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B
*
Glomerular Bioengineering Unit, Department of Medicine, University College
London Medical School, London
Division of Renal and Inflammatory Disease, School of Medical and Surgical
Sciences, University Hospital, Nottingham, United Kingdom.
Correspondence to Dr. Masanori Kitamura, Department of Medicine, University College London Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ, United Kingdom. Phone: +44 171 209 6191; Fax: +44 171 209 6211; E-mail: m.kitamura{at}medicine.ucl.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B
(NF-B) and activator protein-1 (AP-1), were examined. Exposure of the
cells to IL-1ß caused activation of NF-B without significant
upregulation of AP-1 activity. NF-B inhibitor MG132 diminished the
IL-1-induced expression of MCP-1 in mesangial cells and isolated glomeruli,
whereas c-Jun/Ap-1 inhibitor curcumin did not affect this process.
Consistently, NF-B-inactive mesangial cells expressing a
super-repressor mutant of IB
showed blunted expression of MCP-1
by IL-1ß. In contrast, AP-1-inactive mesangial cells expressing a
dominant-negative mutant of c-Jun exhibited the same level of MCP-1 mRNA as
that in control cells. These results suggest that: (1) quercetin has
the ability to attenuate activation of NF-B; and (2) it
inhibits IL-1-triggered MCP-1 expression via suppression of NF-B, but
not AP-1, in glomerular cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Flavonoids are semi-essential food components that are ubiquitously present in nature. These constituents of the diet are important in the maintenance of the body. Clinically relevant functions ascribed to flavonoids include antihypertensive activity, anti-inflammatory properties, hypocholesterolemic activity, and platelet stabilization (9). Quercetin is one of the most widely distributed flavonoids in the plant kingdom. Previous reports have shown that quercetin may affect various signaling pathways mediated by protein tyrosine kinases, cAMP-dependent kinase, protein kinase C, and calmodulin-dependent kinase (9).
Several signaling pathways have been proposed for the transcriptional
regulation of MCP-1. The 5' flanking region of the MCP-1 gene contains
multiple 12-o-tetradecanoylphorbol-13-acetate response elements (TRE)
and B sites (10,
11,
12), suggesting potential
roles of activator protein-1 (AP-1) and nuclear factor-B (NF-B).
Indeed, activation of AP-1 is required for induction of MCP-1 by growth
factors, lipopolysacharide, and mechanical stress in osteoblastic cells,
macrophages, and vascular endothelial cells, respectively
(13,
14,
15). In tumor cells,
fibroblasts, and mesangial cells, activation of NF-B is essential for
the induction of MCP-1 by interleukin-1ß (IL-1ß), tumor necrosis
factor- (TNF-), and
12-O-tetradecanoylphorbol-13-acetate
(10,16,17).
In endothelial cells, NF-B and AP-1 cooperatively upregulate expression
of MCP-1 in response to IL-1ß
(18). To explore molecular
mechanisms involved in the suppressive effect of quercetin on MCP-1, the
present study investigated: (1) whether NF-B and AP-1 are
required for the induction of MCP-1 by IL-1ß; and (2) how
quercetin modulates the activity of these transcription factors in glomerular
cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Stable Transfectants
SM/JUNDN1 cells in which AP-1 is selectively inactivated were established
by stable transfection of SM43 mesangial cells with a dominant-negative mutant
of c-jun, TAM-67
(21). TAM-67 is a deletion
mutant that is lacking amino acids 3 to 122 of c-Jun
(22). The protein encoded by
this truncated c-jun gene retains the DNA binding and leucine zipper
domains but lacks the transactivating domain. Overexpression of TAM-67,
therefore, inhibits AP-1-mediated transactivation via blocking formation or
binding of functional AP-1 complexes in a dominant-negative manner
(22). SM/JUNDN1 cells exhibit
depressed activity of AP-1 under both basal and stimulated conditions
(21).
SM/IBM cells in which NF-B is selectively inactivated
were established as follows. pLIBMSN
(23), which introduces a
superrepressor mutant of IB (IBM) and a neomycin
phosphotransferase gene (neo), was transfected into a helper-free
ecotropic packaging line, 
E
(19). Stable transfectants
were selected in the presence of neomycin analogue G418 (500 µg/ml).
Conditioned media of the transfectants were used as sources of the
IBM retrovirus. In the presence of 10 µg/ml polybrene, SM43
mesangial cells were exposed to diluted retrovirus, as described before
(19). Stable infectants were
selected in the presence of G418 (750 µg/ml), and SM/IBM
cells were established. SM/IBM cells exhibit blunted activation
of NF-B when stimulated by proinflammatory cytokines IL-1ß and
TNF- (24).
As a control, mock-transfected mesangial cells SM/Neo that express neo alone were created, as described previously (25).
Pharmacologic Manipulations
Confluent mesangial cells cultured in the presence of 1% FCS for 24 to 48 h
were treated by recombinant human IL-1ß (10 ng/ml; Otsuka Pharmaceutical
Co., Tokushima, Japan) for 8 to 24 h. To examine effects of pharmacologic
agents, mesangial cells were pretreated with quercetin (1 to 100 µM; Sigma
Immunochemicals, St. Louis, MO), c-Jun/AP-1 inhibitor curcumin (10 to 20
µM; Sigma) (25), or
NF-B inhibitors N-acetylcysteine (5 to 10 mM; Sigma)
(26) and MG132 (25 to 50
µM; Peptide Institute, Osaka, Japan)
(27) for 1.5 h and stimulated
by IL-1ß for 8 to 24 h.
Isolated glomeruli were suspended in 1% FCS, stimulated by IL-1ß (10 ng/ml) for 6 h in the presence or absence of quercetin (50 µM) or MG132 (50 µM), and subjected to Northern blot analysis.
Northern Blot Analysis
Total RNA was extracted by a single-step method
(28) and subjected to Northern
blot analysis, as described before
(14). In brief, RNA samples
were electrophoresed on 1.2% agarose gels containing 10% formaldehyde and
transferred onto nitrocellulose membranes. As probes, a mouse
JE/MCP-1 cDNA (29)
and a rat glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA
(30) were labeled with
32P-dCTP using the random priming method. The membranes were
hybridized with probes at 65°C overnight in a solution containing
4xSSC (600 mM sodium chloride, 60 mM sodium citrate), 5x
Denhardt's solution, 10% dextran sulfate, 50 µg/ml herring sperm DNA, and
50 µg/ml poly(A), washed at 50°C, and exposed to Kodak XAR films at
-80°C.
Transient Transfection
AP-1 binds to the particular cis element TRE and triggers
transcription of target genes. To evaluate the activity of AP-1 in mesangial
cells, a transient transfection assay was used
(31). In brief, using the
calcium phosphate coprecipitation method, mesangial cells cultured in 24-well
plates (1.0 to 1.2 x 105/well) were transfected with a
reporter plasmid pTRE-LacZ (a gift from Dr. A. Alberts, Imperial Cancer
Research Fund, United Kingdom)
(32) or a control plasmid
pCI-ßgal (a gift from Promega, Madison, WI) at 0.3 to 0.5 µg per well.
pTRE-LacZ introduces a ß-galactosidase gene (lacZ) under the
control of TRE. pCI-ßgal introduces lacZ under the control of
the immediate-early enhancer/promoter of human cytomegalovirus. After
incubation for 48 h in 10% FCS with or without quercetin (50 µM), cells
were subjected to 5-bromo-4-chloro-3-indolyl ß-D-galactopyranoside
(X-gal) assay, as described below. To examine the effect of quercetin on the
activity of TRE in IL-1-stimulated cells, transfected cells were incubated in
the presence of 1% FCS for 48 h, pretreated with or without quercetin for 1.5
h, and stimulated by IL-1ß (10 ng/ml) for 24 h. Activity of AP-1 was
evaluated by counting X-gal-positive cells in each well
(25). That is, the number of
X-gal-positive cells transfected with pTRE-LacZ was normalized by the number
of positive cells transfected with the control plasmid pCI-ßgal. Assays
were performed in quadruplicate.
Activity of NF-B was similarly assessed by the transient
transfection assay. As described above, mesangial cells were transfected with
pCI-ßgal, a B reporter plasmid pHIVLTRß-gal, or its control
construct pmuHIVLTRß-gal
(33) (gifts from Dr. A.
Rattner, The Weizmann Institute of Science, Rehovot, Israel).
pHIVLTRß-gal introduces lacZ under the control of the HIV
promoter that contains two B motifs. The control plasmid
pmuHIVLTRß-gal contains a B-mutated HIV promoter. NF-B
activity was evaluated by the number of X-gal-positive cells in each group,
which was normalized by the number of positive cells transfected with the
control plasmid pCI-ßgal. Each normalized value of the pHIVLTRß-gal
transfection was then subtracted by the normalized value of the
pmuHIVLTRß-gal transfection, and the resultant value was used as an
indicator of NF-B activity
(25). Assays were performed in
quadruplicate. The transfection efficiency achieved in these studies was
approximately 0.1 to 0.4%.
X-Gal Assay
X-gal assay was performed, as described before
(34). In brief, cells were
fixed in 0.5% glutaraldehyde, 2 mM MgCl2, and 1.25 mM
ethyleneglycol-bis(ß-aminoethyl ether)-N,N'-tetra-acetic
acid in phosphate-buffered saline at room temperature for 10 min and then
incubated at 37°C for 2 to 4 h in a substrate solution containing 1 mg/ml
X-gal, 20 mM K3Fe(CN)6, 20 mM
K4Fe(CN)6·3H2O, 2 mM MgCl2,
0.01% sodium desoxycholate and 0.02% NP-40 in phosphate-buffered saline.
Electrophoretic Mobility Shift Assay
Confluent mesangial cells cultured in 1% FCS for 24 h were pretreated with
or without quercetin for 1.5 h and stimulated by IL-1ß for 4 and 24 h.
After the treatment, cells were harvested on ice, lysed in lysis buffer (10 mM
Hepes, pH 7.9, containing 1.5 mM MgCl2, 10 mM KCl, 50 µM
dithiothreitol, 100 µM phenanthroline, 1 µg/ml pepstatin, 100 µM
1-trans-epoxysuccinyl-leucylamide(4-guanidino)butane, 100 µM
3,4-dichloroisocoumarin, 10 mM NaF, 100 µM sodium orthovanadate, 25 mM
ß-glycerophosphate, and 0.2% [vol/vol] NP-40) for 10 min on ice, and
centrifuged. The pellets were resuspended in extraction buffer (20 mM Hepes,
pH 7.9, containing 420 mM NaCl, 1.5 mM MgCl2, 0.2 mM
ethylenediaminetetra-acetic acid, 25% [vol/vol] glycerol, and 100 µM
dichloroisocoumarin), incubated for 15 min at 4°C, and centrifuged. The
supernatants containing nuclear protein were used for electrophoretic mobility
shift assay to evaluate NF-B activity
(35).
As probes, double-stranded wild-type NF-B (5'-AGT TGA GGG GAC
TTT CCC AGG C-3') and mutant NF-B (5'-AGT TGA
GGC GAC TTT CCC AGG C-3') oligonucleotides were
purchased from Promega. These oligonucleotides were radiolabeled with
[
-32P]ATP by T4 polynucleotide kinase. DNA-binding reactions
were performed in binding reaction buffer (10 mM Tris/HCl, pH 7.5, 100 mM
NaCl, 1 mM ethylenediaminetetra-acetic acid, 4% [vol/vol] glycerol, 5 mM
dithiothreitol, 100 µg/ml nuclease-free bovine serum albumin) containing
the nuclear extract (15 µg), 32P-labeled oligonucleotide probe
(0.14 pmol), and poly(dI-dC) (6 µg). After incubation for 15 min at room
temperature, samples were electrophoresed on native 5% acrylamide gels. After
the electrophoresis, gels were dried and exposed to x-ray film. To confirm the
specificity of the reaction, competition assays were performed with 100-fold
excess of unlabeled wild-type oligonucleotides that were added to the reaction
mixtures 5 min before the addition of the labeled NF-B probe. A
negative control experiment without nuclear extract was also performed in
parallel.
Statistical Analyses
Data were expressed as means ± SEM. Statistical analyses were
performed using the nonparametric Mann-Whitney U test to compare data
in different groups. A P value <0.05 was used to indicate a
statistically significant difference.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effect of quercetin on the expression of MCP-1 was further examined using isolated glomeruli. Isolated glomeruli incubated in 1% FCS exhibited modest MCP-1 expression. Stimulation of glomeruli by IL-1ß markedly enhanced the induction of MCP-1 mRNA. Consistent with the result in cultured mesangial cells, quercetin abrogated the IL-1-induced expression of MCP-1 in isolated glomeruli (Figure 1C).
Effect of Quercetin on the Activity of AP-1 and NF-B
Several signaling molecules including NF-B and AP-1 have been
proposed as transcriptional regulators for MCP-1. To examine the possibility
that quercetin inhibits MCP-1 expression via suppression of these
transcription factors, reporter assays were performed. Serum-stimulated
mesangial cells were transiently transfected with either a B reporter
plasmid or a TRE reporter plasmid, treated with or without quercetin, and
activity of NF-B and AP-1 was evaluated. Under serumstimulated culture
conditions, mesangial cells exhibit constitutive activity of NF-B and
AP-1
(21,25).
Treatment with quercetin significantly inhibited the activity of both
NF-B (33 ± 6% versus untreated control [100%], mean
± SEM, P < 0.05) and AP-1 (49 ± 4% versus
untreated control [100%]) (Figure
2A).
|
We next examined whether IL-1ß induces activation of NF-B and
AP-1, and if so, how quercetin modulates the activation of these transcription
factors. Mesangial cells transfected with reporter plasmids were cultured in
1% FCS, pretreated with quercetin, and stimulated by IL-1ß. X-gal assay
showed that IL-1ß significantly induced activation of NF-B (431
± 41% versus untreated control [100%])
(Figure 2B, left) but did not
upregulate the activity of AP-1 (121 ± 11% versus untreated
control [100%]) (Figure 2B,
right). Treatment with quercetin dramatically diminished the activation of
NF-B in IL-1-stimulated mesangial cells from 431 ± 41%
(IL-1ß alone) to 85 ± 15% (quercetin + IL-1ß), when compared
with untreated control (100%) (Figure
2B, left).
The suppressive effect of quercetin on the NF-B activation was
further confirmed by electrophoretic mobility shift assay. Mesangial cells
were pretreated with or without quercetin for 1.5 h and stimulated by
IL-1ß for 4 and 24 h. As shown in
Figure 2C, the DNA binding
activity of NF-B induced by IL-1ß was significantly inhibited by
quercetin. The mutant probe and cold competition demonstrated that the band
observed is NF-B-specific. Four hours after the stimulation, the
inhibitory effect of quercetin was partial. However, after 24 h, the DNA
binding activity observed in IL-1-stimulated cells was completely abrogated in
the cells treated with quercetin.
Roles of NF-B and AP-1 in the IL-1-Triggered MCP-1
Expression
The roles of NF-B and AP-1 in the expression of MCP-1 were examined
using pharmacologic inhibitors. Mesangial cells were pretreated with an
inhibitor of c-Jun/AP-1, curcumin
(25), or an inhibitor of
NF-B, MG132 (27), and
stimulated by IL-1ß. As shown in
Figure 3A, induction of MCP-1
by IL-1ß was substantially diminished by MG132 (25 to 50 µM). Similar
suppression was also observed by another NF-B inhibitor,
N-acetylcysteine (10 mM) (data not shown). In contrast, the induction
of MCP-1 was not obviously affected by the treatment with the AP-1 inhibitor
curcumin (10 to 20 µM) (Figure
3A), which effectively inhibits expression of the AP-1-dependent
genes gelatinase B and stromelysin in mesangial cells
(25,36).
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The crucial role of NF-B in the cytokine induction of MCP-1 was
further examined using isolated glomeruli. Normal glomeruli were stimulated by
IL-1ß for 6 h in the presence or absence of MG132 and subjected to
Northern blot analysis. Consistent with the result in mesangial cells, MG132
abolished the induction of MCP-1 in isolated glomeruli
(Figure 3B).
The roles of NF-B and AP-1 were further investigated using mesangial
cells that stably express a super-repressor mutant of IB and a
dominant-interfering from of c-Jun. As reported previously,
SM/IBM cells exhibit blunted activation of NF-B when
stimulated by IL-1ß and TNF-
(24). SM/JUNDN cells show
attenuated activity of AP-1 under both basal and stimulated conditions
(21). Untransfected SM43
mesangial cells, mock-transfected SM/Neo cells, SM/IBM cells,
and SM/JUNDN cells were treated with or without IL-1ß, and expression of
MCP-1 was evaluated by Northern blot analysis. Compared with SM43 and SM/Neo
cells, SM/IBM cells exhibited blunted expression of MCP-1 in
response to IL-1ß (Figure
4). In contrast, SM/JUNDN cells showed the same level of MCP-1
mRNA as that observed in control mesangial cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B, but not AP-1, in mesangial cells.
The molecular mechanisms involved in the suppressive effect of quercetin on
NF-B are currently unknown, but several possibilities may be
postulated. Quercetin is known to have the ability to modulate intracellular
redox states (9). The first
possibility is that quercetin may inhibit NF-B by functioning as an
antioxidant (37). It is known
that NF-B is a redox-sensitive transcription factor and activated by
oxidant stress (38). A
previous study showed that IL-1-triggered MCP-1 expression was inhibited by
antioxidants (39). The
inhibitory effect of quercetin, therefore, may be ascribed to its ability to
scavenge reactive oxygen intermediates generated in IL-1-stimulated cells.
The second possibility is that quercetin may inhibit NF-B via
suppression of certain protein kinase(s). As has been reported, quercetin is a
potential inhibitor of tyrosine kinases
(9). A previous study showed
that in human mesangial cells, IL-1-triggered MCP-1 expression is mediated by
protein tyrosine kinases (40).
We showed that in rat mesangial cells, activation of NF-B in response
to IL-1ß is mediated by tyrosine kinases
(25). These data suggest that
tyrosine kinase may be a proximal target of quercetin for its inhibitory
action on NF-B.
Quercetin may affect not only protein tyrosine kinases, but also activity
of other kinases including cAMP-dependent kinase, protein kinase C, and
calmodulin-dependent kinase
(9). Activation of the family
of mitogen-activated protein (MAP) kinases, including extracellular
signal-regulated kinases and p38 MAP kinases, is also attenuated by quercetin
(Y. Ishikawa and M. Kitamura, submitted for publication). On the basis of its
multipotent, inhibitory action on protein kinases, it might be speculated that
quercetin inhibits NF-B via suppression of certain kinases directly
linked to NF-B activation. For example, recent investigations disclosed
the crucial roles of NF-B-inducing kinase, MAP kinase kinase kinasel,
and IB kinases in the activation of NF-B by IL-1ß
(41,
42,
43). Further investigation
will be required to determine the effect of quercetin on the
NF-B-activating kinases.
Induction of MCP-1 by cytokines and growth factors plays an important role in various pathologic situations. During glomerular injury, infiltration of monocytes/macrophages is a common pathologic feature (4). High levels of MCP-1 expression are observed in the mesangium of inflamed glomeruli (5, 6, 7). In the early phase of glomerulonephritis, the cells responsible for the MCP-1 production are resident mesangial cells (8). Using blocking antibodies, several reports have shown that in vivo neutralization of local MCP-1 attenuated crescentic glomerulonephritis in mice and rats (8,44,45). MCP-1 produced by mesangial cells supposedly contributes to accumulation of macrophages and generation of glomerular injury. From this viewpoint, administration of quercetin could be useful for therapeutic intervention in macrophage-mediated glomerulonephritis. Of note, it has been shown that quercetin attenuated ischemia-reperfusion injury with concomitant suppression of MCP-1 in the kidney (46).
In this report, we highlighted the effect of quercetin on the induction of
MCP-1, but expression of other cytokine-inducible genes may also be attenuated
by quercetin. The fact that quercetin significantly inhibited activity of both
NF-B and AP-1 (47)
(present data) suggests that it can suppress induction of various genes
controlled by NF-B and AP-1. Under pathologic circumstances, activation
of these transcription factors is triggered by inflammatory stimuli, including
cytokines/growth factors, microbial pathogens, and oxidant stress. A wide
array of genes is subsequently induced and contributes to the initiation and
progression of diseases
(48,49).
Based on this, pharmacologic inhibitors of NF-B and AP-1, including
quercetin, should serve as useful agents for therapeutic intervention.
Quercetin and other flavonoids have been considered as therapeutic agents
for various pathologic conditions, including cancer, viral infection,
inflammation/allergy, hypertension, and atherosclerosis. These agents possess
carcinostatic and antiviral activities, suppress cell proliferation, modify
eicosanoid synthesis, protect LDL from oxidation, prevent platelet
aggregation, stabilize immune cells, and promote relaxation of cardiovascular
smooth muscle (9). Our data
suggest that some of these therapeutically relevant actions of quercetin can
be ascribed to its inhibitory effects on NF-B and AP-1.
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Acknowledgments |
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This work was supported in part by grants from Baxter Healthcare Corporation (Extramural Grant Program), the Wellcome Trust, and the National Kidney Research Fund to M. Kitamura.
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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