-induced MIP-2, KC, JE/MCP-1, MIP-1, and
MIP-1 mRNA and/or protein. Like the response to IFN-,
LPS-mediated induction of IP-10 and MCP-5 was Stat1 dependent.
Interestingly, only the IFN--mediated suppression of LPS-induced KC
gene expression was IFN regulatory factor-2 dependent. Treatment of
mice with LPS in vivo also induced high levels of chemokine mRNA in the
liver and lung, with a concomitant increase in circulating protein.
Hepatic expression of MIP-1, MIP-1, RANTES, and MCP-5 mRNAs were
dramatically reduced in Kupffer cell-depleted mice, while IP-10, KC,
MIP-2, and MCP-1 were unaffected or enhanced. These findings indicate
that selective regulation of chemokine expression in vivo may result
from differential response of macrophages to pro- and antiinflammatory
stimuli and to cell type-specific patterns of stimulus sensitivity.
Moreover, the data suggest that individual chemokine genes are
differentially regulated in response to LPS, suggesting unique roles
during the sepsis cascade. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Among the cytokine products expressed by LPS-stimulated macrophages are
chemoattractant cytokines or chemokines. These products are believed to
control the nature and magnitude of inflammatory cell infiltration
(7, 8, 9). The chemokine superfamily consists of small (7–14
kDa), basic, heparin-binding proteins that are categorized into four
subfamilies, CXC, CC, C (10), and
CX3C (11, 12), based on the
arrangement of positionally conserved cysteine motifs within the N
terminus of their amino acid structure. The CXC and CC chemokines
predominate and, thus, have been the most extensively studied. Within
the CXC subfamily, the presence of a glutamate-leucine-arginine (ELR)
motif before the first conserved cysteine residue confers selectivity
in recruiting neutrophils (13, 14), and the ELR-containing
CXC chemokines, KC and macrophage
inflammatory protein (MIP)-2,4 are potent inducers of
neutrophil activation and their directional migration
(15). A non-ELR-containing CXC chemokine,
IFN--inducible protein (IP-10), had been reported to recruit
monocytes, T lymphocytes, and NK cells (16, 17); however,
the recently cloned IP-10 receptor, CXCR3, has only been demonstrated
on NK cells and activated T lymphocytes (18). The CC
chemokines, JE/monocyte chemoattractant protein (MCP)-1, MCP-5,
MIP-1, MIP-1, and RANTES are all chemotactic for
monocytes/macrophages and T cells (19), although several
CC chemokines have been reported to attract NK cells, basophils,
eosinophils, dendritic cells, and mast cells (7, 8).
Examination of chemokine expression in vivo has revealed a much more
restricted pattern of expression than would be predicted from analysis
of chemokine expression in vitro. Furthermore, though many different
chemokines have been detected at sites of inflammation and in tissues
during systemic sepsis (20, 21, 22, 23, 24, 25), numerous
reports demonstrate nonredundant roles for individual chemokines. For
example, anti-MIP-2 Ab administration reduced neutrophil
infiltration into the lung, but failed to protect against LPS-induced
mortality (23), while neutralization of MIP-2 in a murine
model of peritonitis decreased both mortality and neutrophil
recruitment into the peritoneal cavity (21). Increased
pulmonary expression of MIP-1 and RANTES has been associated with
the influx of monocytes into the lungs of mice after LPS challenge
(22, 24). Administration of anti-MIP-1 Ab to
mice reduced monocyte, lymphocyte, and neutrophil infiltration into the
lungs with only a modest effect on mortality (24), while
anti-RANTES Ab only reduced monocyte influx into the lungs
(22). In contrast, JE/MCP-1 protected mice from
LPS-induced mortality (20).
While the majority of recent studies have focused on the role of
individual chemokines in sepsis or endotoxemia, we sought to enhance
our understanding of the complex inflammatory cascade initiated after
LPS challenge by systematically evaluating a more comprehensive panel
of CXC and CC chemokine genes. To this end, the regulation of
LPS-induced mRNA expression of the CXC chemokines, IP-10, MIP-2, and
KC, as well as the CC chemokines, JE/MCP-1, MCP-5, MIP-1, MIP-1,
and RANTES, was evaluated both in vitro and in vivo. We wished to
evaluate the cellular and molecular mechanisms that may be responsible
for selective expression and function in vivo. Despite apparent
functional redundancies and intrafamily structural homologies, these
studies clearly demonstrate that individual chemokine genes are
differentially regulated. Novel key findings from this study include:
1) IL-10 down-regulates LPS-induced mRNA expression for all chemokine
genes examined, 2) IFN- induces or inhibits distinct subsets of
LPS-induced chemokine genes, 3) only induction of IP-10 and MCP-5 mRNA
by LPS or LPS and IFN- is Stat1 dependent, 4) only IFN--mediated
inhibition of KC expression was dependent upon IFN regulatory factor
(IRF)-2 (but not IRF-1), and 5) hepatic expression of LPS-induced
MIP-1, MIP-1, MCP-5, and RANTES mRNA occcurs predominantly in
Kupffer cells, while IP-10, MCP-1, and MIP-2 expression occurs within
other liver cell types. These findings illustrate the complex nature of
chemokine regulation and support the hypothesis that individual
chemokines fulfill unique roles during the sepsis cascade.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Protein-free (<0.008%), phenol-water-extracted
Escherichia coli K235 LPS was prepared according to the
method of McIntire et al. (26). Recombinant murine IL-10
and recombinant murine IFN- were provided by DNAX (Palo Alto, CA)
and Genentech (South San Francisco, CA), respectively. Liposomes that
contain either dichloromethylene bisphosphonate
(Cl2MBP; a gift of Boehringher Mannheim,
Mannheim, Germany) or PBS were prepared as described previously
(27).
Mice
C57BL/6J, C3H/OuJ, and C3H/HeJ mice (5–6 wk old) were purchased from The Jackson Laboratories (Bar Harbor, ME). IRF-1-/- and IRF-2-/- mice were generated by targeted mutation as described elsewhere (28). IRF-1+/-, IRF-1-/- and IRF-2+/-, IRF-2-/- breeding pairs, backcrossed to C57BL/6 mice, were provided originally by Dr. Tak Mak (Amgen Institute, Toronto, Canada). The mice used in these studies were the progeny of either homozygotic or heterozygotic matings as detailed elsewhere (29). The genotype of every mouse used in this study was confirmed as detailed previously (29). Stat1-/- and Stat1+/+ mice were kindly provided by Dr. Robert Schrieber (Washington University, St. Louis, MO) (30). Mice were housed in a laminar flow hood in filter-topped cages and were fed standard laboratory chow and acid water ad libitum.
For kinetic analysis of chemokine gene induction in vivo, C57BL/6J mice
were injected i.p. with 25 µg (
1.25–1.4 mg/kg) LPS. In macrophage
depletion studies, C57BL/6J mice were administered 0.2 ml of saline and
Cl2MBP- or PBS-liposomes i.v. 2 days before i.p.
challenge with 25 µg of LPS. In each experiment, four to five mice
were used per timepoint for each treatment. Previous studies have shown
that i.v. injection of Cl2MBP-liposomes
selectively depletes macrophages from the liver and the splenic red
pulp (27, 31, 32). Macrophage depletion was confirmed as
detailed previously (27, 33).
Macrophage isolation and culture conditions
Peritoneal exudate macrophages were harvested by peritoneal lavage from mice 4 days after i.p. injection with 3 ml of sterile 3% thioglycollate broth. The cells were washed and resuspended in RPMI 1640 supplemented with 2% FCS, 7.5% sodium bicarbonate, 10 mM HEPES, 2 mM glutamine, and 100 U/ml penicillin-100 µg/ml streptomycin. For culture supernatants and isolation of RNA, cells were plated in six-well plates at a final concentration of 4 x 106 cells/well in 2 ml of medium. Following overnight incubation at 37°C, nonadherent cells were removed by washing, and adherent monolayers were treated in a final volume of 2 ml as indicated. Macrophage culture supernatants were harvested at indicated time points and stored at -70°C until analyzed by ELISA. Remaining adherent monolayers were used for RNA isolation as detailed below.
Chemokine ELISAs
Mice were bled by cardiac puncture at the indicated times after
LPS challenge. Serum was collected and stored at -70°C. JE/MCP-1,
MIP-1, and MIP-2 in serum and macrophage culture supernatants were
measured by ELISA (R&D Systems, Minneapolis, MN) according to the
manufacturer’s instructions. KC was measured in macrophage culture
supernatants by ELISA using matched Ab pairs (rat anti-mouse KC
IgG2A (1 µg/ml) and biotinylated goat anti-mouse KC IgG (0.5
µg/ml); R&D Systems) according to the manufacturer’s instructions.
The lower limit of detection for JE/MCP-1, MIP-1, MIP-2, and KC was
15.6, 4.7, 7.8, and 15.6 pg/ml, respectively.
Analysis of mRNA by RT-PCR
For peritoneal macrophage cultures, supernatants were removed after treatment and cells were lysed with RNA Stat-60 (Tel-Test, Friendswood, TX). For in vivo studies, organ tissue was harvested at indicated time points following treatment, frozen at -70°C, and later homogenized in RNA Stat-60. Total RNA was isolated as specified by the manufacturer and the concentration of RNA was determined by spectrophotometric analysis. The relative quantities of mRNA for each gene of interest was assessed by RT-PCR, followed by Southern blot analysis and detection by chemiluminescence, as detailed previously (34). The sequences for the PCR primers and probes used have been detailed elsewhere (25, 34, 35). The optimal cycle number for each gene in which detectable PCR-amplified product was achieved under nonsaturating conditions was determined empirically. Normalization for the relative quantity of mRNA was accomplished by comparison to either GAPDH or hypoxanthine-guanine phosphoribosyl transferase (HPRT), as previously described (34, 36). Increases in mRNA were expressed as mean-fold induction relative to untreated controls, which were arbitrarily assigned a value of 1. This precludes comparison of basal gene expression between organs, as well as among the different genes analyzed.
Statistics
Comparisons between two groups were analyzed using paired Student’s t test or ANOVA. The accepted level of significance was p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To establish the time course of induction of chemokine genes in
response to LPS, peritoneal macrophages from LPS-responsive C3H/OuJ
mice were incubated with 200 ng/ml LPS from 0.5 to 48 h, and
steady-state mRNA expression was measured by RT-PCR. Fig. 1
shows that mRNA expression of all
chemokines, except RANTES, was induced 2- to 20-fold as early as
0.5 h after LPS treatment. Induction of RANTES mRNA above basal
levels was not observed until 2 h post-LPS. KC, MIP-2, and
MIP-1 mRNA reached peak levels (
15- to 60-fold) as early as 1–2
h after LPS treatment, while IP-10, MIP-1, RANTES, JE/MCP-1, and
MCP-5 mRNA required 6 h before peak levels (10- to 90-fold)
were achieved. In general, CXC and CC chemokine mRNA expression
remained sustained for 48 h, with only a gradual decline in
steady-state mRNA from peak levels. Steady-state mRNA expression for
all of the CXC and CC chemokines was induced over basal levels by as
little as 0.1 ng/ml LPS, and maximal mRNA expression was achieved with
1–10 ng/ml LPS (data not shown).
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Several studies have demonstrated the ability of IL-10 to
down-regulate LPS-inducible mRNA expression of proinflammatory
cytokines (IFN-, IL-1, IL-6, IL-12, and TNF-)
(37, 38, 39, 40) and chemokines (IP-10, KC, MIP-1, and
MIP-1) (41, 42, 43, 44) in macrophages. To determine whether
the expression of different chemokine genes might be variably sensitive
to IL-10, C3H/OuJ macrophages were incubated for 6 h with medium
alone or 0.1–100 ng/ml LPS in the absence or presence of IL-10 (100
U/ml). Fig. 2 depicts representative
Southern blots illustrating the suppressive effect of IL-10 on
LPS-induced MIP-2, JE/MCP-1, and MCP-5 mRNA expression. The ability of
IL-10 to down-regulate the LPS-induced mRNA expression proved to be a
generalized effect observed for the entire panel of chemokines,
although certain chemokine genes, e.g., MIP-1 and RANTES, were less
sensitive to inhibition (Fig. 2 and data not shown). While the
inhibitory capacity of IL-10 was evident over a range of LPS doses, the
most dramatic reductions (10- to 80-fold) were observed at lower
doses of LPS (0.1 and 1 ng/ml). The inhibitory effects of IL-10 were
confirmed at the level of protein production for MIP-2 and JE/MCP-1
(Table I).
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Like LPS, IFN- serves as a potent activating factor of
macrophages. Although IFN- has been shown to interact
synergistically with LPS to induce the mRNA for inflammatory mediators
like TNF- and inducible NO synthase (34, 45, 46), it
also has been shown to suppress LPS-induced mRNA of other inflammatory
mediators like MIP-1, MIP-1, JE/MCP-1, and KC (43).
To investigate further the effect of IFN- on the panel of chemokines
in this study, C3H/OuJ macrophages were incubated for 6 h with
medium alone or LPS (1 ng/ml) in the absence or presence of IFN- (5
U/ml). Of the eight chemokine genes evaluated, treatment with IFN-
alone was capable of inducing only MCP-5 (20- to 25-fold) and IP-10
(14-fold) mRNA expression (Fig. 3).
IFN- inhibited LPS-induced MIP-1 and KC mRNA (60–70%)
and both mRNA and protein for MIP-1, JE/MCP-1, and MIP-2 (Fig. 3 and Table II). In contrast, LPS-induced
mRNA levels of RANTES, MCP-5, and IP-10 were unaffected by simultaneous
treatment with IFN-.
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is
Stat1 dependent
IP-10 and MCP-5 were the only two chemokine genes that were
inducible by either IFN- or LPS alone. Because IFN--mediated
responses use activated Stat1 as a major transactivating factor, we
sought to evaluate the role of Stat1 in LPS-induced chemokine gene
expression. Thus, macrophages derived from wild-type and Stat1 knockout
mice were compared for their ability to respond to LPS or LPS and
IFN-. Of the eight chemokine genes examined, only LPS-induced IP-10
and MCP-5 mRNA expression was markedly abrogated in macrophages from
Stat1-/- mice, while the other genes, like
RANTES, were unchanged (Fig. 4). These
data suggest a key role for Stat1 in the induction of IP-10 and
MCP-5.
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-mediated inhibition of LPS-induced KC mRNA is dependent on
IRF-2
The availability of mice deficient in the IFN-responsive
transcription factor genes, IRF-1 and IRF-2, provided an opportunity to
assess the role of these factors in the suppressive activity of IFN-
on selected chemokine genes. Peritoneal macrophages from
IRF-1+/+ or IRF-1-/- or
IRF-2+/+ or IRF-2-/- mice
were incubated for 6 h with medium alone or LPS (1 ng/ml) in the
absence or presence of IFN- (5 U/ml). Induction of chemokine mRNA by
LPS was neither IRF-1 nor IRF-2 dependent (data not shown). However,
the ability of IFN- to suppress KC gene expression was entirely lost
in macrophages from IRF-2-/- mice, while
suppression of the other IFN--sensitive chemokine genes (e.g.,
JE/MCP-1, MIP-2, MIP-1, and MIP-1) was unaffected by deletion of
either gene (Fig. 5). Specifically,
IFN- inhibited the LPS-induced KC mRNA expression (72–84%) in
IRF-2+/+ macrophages, while KC mRNA levels in
IRF-2-/- macrophages were reduced only
slightly. This derepression of LPS-induced KC mRNA by IFN- observed
in IRF-2-/- macrophages was accompanied by
elevated levels of KC protein in culture supernatants (Table III). In contrast, the IFN--mediated
inhibition of LPS-induced JE/MCP-1, MIP-2, MIP-1, and MIP-1 mRNA
was not reversed in IRF-1-/- or
IRF-2-/- macrophages (Fig. 5 and data not
shown). These data support a role for IRF-2 in IFN--mediated
inhibition of LPS-induced KC mRNA.
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To determine whether the pattern of LPS-inducible chemokines
observed in vitro paralleled their induction in major shock organs, we
measured the kinetics of hepatic chemokine mRNA expression in response
to LPS (Fig. 6; open bars). All chemokine
genes except RANTES were rapidly induced in the liver within 1 h
of LPS challenge, and most reached peak levels (50- to 100-fold)
within 3 h of LPS administration. LPS-induced RANTES mRNA was
delayed (3 h) and increased only 20-fold. The kinetics of
LPS-induced chemokine mRNA expression in the lung generally paralleled
that observed in the liver, although reduced levels of pulmonary
chemokine mRNA expression were observed for MIP-1 and MCP-5 (data
not shown). Fig. 7 illustrates that
MIP-2, JE/MCP-1, and MIP-1 were rapidly and substantially elevated
in the serum within 1 h of LPS administration. Not only was the
magnitude of JE/MCP-1 production the most profound, but it remained
substantially elevated over baseline 48 h after LPS.
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clearly shows that systemic administration
of LPS to mice induces chemokine gene expression in the liver, the
precise cell types that participate have not been clearly defined. To
determine whether the Kupffer cell, the resident hepatic
macrophage, is a predominant source of chemokines under these
circumstances, we examined chemokine mRNA expression in livers from
mice selectively depleted of Kupffer cells following i.v.
administration of Cl2MBP-liposomes (27, 32, 33, 47). Fig. 6 (solid bars) illustrates that induction of
MIP-1, MIP-1, RANTES, and MCP-5 mRNA by LPS was reduced by
80–97% in the liver of Kupffer cell-depleted mice when compared with
saline-pretreated, LPS-challenged control mice, indicating that
macrophages and/or their secreted products are largely responsible for
the expression of these genes in response to LPS. In contrast, the
LPS-induction of MIP-2, IP-10, and JE/MCP-1 in the livers of
macrophage-depleted mice were not reduced, but rather exhibited modest
elevation 1–3 h after LPS challenge compared with control mice.
However, by 6 h after LPS the level of MIP-2 mRNA from
macrophage-depleted mice was reduced by 90%. The LPS-induction of
KC in both treatment groups remained largely unaffected until 6 h
after LPS when a slight decrease in mRNA from macrophage-depleted mice
was detected. Because i.v. administration of
Cl2MBP-liposomes does not deplete pulmonary
macrophages (27), chemokine mRNA expression in the lung
was not examined. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because the interaction of LPS with macrophages is pivotal in eliciting
the proinflammatory cascade associated with sepsis (48, 49), we initially focused on a characterization of the
regulation of LPS-induced chemokine gene expression in macrophage
cultures. We sought to identify stimuli (both pro- and
antiinflammatory) in vitro that might account for differential
expression in vivo. Furthermore, we wished to determine potential
mechanisms operating in vivo that might account for distinct patterns
of expression and/or function. Kinetic analyses of macrophage mRNA
indicates that LPS rapidly induced (0.5 h) chemokine mRNA expression
for all genes except RANTES (2 h), and, in contrast to the transient
expression exhibited by most LPS-inducible early genes (36, 40, 50), chemokine steady-state mRNA levels remained elevated for
48 h. KC and MIP-2 both exhibited early (1–2 h) peak levels of
mRNA expression, consistent with their role in the recruitment of
neutrophils, the first leukocyte population to arrive at a site of
inflammation. Likewise, chemokines responsible for recruiting
subsequent leukocyte infiltrates, i.e., monocytes and T lymphocytes
(i.e., IP-10, JE/MCP-1, MCP-5, MIP-1, and RANTES), all exhibited
delayed (6 h) peaks of mRNA expression. Thus, temporal regulation of
macrophage chemokine expression may, in part, contribute to the
sequence of inflammatory cell types that enter an inflamed
site.
IL-10 is among the most potent antiinflammatory agents induced in
response to LPS (reviewed in Refs. 51 and
52)]. The protective role of endogenous IL-10 in
endotoxicity and sepsis is underscored by the increased lethality
following neutralization of IL-10 in mice (23) and by the
ability of exogenous IL-10 administration to prevent lethal shock in
mice (53, 54). The antiinflammatory action of IL-10 has
been attributed to its ability to inhibit transcription, to promote
degradation of mRNA, and/or to reduce translation of numerous
proinflammatory cytokines and chemokines (37, 41, 42, 55, 56). However, it has been recently demonstrated that IL-10 may
suppress gene expression in stimulus-selective fashion
(44) and we wished to determine whether differential
sensitivity to IL-10 might be an important mechanism for generating
differential expression of various chemokines. The LPS-induced
chemokines previously reported to be sensitive to IL-10 inhibition
include IP-10, KC, MIP-1, and MIP-1 (41, 44). Our
present findings confirm these observations and further demonstrate
that IL-10 also inhibits LPS-induced MIP-2, JE/MCP-1, MCP-5, and RANTES
mRNA expression, although RANTES and MIP-1 were considerably less
sensitive to inhibition by IL-10, particularly at higher doses of LPS.
Collectively, these findings support a novel role for IL-10 as a key
antiinflammatory agent in vivo: As a result of IL-10’s inhibition of
the panel of eight LPS-induced chemokine genes examined, leukocyte
infiltration (and subsequent release of proinflammatory mediators) into
tissues would likely be attenuated.
In contrast to the broad antiinflammatory actions of IL-10, IFN- is
generally considered to be a potent macrophage activator that interacts
synergistically with LPS to induce inflammatory mediators like TNF-
and iNOS (34, 45, 46), in addition to enhancing
LPS-induced lethality (57, 58, 59). LPS-induced MCP-5 and
IP-10, genes which are inducible by IFN- alone, and RANTES were
unaffected by cotreatment with LPS and IFN-. However, IFN- has
been shown to antagonize induction of JE/MCP-1, KC, MIP-1, and
MIP-1 gene expression in LPS-stimulated macrophages (43, 60), and the present study extends this to include MIP-2. Thus,
the differential action of IFN- on individual chemokine genes
provides an example of selective stimulus sensitivity that may be
important in mediating the highly restricted patterns of chemokine gene
expression noted in vivo.
The availability of mice in which transcription factors that mediate
responses to IFNs have been deleted by gene targeting provides the
opportunity to explore further the mechanisms involved in the
regulation of LPS-induced chemokine expression. Activated Stat1
homodimers are the primary transcriptional activation complex formed by
IFN--stimulated cells and are necessary for the expression of IP-10
in response to IFN- (61). Because IP-10 and MCP-5 are
inducible with either IFN- or LPS, we wished to determine whether
Stat1 were also necessary for chemokine expression in response to LPS.
Analysis of the LPS inducibility of all of the chemokine genes examined
revealed that only IP-10 and MCP-5 were strongly dependent on Stat1 for
their induction by LPS.
Both IFN- and LPS also activate expression of two other
well-characterized IFN-responsive DNA binding proteins, IRF-1 and IRF-2
(36, 62). IRF-1 serves predominantly as a transcriptional
activator (63), whereas IRF-2 functions generally as a
transcriptional repressor (64, 65, 66). Although neither IRF-1
nor IRF-2 were required for induction of the chemokine genes examined,
our studies also revealed a novel role for IRF-2 in the
IFN--mediated inhibition of LPS-induced KC, but not of other
IFN--inhibitable genes. Promoter analysis of the murine KC gene has
revealed two NF-
B motifs that allow for its induction by LPS;
however, no functional IFN-responsive regulatory sequences have been
defined (67). Nevertheless, it is possible that the
requirement for IRF-2 in negative transcriptional regulation of the KC
gene by IFN- is not mediated through interaction with an
IFN-responsive sequence motif. In support of this possibility is the
recent finding that both IRF-1 and IRF-2 can interact with NF-B to
control the transcriptional regulation of the MHC class I gene
(68), as well as others. Even though KC was the only
LPS-inducible chemokine gene to exhibit IRF-2-dependent,
IFN--mediated inhibition, it is not the only gene that we have found
to exhibit this pattern of regulation: IFN--mediated suppression of
LPS-induced IL-12 p35 mRNA expression is also derepressed in
macrophages derived from IRF-2-/- mice
(69). The molecular basis for the role of IRF-2 in this
process will require further analysis. Nonetheless, the finding that no
other IFN--inhibited, LPS-induced chemokine gene was regulated by
either IRF-1 and IRF-2 further highlights the exquisite differential
regulation of these genes.
Our in vivo results demonstrate that the entire panel of CXC and CC
chemokines (with the exception of RANTES) were also rapidly induced in
the lung and liver after LPS administration. The pattern of chemokine
mRNA induction that we observed in the tissue following LPS challenge
was paralleled by rapid and sustained production of chemokines (i.e.,
JE/MCP-1, MIP-1, and MIP-2) in the serum (Figs. 6 and 7). Although
elevated serum chemokine levels may be required to sustain leukocyte
mobilization from the circulation, as well as from the bone marrow,
over the duration of an inflammatory response, the profoundly elevated
and sustained levels of JE/MCP-1 in the serum may reflect its recently
discovered role as an antiinflammatory mediator (20).
Although the influx of neutrophils typically precedes that of monocytes
and lymphocytes into tissues (24), our in vivo data do not
support the hypothesis that this process is regulated by production of
neutrophil chemoattractants before production of monocyte and
lymphocyte chemoattractants, as suggested by our in vitro data that
demonstrated a temporal staggering of neutrophil vs monocyte
chemoattractant mRNA expression. Thus, the rapid influx of neutrophils
to the site of inflammation is likely to be controlled by additional
factors such as the relative abundance of neutrophils in the
bloodstream or the differential modulation of other mediators of
cellular trafficking, such as adhesion molecules and chemokine
receptors.
The selective depletion of Kupffer cells by
Cl2MBP-liposome treatment (27, 32, 33, 47) allowed us to assess the relative contribution of
macrophages in the induction of chemokine mRNA in the liver following
LPS challenge. To our knowledge, Fig. 6 provides the first direct
evidence that macrophages and/or their secreted products contribute
significantly to the induction of MIP-1, MIP-1, RANTES, and MCP-5
mRNA in the liver following LPS challenge. The observation that
macrophages are the major source of certain chemokines is consistent
with a previous report that identified macrophages as the primary
source of MIP-1 in the lungs of LPS-challenged mice
(24). Conversely, cell types apart from Kupffer cells
produce IP-10, JE/MCP-1, KC, and MIP-2 mRNA in the livers of
LPS-challenged, macrophage-depleted mice. The observed elevated
expression of IP-10, JE/MCP-1, and MIP-2 mRNA in macrophage-depleted
mice may reflect the absence of a negative regulator like IL-10, which
is ablated in the liver by macrophage depletion (33).
In summary, we have identified molecular and cellular mechanisms that may contribute to differential patterns of chemokine expression in vivo. The specific pattern of expression of each individual chemokine is likely to reflect its unique function in the regulation and progression of an inflammatory response. The complex orchestration of chemokines in response to LPS highlights the necessity for understanding the timing and localization of chemokine expression and production to identify potential targets for therapeutic intervention.
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Acknowledgments |
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Footnotes |
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2 This work was conducted by K.M.K. in partial fulfillment of the requirements for the Ph.D. degree from the Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences.
3 Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. E-mail address:
4 Abbreviations used in this paper: MIP, macrophage inflammatory protein; IP-10, IFN- inducible protein; MCP, monocyte chemoattractant protein; IRF, IFN regulatory factor; Cl2MBP, dichloromethylene bisphosphonate; HPRT, hypoxanthine-guanine phosphoribosyl transferase.
Received for publication June 8, 1998. Accepted for publication May 14, 1999.
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A. E. Medvedev, K. M. Kopydlowski, and S. N. Vogel Inhibition of Lipopolysaccharide-Induced Signal Transduction in Endotoxin-Tolerized Mouse Macrophages: Dysregulation of Cytokine, Chemokine, and Toll-Like Receptor 2 and 4 Gene Expression J. Immunol., June 1, 2000; 164(11): 5564 - 5574. [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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 Z.-M. Wang, C. Liu, and R. Dziarski Chemokines Are the Main Proinflammatory Mediators in Human Monocytes Activated by Staphylococcus aureus, Peptidoglycan, and Endotoxin J. Biol. Chem., June 30, 2000; 275(27): 20260 - 20267. [Abstract] [Full Text] [PDF]
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E. Trogan, R. P. Choudhury, H. M. Dansky, J. X. Rong, J. L. Breslow, and E. A. Fisher Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice PNAS, February 19, 2002; 99(4): 2234 - 2239. [Abstract] [Full Text] [PDF]
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L. H. K. Lim, B. S. Bochner, and E. M. Wagner Leukocyte recruitment in the airways: an intravital microscopic study of rat tracheal microcirculation Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L959 - L967. [Abstract] [Full Text] [PDF]
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