1 Environmental Energies
Technologies Division, The cell adhesion molecule intercellular adhesion molecule-1
(ICAM-1) plays a pivotal role in inflammatory responses. Quercetin (3,3',4',5,7-pentahydroxyflavone), a naturally occurring
dietary flavonol, has potent anti-inflammatory properties. The effect of quercetin on ICAM-1 expression induced by agonists phorbol 12-myristate 13-acetate (PMA) and tumor necrosis factor-
flavonoids; intercellular adhesion molecule-1; activator protein-1; kinases; inflammation; c-Jun amino-terminal kinase
THE ADHESION OF LEUKOCYTES to the vascular endothelial
cells is a critical step in the inflammatory response and involves recruitment and infiltration of leukocytes to the site of tissue injury, infection, or lesion formation. These processes are mediated by
a wide variety of adhesion molecules. Intercellular adhesion molecule-1
(ICAM-1, CD54) expressed on endothelial cells is one of the major cell
surface glycoproteins that contribute to the cell adhesion processes
(7). Although ICAM-1 is constitutively expressed on endothelial cells,
it can be significantly induced in response to proinflammatory
mediators such as tumor necrosis factor- Quercetin, a plant flavonoid that occurs naturally, is widely
distributed in fruits and vegetables such as apples, berries, and
onions. The daily intake of various flavonoids has been estimated to be
~23-34 mg, and quercetin constitutes a major fraction of such
intake. It has been estimated that sometimes quercetin may represent as
much as 60% of the total flavonoids consumed (18, 26).
Quercetin, related flavonoids, and plant extracts from tea and ginkgo
have been reported to have various clinically relevant properties such
as antioxidant (40, 42, 45, 48), anti-inflammatory (2, 23), and
tumoricidal activity (3). Furthermore, beneficial associations between
the consumption of quercetin and lower incidences of coronary heart
diseases and stroke have been reported (25, 33). Despite much interest
in the pharmacological activities of flavonoids as anti-inflammatory
agents, only a few studies have investigated the role of flavonoids,
especially quercetin, in the regulation of cell adhesion processes.
The ICAM-1 gene contains several transcription factor binding elements
within the 5'-flanking region that are recognized by proteins of
the nuclear factor- Cells and Cell Culture
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
(TNF-
) in human endothelial cell line ECV304 (ECV) was
investigated. Quercetin treatment downregulated both PMA-
and TNF-
-induced surface expression, as well as the ICAM-1 mRNA
levels, in ECV cells in a dose-dependent (10-50 µM) manner.
Quercetin had no effect on PMA- or TNF-
-induced nuclear factor-
B
(NF-
B) activation. However, under similar conditions a remarkable
dose-dependent downregulation of activator protein-1 (AP-1) activation
was observed. This decrease in AP-1 activation was observed to be
associated with the inhibitory effects of quercetin on the c-Jun
NH2-terminal kinase (JNK) pathway.
These results suggest that quercetin downregulates both PMA- and
TNF-
-induced ICAM-1 expression via inhibiting both AP-1 activation
and the JNK pathway.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
(TNF-
) and
interleukin-1
(44), as well as phorbol 12-myristate 13-acetate (PMA)
(47, 55), oxidants (46), and human immunodeficiency
virus-1 tat proteins (19). Elevated levels of ICAM-1
expression have been shown to be critically involved in the development
of a variety of autoimmune diseases and pathologic inflammatory
disorders, e.g., rheumatoid arthritis, psoriasis, and atherosclerosis
(14, 53). Recently, ICAM-1 expression by tumor cells has been reported
to be a major contributing factor that facilitates metastatic
progression (30). The modulation of ICAM-1 expression is therefore an
important therapeutic target, as shown by the beneficial effects of
anti-ICAM-1 antibodies and other pharmacological agents on the
progression of inflammatory responses in several in vivo studies (1,
5).
B (NF-
B) and activator protein-1 (AP-1)
families (13). Deletion and point mutation studies have demonstrated
that the interaction of transcription factors and these elements is
necessary for the induction of ICAM-1 expression by cytokines or
phorbol ester (13, 22, 46). Activations of NF-
B and AP-1 are known
to occur by distinct pathways both of which are thought to be redox
sensitive (4, 31, 50). The inhibitory effect of flavonoids on the
expression of adhesion molecules has been suggested to be mediated by
downregulation of induced NF-
B activation (23). The role of AP-1 in
mediating the inhibitory effect of flavonoids on agonist-induced
adhesion molecule expression remains to be elucidated. Quercetin and
related flavonoids have been demonstrated to modulate the activities of certain kinases that are critical in the AP-1 signaling pathway (20).
Our aim was to investigate the effect of quercetin on agonist (PMA and
TNF-
)-induced ICAM-1 expression in ECV304 (ECV) human endothelial
cells. Results of this study demonstrate for the first time that at low
concentrations quercetin downregulates both PMA- and TNF-
-induced
ICAM-1 expression in human endothelial cells via inhibition of the
c-Jun NH2-terminal kinase (JNK) pathway.
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
Determination of ICAM-1 Surface Expression
ECV cells were washed twice with Dulbecco's PBS (D-PBS), pH 7.4, and incubated with FITC-labeled ICAM-1 monoclonal antibody (Immunotech, Marseille, France) for 30 min at 4°C. After incubation cells were washed twice with D-PBS and finally resuspended in fresh D-PBS. Expression of ICAM-1 was immediately assayed with the flow cytometer described in the following section. Appropriate isotypic controls were used for background fluorescence in the ICAM-1 assay.Flow cytometric analysis. The fluorescence and light-scattering properties (forward scatter and side scatter) of the cells were determined by using an EPICS-Elite (Coulter, Miami, FL) flow cytometer. Cells with the FITC-conjugated ICAM-1 antibody were excited with a 488-nm argon ion laser, and emission was recorded at 525 nm. In each sample, at least 10,000 gated viable cells were examined. A logarithmic scale was used to measure both background and endothelial cell fluorescence. Background fluorescence was then subtracted from endothelial cell fluorescence, allowing linear comparisons of ICAM-1 expression among various samples.
RNA Isolation and Analysis
Total RNA was extracted from 2-3 × 106 ECV cells with guanidinium isothiocyanate by following the method of Chomczynski and Sacchi (12).Northern blot analysis.
RNA samples (10 µg) were subjected to electrophoresis in 1% (wt/vol)
formaldehyde-agarose gels and transferred to Hybond-N nylon membranes
(Amersham, Piscataway, NJ) overnight in 10× SSC (1.5 M NaCl, 0.15 M sodium citrate, pH 7.0). The RNA was cross-linked to the nylon
membrane by 5 min of UV exposure. Blots were then prehybridized for at
least 1 h at 37°C in 50% formamide, 5× SSC, 0.1% SDS,
5× Denhardt's solution (0.1% BSA, Ficoll, and
polyvinylpyrrolidine), and 100 µg/ml denatured sperm DNA (Life
Technologies). Blots were hybridized at 37°C for 16 h
with human ICAM-1 cDNA probes (R & D systems, Minneapolis, MN). cDNA
probes were labeled with
[-32P] ATP by using
T4 polynucleotide kinase. Blots were washed twice with a wash solution
containing 1× SSC and 0.1% SDS for 10 min at 37°C and twice
with one containing 0.2× SSC and 0.1% SDS for 10 min at
60°C. To normalize mRNA content, the blots were stripped and
reprobed with a radiolabeled human
-actin cDNA probe (R & D Systems).
RT-PCR. Reverse transcription was performed with an RNA PCR kit (Perkin-Elmer). One microgram of total RNA was reverse transcribed to cDNA by following the manufacturer's procedures. Reverse transcription-generated cDNA containing human c-fos, c-jun, and the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene was amplified with specific primers (Clontech, Palo Alto, CA) by PCR as described below. The reaction volume was 50 µl and contained (final concentration) 1× PCR buffer, 0.2 mM (each) deoxynucleotide, 2 mM MgCl2, 2 units of Taq DNA polymerase, 0.5 µM (each) oligonucleotide primers, and reverse transcription products. After an initial denaturation for 2 min at 95°C, 30 cycles of amplification (95°C for 45 s, 65°C for 45 s, and 72°C for 1 min), followed by a 7-min extension at 72°C, were performed.
An aliquot (10 µl) from each PCR mixture was electrophoresed in a 1.7% agarose gel containing 0.2 µg/ml ethidium bromide. The gel was then photographed under ultraviolet transillumination. For quantification, the c-jun and c-fos signals were normalized relative to the corresponding GAPDH signal from the same sample with National Institutes of Health (NIH) Image 1.58b29 software.PKC Activity
Protein kinase C (PKC) activity was determined by 32P incorporation into the PKC-specific peptide substrate (Pro-Leu-Ser-Arg-Thr-Leu-Ser-Val-Ala-Ala-Lys-Lys; Sigma) as described previously (47). The ECV cells (0.1 × 106 cells) were incubated with streptolysin-O (0.3 IU), ATP (250 µM), [Nuclear Extraction and EMSA
Nuclear extracts from ECV cells were prepared from 1 × 106 cells. Electrophoretic mobility shift assays (EMSAs) were performed with double-stranded DNA probes (Santa Cruz Biotechnology, Santa Cruz, CA) corresponding to that for AP-1 (sense strand; 5'-CGCTTGATGACTCAGCCGGAA-3') and NF-JNK Activity
This assay was performed by following the manufacturer's procedures with a c-Jun kinase assay kit (Stratagene, La Jolla, CA). ECV cells (2 × 106 cells) were incubated in the absence or presence of quercetin for 3 h and then activated with 100 nM PMA or 10 ng/ml TNF-Statistical Analyses
All the results reported are means ± SD of at least three independent experiments. Differences between means of groups were determined by Student's t-test and ANOVA. The minimum level of significance was set at P < 0.05. ![]() |
RESULTS |
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ICAM-1 Expression
To determine whether quercetin modulates PMA- and TNF-
|
ICAM-1 mRNA Levels
To characterize the molecular mechanisms underlying the inhibitory effects of quercetin on PMA- and TNF-
|
PMA-Induced PKC Activity
It has been reported that the activation of PKC in response to PMA, but not TNF-
|
ICAM-1 mRNA Stability
To investigate whether the inhibitory effect of quercetin on PKC activity is able to influence the stability of ICAM-1 mRNA in ECV cells, the rate of mRNA degradation was evaluated. The cells were stimulated with PMA alone for 4 h, and then actinomycin D (5 µg/ml) was added to prevent further mRNA synthesis in the absence or presence of quercetin (50 µM). No significant difference in the rates of degradation (half-life ~ 4 h) of ICAM-1 mRNA with or without quercetin was observed (Fig. 4). These results indicate that the inhibitory effect of quercetin on PMA-induced ICAM-1 mRNA expression is not due to the decreased stability of ICAM-1 mRNA.
|
AP-1 and NF-B Activation
|
Expression of c-jun and c-fos
To elucidate mechanisms by which quercetin inhibits AP-1 activity, the effect of quercetin on the induction of c-jun and c-fos in ECV cells was investigated (Fig. 6). RT-PCR measurements showed that c-jun mRNA was remarkably induced in response to the treatment of cells with PMA and that such an increase in c-jun mRNA was prevented in a dose-dependent manner by quercetin pretreatment (Fig. 6). Quercetin did not decrease PMA-induced c-fos mRNA expression. These results indicate that quercetin modulates events that are upstream of the induction of c-jun.
|
Inhibition of the Activation of JNK
JNK is a member of the family of mitogen-activated protein (MAP) kinases, and its activation has been suggested to regulate the induction of c-jun through the phosphorylation of c-Jun (31). The activation of JNK in ECV cells by treatment with PMA or TNF-
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DISCUSSION |
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Recently, several in vivo studies have suggested that plant flavonoids possess potent anti-inflammatory (9, 23) and antioxidant properties. Adhesion molecule ICAM-1 is known to play a central role in the regulation of cellular inflammatory responses (7). Regulation of ICAM-1 gene expression has been related to oxidative stress through specific redox-sensitive transcriptional or posttranscriptional mechanisms (29, 38). Various antioxidants, including flavonoids, have been reported to regulate the expression of adhesion molecules on the cell surface (23, 47). Quercetin is known to have beneficial effects in cardiovascular and circulatory disorders (25) and is one of the most potent antioxidants among dietary flavonoids (45). Several studies have shown recovery of dietary quercetin from plasma, suggesting the bioavailability of this flavonoid (18, 37). Furthermore, because of the long half-life of elimination (~24 h), repeated consumption of quercetin-containing foods has been suggested to cause accumulation of quercetin in blood (28). This study shows for the first time that quercetin is an inhibitor of agonist-induced ICAM-1 protein and mRNA expression.
Treatment of human endothelial cells with certain hydroxyflavones and
flavonols has been reported to inhibit cytokine-induced ICAM-1,
vascular cell adhesion molecule-1, and E-selectin expression in human
endothelial cells (23). For example, apigenin is a flavone that
inhibits adhesion molecule expression in endothelial cells in a dose-
and time-dependent manner. An effect of this flavone at the
transcriptional level has been demonstrated (23). Apigenin also
inhibits TNF--induced ICAM-1 expression in vivo (43). Cell adhesion
regulatory effects of flavonoids are also consistently evident from
other independent studies. The flavonoid delphinidin chloride (CAS
528-53-0, IdB 1056) inhibited acetylcholine- and sodium
nitroprusside-induced adherence of leukocytes to the venular
endothelium in diabetic hamsters (6). The flavonoids 5-methoxyflavanone, and more potently 5-methoxyflavone, downregulated indomethacin-induced leukocyte adherence to mesenteric venules (8).
The inhibition of PMA-induced ICAM-1 expression by quercetin correlated
with decreases in steady-state mRNA levels. Similar inhibitory patterns
of TNF--induced ICAM-1 mRNA expression in ECV cells were observed.
PKC is known to be involved in PMA-induced cell activation pathways.
Upregulation of ICAM-1 mRNA expression by PMA has been reported to be
mainly due to an increase in posttranscriptional stabilization of mRNA
via PKC activity (55). Studies from other laboratories and our
laboratory (not shown) have shown that the PKC inhibitor staurosporine
(50 nM) inhibits PMA-induced ICAM-1 expression (10, 15, 24). Quercetin
treatment downregulated PMA-induced PKC activity in ECV cells. However,
quercetin treatment did not affect the stability of PMA-induced ICAM-1
mRNA. It is not clear whether the modest inhibition of inducible PKC
activity by quercetin would require a comparable change in the
stability of ICAM-1 mRNA.
Activation of NF-B is known to be involved in the regulation of
inducible ICAM-1 gene expression (16, 51, 54). At concentrations up to
50 µM, quercetin had no effect on PMA- or TNF-
-mediated activation
and nuclear translocation of NF-
B. This observation suggests that
quercetin does not affect the activities of kinases that are involved
in nuclear translocation of NF-
B after PMA or TNF-
activation.
AP-1 is another transcription factor that plays an important role in
the induction of the ICAM-1 gene (46, 54). Quercetin prevented PMA- or
TNF-
-mediated activation of AP-1 in the same dose range that is
effective in downregulating the induced ICAM-1 mRNA expression. AP-1
transcription factors consist of homodimers and heterodimers of Jun and
Fos and protein products of their related gene family (31). The
antibody-clearing and supershift assays confirmed the presence of c-Fos
and c-Jun in the activated AP-1 complex. Both PMA and TNF-
are known
inducers of c-jun and
c-fos expression (31). The inhibitory
effect of quercetin on AP-1 activation may be due to its inhibitory
effects on c-jun expression. Quercetin
has previously been shown to inhibit the expression of
c-jun mRNA (59).
Several members of the MAP kinase family have been reported to regulate
the activation of AP-1 (31). The extracellular signal-regulated kinase
(ERK) stimulates AP-1 activity through induction of c-Fos synthesis.
Fos-regulating kinase increases AP-1 activity by enhancing the
transactivation function of c-Fos. After activation of cells by an
appropriate stimulus, JNK phosphorylates c-Jun and activating factor-2,
which are involved in the induction of the
c-jun protooncogene (31). In addition
to the activation of c-jun expression,
JNK also enhances the DNA-binding activity of AP-1 by phosphorylating the activation domain of c-Jun (31). JNK is known to be activated in
response to a wide variety of extracellular signals such as TNF-,
interleukin-1
, PMA,
H2O2,
hypertension, shear stress, ischemia-reperfusion, and UV (11,
21, 27, 32, 34, 36, 52, 56, 57). The specific inhibitory effect of
quercetin on c-jun mRNA and JNK
activity observed in this study suggests that quercetin regulates AP-1
activation by modulating JNK activity. No effect of quercetin on
c-fos mRNA induction suggests that
ERK, known to regulate the expression of c-Fos, is not involved in mediating the inhibitory effect of quercetin on ICAM-1 mRNA expression.
The induction of ICAM-1 expression in human endothelial cells by PMA
and TNF- is known to occur via distinct pathways (41, 55). Results
of this study show that both TNF-
and PMA activated signaling
pathways leading to the activation of NF-
B and AP-1. It is apparent
that MAP kinase/ERK kinase kinase-1 (MEKK1), functional upstream of JNK, activates I
B phosphorylation, which is involved in
NF-
B activation (35). However, the activities of JNK and ERK are not
required for NF-
B translocation (39). A specific inhibitory effect
of quercetin on JNK activity suggests that the flavonol regulated JNK
activity through either direct interaction with the kinase or
downregulation of upstream kinases, such as MKK4/SEK1 and MKK7, which
are known to activate JNK directly by catalyzing phosphorylation (17,
49, 58). Further studies are required to elucidate the precise
mechanism for the specific JNK-inhibitory action of quercetin.
In summary, this study provides evidence for a novel mechanism of
agonist-induced ICAM-1 downregulation by quercetin in a human
endothelial cell line. Our results demonstrate that quercetin downregulates ICAM-1 expression induced by either the PKC activator PMA
or the proinflammatory cytokine TNF-. This effect of quercetin in
part is due to its inhibitory action on AP-1 transactivation induced by
PMA and TNF-
. JNK is involved in such regulation via downregulating
the expression of c-jun mRNA. This
inhibitory effect of quercetin on inducible ICAM-1 expression
represents a mechanism that contributes to the anti-inflammatory
property of this dietary flavonol.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institute of General Medical Sciences Grant GM-27345 and the Ipsen Institute, Paris, France.
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FOOTNOTES |
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H. Kobuchi is on leave from the Center for Adult Diseases, Institute of Medical Sciences, Kurashiki 710, Japan.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. Roy, 251 Life Sciences Addition, Dept. of Molecular and Cell Biology, Univ. of California, Berkeley, CA 94720-3200 (E-mail: sashwati{at}socrates.berkeley.edu).
Received 4 September 1998; accepted in final form 11 May 1999.
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