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,
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Istituto di Patologia Generale, Università degli Studi di Milano, Milan, Italy;
Pharma Division, Preclinical Centre National Scientifique Research, F. Hoffmann-La Roche, Basel, Switzerland;
Department of Biotechnology and Biomedical Sciences, Section of General Pathology and Immunology, University of Brescia, Brescia, Italy;
Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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,
CCL2/monocyte chemotactic protein-1, and the CCL5 receptor CCR1) and
molecules involved in extracellular matrix recognition and digestion
(e.g., CD44 splice transcripts, urokinase-type plasminogen activator
receptor, matrix metalloprotease (MMP)-9 , and MMP-19). Transcript
expression, confirmed by quantitative real-time PCR analysis for
selected genes, was associated with protein induction for some (e.g.,
CCL2), but not all (e.g., IL-1), transcripts examined. The
chemokine-induced gene profile was distinct from that activated by LPS,
a prototypic phagocyte activator. Although certain transcripts were
stimulated by both agonists (e.g., IL-1 and CCL2), others were
induced only by either LPS (e.g., TNF-
and IL-6) or CCL5 (e.g.,
MMP-19) or were divergently regulated (e.g., CCR1). Thus, CCL5, a
prototypic CC inflammatory chemokine, activates a restricted
transcriptional program in monocytes distinct from that induced by the
prototypic pathogen-derived proinflammatory stimulant LPS.
Chemokine-induced chemokines production could represent a novel
amplification loop of leukocyte recruitment, while a subset of
chemokine-inducible transcripts could be involved in monocyte
extravasation and tissue invasion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemokines exert their biological functions through interaction with seven-transmembrane G protein-coupled specific receptors differentially expressed on leukocyte populations (1). Agonist binding causes activation of incompletely defined signaling events, leading to cytoskeleton reorganization and cell movement. There is also evidence that chemokines can regulate functions other than cell adhesion and migration, including cell proliferation and death (4, 5, 6, 7, 8) and cytokine production (9, 10, 11). However, available information on the mode by which chemokines regulate gene expression-dependent functions is fragmentary and conflicting, possibly depending on the presence of costimulatory signals (4, 5, 9, 10). The aim of the present study was to define the gene expression profile of human monocytes exposed to the prototypic inflammatory CC chemokine ligand (CCL)5 5/RANTES and to compare it with a prototypic primary proinflammatory pathogen-derived signal represented by LPS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant human CCL5 was obtained from PeproTech (Rocky Hill, NJ). LPS from Escherichia coli (serotype 055:B5), and all other chemicals not specified were obtained from Sigma-Aldrich (St. Louis, MO).
Cell preparation and stimulation
Human monocytes were obtained from buffy coats of blood healthy donors through the courtesy of the Centro Trasfusionale, Spedali Civili (Brescia, Italy). Blood was washed twice in saline at 200 x g to remove plasma and platelets and stratified on isotonic Ficoll separating solution (Biochrom, Berlin, Germany) at 400 x g for 30 min at room temperature. Mononuclear cells were collected, and monocytes were further purified (>90% pure) by centrifugation at 600 x g for 30 min at room temperature on 46% iso-osmotic Percoll (Amersham Biosciences, Uppsala, Sweden) gradient, as previously described (12). Monocytes were resuspended at 5 x 106/ml in RPMI 1640 medium (Biochrom) supplemented with 2% FCS (HyClone Laboratories, Logan, UT), plated in hydrophobic petriperm dishes (Sigma-Aldrich), and stimulated for indicated time.
Analysis of gene expression profile using oligonucleotide array
Analysis of gene expression was performed with commercial human gene probe arrays displaying 5600 human known genes (HuGeneFL array; Affymetrix, Santa Clara, CA). After cell stimulation, total RNA was prepared using TRIzol reagent (Life Technologies, Gaithersburg, MD) following the manufacturer’s instructions. Sample labeling and processing were performed according to the supplier’s instructions essentially as previously described (13), except that hybridization was performed in 1 x 0.1 M 2-(N-morpholino)ethanesulfonic acid (MES) buffer (MES (pH 6.7), 1 mM NaCl, and 0.01% Triton X-100), and chips were washed using 0.1x MES buffer at 45°C. Data were collected by laser scanning, and pixel levels were analyzed with GeneChip 3.0 software (Affymetrix). Expression values of transcripts scoring as present (according to an internal program algorithm) were normalized, according to the total signal intensity on the chip, and compared. In agreement with the indications of the manufacturer and other users (13), transcripts with a ratio of normalized expression levels between two different experimental conditions >2.0 or <0.5 were regarded as modulated in the single experiment under evaluation. We considered a gene as CCL5-responsive if it satisfied these criteria in at least three of four independent experiments with cell preparations from different donors and was not acting in the opposite manner in the fourth experiment.
Quantitation of gene expression by real-time PCR analysis
Total RNA was prepared using TRIzol reagent (Life Technologies),
treated with DNase I using the DNA-free kit (Ambion, Austin, TX), and
reverse transcribed for 1 h at 42°C using an
oligo(dT)12–18 primer (Life Technologies) and
the SuperScript II RT kit (Life Technologies). A cDNA amount
corresponding to 100 ng total RNA was boiled for 3 min and quenched on
ice before amplification. Quantitative real-time PCR was performed
using the SYBRGreen PCR core reagents mix (Applied Biosystems, Foster
City, CA) containing 1 x SYBRGreen PCR buffer; 3 mM
MgCl2; 100 µM dATP, dCTP, and dGTP; 200 µM
dUTP; 0.025 U/µl AmpliTaq Gold DNA polymerase; 0.01 U/µl AmpErase
UNG; and 2 pmol/µl gene-specific forward and reverse primers
designated using the Primer Express software (Applied Biosystems,
Foster City, CA) and listed in Table I
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The reaction conditions were as follows: 2 min at 50°C (one cycle),
10 min at 95°C (one cycle), and 15 s at 95°C and 1 min
at 60°C (40 cycles). Gene-specific PCR products were continuously
measured by means of an ABI PRISM 5700 detection system (PerkinElmer,
Norwalk, CT). Samples were normalized using the housekeeping
gene -actin. Five replicates for each experimental point were
performed, and differences were assessed with the two-tailed Student’s
t test. Results are expressed as the relative fold increase
of the stimulated over the control group, which was used as a
calibrator.
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After purification, monocytes were resuspended at 2.5 x
106/ml in RPMI 1640 medium supplemented with 2%
FCS, plated on hydrophobic petriperm dishes, and incubated at 37°C in
5% CO2. After 6-h cell stimulation, supernatants
were collected, and cells were lysed by three cycles of freezing and
thawing. Cytokine concentrations were measured in triplicate for each
sample using sandwich ELISAs based on a rabbit antiserum and a mAb
(5D3-F7) for monocyte chemotactic protein CCL2/MCP-1 (14)
and a biotinylated anti-IL-1 mAb (Endogen, Woburn, MA) for
IL-1 (15).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The gene expression profile activated by the prototypic
inflammatory chemokine CCL5 in human monocytes was analyzed using
oligonucleotide array technology. Fig. 1
shows one experiment in which monocytes purified from healthy donors
were stimulated under nonadherent conditions with 300 ng/ml CCL5 for
2 h. By way of comparison, monocytes were also stimulated for
2 h with 100 ng/ml LPS, a prototypic activation signal for
mononuclear phagocytes. In agreement with previous reports (16, 17), LPS modulated a significant number of genes (
4%),
up-regulating 105 and concomitantly down-regulating 136 transcripts in
the experiment shown (Fig. 1A). As shown in Fig. 1B, monocyte exposure to CCL5 also resulted in the
regulation of transcription of a restricted subset of genes (2%),
with up-regulation of 114 genes and mild inhibition (0.4- to 0.5-fold)
of nine genes in this particular experiment.
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shows
the time course of CCL5-responsive genes, clustered
according to gene function. A first set of stimulated transcripts was
represented by cytokines and their receptors, including IL-1
(9.84 ± 2.92- and 6.34 ± 1.70-fold at 2 and 8 h,
respectively), CCL2 (6.85 ± 4.03- and 7.42 ± 9.90-fold at 2
and 8 h, respectively), CCL3/macrophage inflammatory protein-1
(MIP-1); 2.45 ± 1.07- and 1.62 ± 0.75-fold at 2 and
8 h, respectively), CCL4/MIP-1 (3.29 ± 1.60- and
2.23 ± 0.56-fold at 2 and 8 h, respectively), and CXC ligand
(CXCL) 8/IL-8 (5.40 ± 4.87- and 2.37 ± 1.97-fold at 2 and
8 h, respectively). Among receptors, the CC chemokine receptor
CCR1 scored as induced (4.71 ± 1.93- and 2.69 ± 1.41-fold
at 2 and 8 h, respectively). A second set of chemokine-inducible
transcripts is related to interaction with and digestion of
extracellular matrix components and includes the urokinase-type
plasminogen activator receptor (uPA-R; 2.07 ± 0.87- and 1.47
± 0.51-fold at 2 and 8 h, respectively), matrix metalloprotease-9
(MMP-9; 1.58 ± 1.17- and 3.40 ± 2.20-fold at 2 and 8
h, respectively), and MMP-19 (2.37 ± 1.31- and 1.81 ±
0.61-fold at 2 and 8 h, respectively). Moreover, CCL5 induced the
appearance of variable region spliced transcripts of the
hyaluronate receptor CD44 (3.61 ± 1.99- and 1.96 ±
1.03-fold at 2 and 8 h, respectively). Other functional sets
included intracellular enzymes (e.g., cytochrome P450 isoform CYP1B1),
cytoskeleton components (e.g., 2-tubulin), and
molecules involved in cell signaling (e.g., mitogen-activated protein
kinase phosphatases) and regulation of gene expression (e.g., cAMP
response element binding protein-2).
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). In most cases gene induction was
detectable at the lowest concentration tested (30 ng/ml) and was
optimal at higher concentrations. Interestingly, despite the fact that
different monocyte donors were used for array and real-time PCR, the
rank order of gene induction was similar, and a significant correlation
(r = 0.876; n = 16) was observed in the
two sets of measurements. Induction of IL-1, CCL2, and uPA-R
transcripts was also confirmed by Northern blot analysis (not
shown). Transcript vs protein induction
Having observed CCL5-mediated transcript stimulation, it was
important to assess whether protein production was, in fact,
stimulated. As shown in Fig. 3A and concordant with mRNA
data, monocyte exposure to 300 ng/ml CCL5 for 6 h resulted in CCL2
secretion, although LPS was a more potent CCL2 inducer (0.14 ±
0.11, 1.23 ± 0.97, and 2.87 ± 1.90 ng/ml for control,
CCL5-treated, and LPS-treated cells, respectively; n =
5). Similarly, CCL5 augmented the percentage of cell adhesion to
hyaluronate recognized by CD44 and the expression of uPA-R (data not
shown). On the contrary, as shown in Fig. 3B, CCL5-induced
IL-1 mRNA was not followed by protein secretion after 6 h of
stimulation, different from what observed with LPS treatment
(0.07 ± 0.03, 0.05 ± 0.02, and 1.64 ± 1.18 ng/ml for
control, CCL5-treated, and LPS-treated cells, respectively;
n = 5). To test whether CCL5 could induce intracellular
accumulation of IL-1, in a second series of experiments (three
donors; not shown) we analyzed the cell lysate, detecting high
concentrations of IL-1 in response to LPS (3.521 ± 0.592
ng/ml), but only minor concentrations with CCL5 (0.043 ± 0.004
ng/ml). Again, CCL5 did not induce IL-1 release, unlike
LPS.
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As shown in Fig. 4, of 105 genes
stimulated by monocyte treatment with 100 ng/ml LPS for 2 h
(quadrants A + B + C), only 21 were
also induced by monocyte treatment with 300 ng/ml CCL5 for 2 h
(quadrant C), including IL-1 (4.51- and 4.53-fold
induction for LPS and CCL5, respectively) and CCL2 (3.73- and 4.36-fold
induction for LPS and CCL5, respectively). LPS stimulated the
expression of a series of cytokines and chemokines that were unaffected
by CCL5, including TNF- (2.60- and 0.69-fold induction for LPS and
CCL5, respectively), IL-6 (4.87- and 1.07-fold induction for LPS and
CCL5, respectively), and CCL23/myeloid progenitor inhibitory factor-1;
6.34- and 1.60-fold induction for LPS and CCL5, respectively).
Similarly, cyclooxigenase-2 was stimulated by LPS, but not by CCL5
(5.22- and 1.21-fold induction, respectively). In this particular
experiment, 72 genes were stimulated by CCL5 but were unaffected by LPS
(Fig. 4, quadrant F), including MMP-19 (0.88- and 2.41-fold
induction for LPS and CCL5, respectively), lectin-like oxidized low
density lipoprotein receptor (1.42- and 2.40-fold induction for LPS and
CCL5, respectively), and the decay-accelerating factor receptor (1.16-
and 2.49-fold induction for LPS and CCL5, respectively), while 21 genes
induced by CCL5 were oppositely regulated by LPS (Fig. 4, quadrant
I), including CCR1 (0.35- and 2.43-fold of induction for LPS
and CCL5, respectively; in agreement with data reported in Ref.
18), and plectin (0.40- and 2.16-fold of induction for LPS
and CCL5, respectively). As expected, LPS was able to down-regulate a
consistent set of genes that resulted unaffected by CCL5 treatment (114
in the experiment shown; Fig. 4, quadrant H), including CCR5
(0.33- and 0.76-fold induction for LPS and CCL5, respectively; in
agreement with data reported in Ref. 18), and the M-CSF
receptor (0.40- and 1.97-fold induction for LPS and CCL5, respectively;
in agreement with data reported in Ref. 16).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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First, induction of selected components, agonists or receptors, of the
cytokine and chemokine systems was observed. Chemokines have been
recently shown to modulate the expression of Th1/Th2-polarizing
cytokines (11, 19, 20, 21). In contrast, the capacity of
chemoattractants to induce proinflammatory cytokines in mononuclear
phagocytes has been the object of inconsistent findings (8, 9, 10, 22). In our experiments CCL5 consistently stimulated IL-1
transcripts, but not other cytokines, such as TNF- and IL-6, that
were strongly induced by LPS as expected. However, IL-1 production
was not observed after CCL5 stimulation despite transcript induction.
It has previously been reported that nonchemokine chemotactic agents
require a second signal (cell adhesion or primary proinflammatory
mediators) for triggering IL-1 production (22). Hence,
chemoattractants prime mononuclear phagocytes for IL-1 production by
inducing transcript expression, and tissue-derived second signal may
induce protein production. CCL5 also stimulated the expression of a
selected set of chemokines with overlapping, but distinct, spectra of
action (1, 2), including CCL2, CCL3, CCL4, and
CXCL8, whose transcript induction (strongest compared with other
chemokines) was associated with protein induction. In addition to
selected agonists, CCL5 also stimulated expression of chemoattractant
receptors, including the C5a receptor and CCR1 (a receptor for CCL3,
CCL5, and CCL7/MCP-3). Therefore, chemokine-induced chemokine
production may set in motion an amplification and diversification
cascade for leukocyte recruitment.
A second set of genes was related to interaction with extracellular matrix components and included spliced CD44, MMP-9, MMP-19, and uPA-R. CD44 variable region splice variants interact with hyaluronate and represent an important mechanism for tissue invasion by leukocytes and metastatic tumor cells (23). The uPA-R is localized at the leading front of migrating cells and allows localized and polarized digestion of extracellular matrix components (24). MMP-19 and MMP-9 hydrolyze basement membrane and extracellular extracellular matrix components, such as fibronectin, laminin, and type IV collagen (25), and have been shown to mediate extravasation and tissue invasion (26). Therefore, the prototypic CC chemokine CCL5 activates a transcriptional program related to cell migration and tissue penetration.
The CCL5-induced genes included the aryl hydrocarbon receptor and the
cytochrome P450 isoform CYP1B1. The epoxide hydrase cytochrome P450
isoform CYP1B1 is the predominant cytochrome P450 isoform expressed in
all mononuclear phagocytes (27). It metabolizes,
among other substrates, estradiol to carcinogenic metabolites and is
involved in the generation of all-trans-retinoic acid, a
regulator of cell differentiation. CYP1B1 is constitutively expressed
in various cell types, and it is inducible by dioxin through aryl
hydrocarbon receptor transcriptional activity (28)
and TNF-, which induces CYP1B1 expression while inhibiting other
cytochrome P450 isoforms (29). Chemokine-mediated
modulation of cytochrome P450 CYP1B1, either directly or indirectly
through aryl hydrocarbon receptor transcriptional activity, could be
one mechanism by which chemokines participate in carcinogenesis
(1) and in the regulation of precursor cell
differentiation (30).
The miscellaneous transcripts stimulated by CCL5 included the lectin-like oxidized low density lipoprotein receptor, which plays a major role in atherogenesis (31). CCR2 and CCL2 gene-targeted mice are protected from the development of atherosclerotic lesions (32, 33). This finding was interpreted in light of the pivotal role of monocyte recruitment in atherosclerosis. It remains to be elucidated whether the chemokine-regulated transcripts described in this study play a role in the pathogenesis of atherosclerosis and cardiovascular diseases.
The results presented in this study show that the prototypic CC chemokine CCL5 activates a restricted transcriptional profile in human mononuclear phagocytes. The chemokine-activated transcriptional profile overlaps with, but is clearly distinct from, that induced by LPS, which is used as a prototypic primary proinflammatory signal. In particular, a set of chemokine-inducible transcripts is related to leukocyte recruitment and could be relevant to prepare monocytes for extravasation and interaction with extracellular matrix components, and chemokine-induced chemokine production may set in motion a novel amplification loop of leukocyte recruitment.
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Acknowledgments |
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Footnotes |
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2 Current address: Lion Bioscience AG, 69120 Heidelberg, Germany.
3 Current address: Dorris Neurological Institute, Scripps Research Institute, La Jolla, CA 92037.
4 Address correspondence and reprint requests to Dr. Alberto Mantovani, Istituto Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail address: mantovani{at}marionegri.it
5 Abbreviations used in this paper: CCL, CC chemokine ligand; MES, 2-(N-morpholino) ethanesulfonic acid; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; MMP, matrix metalloprotease; CXCL, CXC chemokine ligand; uPA-R, urokinase-type plasminogen activator receptor.
Received for publication May 14, 2001. Accepted for publication January 30, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is mediated by the chemokine receptor CXCR4. Curr. Biol. 8:595.[Medline]
+ dendritic cells. Nat. Immunol. 1:83.[Medline]
: quantitation of IL 1 and inhibition of biological activity. J. Immunol. 138:4236.[Abstract]
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) and after 2 h (
) and
8 h (
) of treatment with CCL5/RANTES are shown. Results
represent the mean value of four independent experiments.
