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J. Biol. Chem., Vol. 275, Issue 47, 36703-36707, November 24, 2000
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From the INSERM U325, Département
d'Athérosclérose, Institut Pasteur de Lille, 1 rue Pr.
Calmette 59019 Lille and Faculté de Pharmacie, Université
de Lille II, 59000 Lille, France
Received for publication, May 11, 2000, and in revised form, September 6, 2000
Chronic inflammation is a hallmark of
degenerative diseases such as atherosclerosis. Peroxisome
proliferator-activated receptors (PPARs) are transcription factors
belonging to the nuclear receptor superfamily, which are expressed in
the cells of the atherosclerosic lesion. PPAR The NF- Peroxisome proliferator-activated receptors (PPARs), transcription
factors belonging to the nuclear receptor superfamily, have also been
reported to be expressed in vascular cells in vitro and
in vivo (10-19). To date, three different PPAR subtypes
have been identified: PPAR However, the influence of PPAR Cell Culture and Chemical Reagents--
Human aortic SMC
(Cascade Biologics, Portland, OR) were cultured in SMC basal medium
containing 5% SMC growth supplement (Cascade Biologics). Cells from
passages 5-8 were used for the experiments. Human primary hepatocytes
were prepared as described previously (23). Wy-14643 was from Chemsyn,
Lenexa, KS; fenofibric acid from Laboratoires Fournier, Dijon, France,
IL-1 IKK Assays--
IKK assays were performed as described
previously (24). Briefly, total protein extracts were subjected to
immunoprecipitation with anti-NEMO antibody (a kind gift of Dr
Israël, Institut Pasteur, France) in TNT buffer (200 mM NaCl, Tris 20 mM, pH 7.5, 1% Triton X-100)
and collected on protein A-Sepharose beads. The beads were then washed
three times with TNT buffer and three times with kinase buffer (20 mM HEPES, 10 mM MgCl2, 100 µM Na3VO4, 20 mM
RNA Analysis--
RNA preparation and Northern blot
hybridizations were performed as described previously (25). Human IL-6,
I Western Blot Analysis--
Protein extracts were fractionated on
10% polyacrylamide gels under reducing conditions (sample buffer
containing 10 mM dithiothreitol, transferred onto
nitrocellulose membranes, and probed with various antibodies as stated
in figure legends). After incubation with a secondary
peroxidase-conjugated antibody, signals were visualized by
chemiluminescence (Amersham Pharmacia Biotech).
Nuclear Extracts and Electrophoretic Mobility Shift Assay
(EMSA)--
SMC cells (3 × 106) were cultured for 2 or 24 h in SMC medium with Wy-14643 (100 µM) or
vehicle (Me2SO, 0.1%) and were subsequently treated
with IL-1 Recently, it was demonstrated that PPAR Next, it was investigated whether PPAR
Induction of I
B
Expression as a Mechanism Contributing to
the Anti-inflammatory Activities of Peroxisome Proliferator-activated
Receptor-
Activators*
,
![]()
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
ligands
have been reported to exert anti-inflammatory activities in different
cell types by antagonizing the transcriptional activity of NF-
B. In
the present study, the influence of PPAR
activators on the NF-
B
signaling pathway was investigated. Our results show that fibrates,
synthetic PPAR
activators, induced the expression of the inhibitory
protein I
B
in human aortic smooth muscle cells as well as in
primary human hepatocytes, whereas neither I
B-kinase activity nor
the degradation rate of I
B
were affected. Using PPAR
-null
mice, we demonstrated that fibrates induced I
B
in liver in
vivo and that this action required PPAR
. Furthermore, fibrate
treatment induced I
B
protein expression in the cytoplasm and also
enhanced IL-1
-induced accumulation of I
B
protein in the
nucleus. These actions of fibrates on I
B
expression were
accompanied by a decrease in NF-
B DNA binding activity as
demonstrated by electrophoretic mobility shift assays. Taken together,
these data provide an additional molecular mechanism for the
anti-inflammatory activity of PPAR
agonists and reinforce their
potential use in the treatment of inflammatory diseases.
![]()
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
B family of transcription factors plays a major role in
the regulation of the expression of a number of genes implicated in
cell growth, inflammation, and apoptosis (1, 2). This NF-
B/Rel
family consists of five members, c-Rel, p65, Rel B, p50, and p52, which
form heterodimeric complexes that are most frequently composed of p50
and p65 proteins. In most non-activated cells, NF-
B remains in a
cytoplasmic inactive complex through its association with the
inhibitory proteins I
Bs (3). Inducers of NF-
B, which include
inflammatory cytokines, reactive oxygen species, and viral products,
activate a dimeric I
B kinase
(IKK)1 complex (4-6), which
phosphorylates I
B
on Ser-32 and Ser-36 leading to subsequent
ubiquitination and degradation of I
B
and release of NF-
B
proteins (1, 2). Free NF-
B dimers translocate to the nucleus where
they regulate target gene transcription. NF-
B has been suggested to
play a crucial role in the pathogenesis of atherosclerosis (7). NF-
B
was reported to be essential for the proliferation of vascular smooth
muscle cells (SMC) (8), and activated NF-
B heterodimers are detected
in human atherosclerotic lesions (9).
, PPAR
/
, and PPAR
. PPARs regulate
gene expression by binding with the retinoid receptor RXR as a
heterodimeric partner to specific DNA sequence elements termed PPAR
response elements (PPRE) (20). In addition to regulating gene
transcription via PPREs, PPARs have recently been shown to modulate
gene transcription also by negatively interfering with other
transcription factor pathways in a DNA binding-independent manner (18,
21). Among the three different PPARs, PPAR
activation has been shown
to repress cytokine-induced activation of a number of inflammatory genes such as VCAM-1, COX-2, and IL-6
by negatively interfering with NF-
B transcriptional activity (14,
22).
activators on the different
components of the NF-
B signaling cascade have not yet been explored. In the present study, we show that fibrates, synthetic PPAR
ligands, induce I
B
expression in a PPAR
-dependent manner.
By contrast, PPAR
agonists do not influence I
B
degradation nor
IKK activity. This induction results in an inhibition of NF-
B DNA
binding leading to a sharp reduction of the p65-mediated gene
activation. These actions may contribute to the anti-inflammatory
activities of PPAR
ligands.
![]()
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
from Genzyme, Cambridge, MD; and ciprofibrate from Sigma, Saint
Quentin, France.
-glycerophosphate, 2 mM dithiothreitol, 50 mM NaCl, pH 7.5). Kinase reactions were performed for 30 min at 30 °C using 5 µCi of [
-32P]ATP and
GST·I
B
-(1-72) as substrate. The reaction products were
analyzed on 10% SDS-polyacrylamide gels and detected by autoradiography.
B
(26), and 36B4 cDNA fragments were used as probes.
(10 ng/ml) for 1 h. Cells were then harvested, and
nuclear extracts were obtained as described previously (27). Nuclear
proteins were quantified using the bicinchonic acid assay and stored at
80 °C. For EMSA, an NF-
B and an OCT1 double-stranded oligonucleotide (Promega) were end-labeled with
[
-32P]ATP using T4 polynucleotide kinase according to
standard protocols. 5 µg of nuclear extracts from SMC cells were
incubated with 50,000 cpm of labeled probes for 20 min at room
temperature in 20 µl of buffer containing 10 mM Tris pH
7.5, 50 mM NaCl, 1 mM dithiothreitol, 1 mM EDTA, 5% glycerol, 0.3 µg bovine serum albumin, and 2 µg of poly(dIdC). The reactions were analyzed by electrophoresis in a
non-denaturing 5% polyacrylamide gel in 0.5× Tris-borate-EDTA buffer. The gels were then dried and exposed at
80 °C for autoradiography.
![]()
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
activators inhibit
IL-1
-induced IL-6 secretion by human aortic SMC (HASMC) in a dose-dependent manner (14). Furthermore, PPAR
activators
negatively regulate IL-1
-induced-IL-6 production at the gene
expression level by inhibiting NF-
B transcriptional activity (21).
Activation of the transcription factor NF-
B is controlled by a
cytokine-activated protein kinase complex, which phosphorylates
I
B
, triggering its polyubiquitination (5). Because PPAR
agonists negatively interfere with IL-1
-induced NF-
B
transcriptional activity in HASMC, we investigated whether PPAR
activators influence IL-1
-induced IKK activity in these cells. IKK
activity was very low in non-stimulated HASMC treated with or without
the PPAR
ligand Wy-14643 (Fig. 1A). Treatment with IL-1
for 10 min resulted in a strong induction of IKK activity. This
induction was not affected by preincubation with the PPAR
activator
Wy-14643 for 2 h, the time period previously reported to inhibit
IL-1
-induced COX-2 gene expression (14). This result
indicates that PPAR
activators do not regulate NF-
B transcriptional activity by modulating IKK function. Furthermore, we
investigated the influence of Wy-14643 on IL-1
-induced-I
B
degradation. Western blot analysis showed that I
B
protein was degraded within 30 min after IL-1
stimulation, followed by
reappearance of the protein at 1 h as previously reported (28)
(Fig. 1B). Fibrate treatment did not affect I
B
protein
degradation, consistent with the absence of any effect on IKK. Taken
together, these data indicate that fibrates do not impair NF-
B
transcriptional activation by modulating IKK activity or I
B
degradation.

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[in a new window]
Fig. 1.
PPAR
activators do
not influence I
B
degradation. A, human aortic SMC (80% confluence)
were incubated for 2 h in standard medium with Wy-14643 (100 µM) or vehicle (Me2SO, 0.1%) and were
subsequently stimulated with IL-1
(10 ng/ml) for different time
periods (min). Cytoplasmic extracts were prepared and subjected to IKK
assay as described previously (46). B, human aortic SMC
(80% confluence) were incubated for 2 h in standard medium with
Wy-14643 (100 µM) or vehicle (Me2SO, 0.1%)
and were subsequently stimulated with IL-1
(10 ng/ml) for different
time periods (min). Total protein extracts were prepared and proteins
(50 µg) were separated by SDS-PAGE, transferred to a Hybond membrane,
and probed with antibodies to I
B
and
-actin (Santa Cruz
Biotechnology).
agonists influence I
B
expression. Incubation of HASMC with IL-1
resulted in the induction
of both IL-6 and I
B
mRNA (Fig.
2A), which is consistent with
the previous demonstration that NF-
B controls the expression of
I
B
by an inducible autoregulatory loop (28). Wy-14643 alone induced I
B
mRNA (Fig. 2A), and this effect was
further enhanced by IL-1
suggesting that PPAR
and IL-1
regulate I
B
gene expression by different
mechanisms. By contrast, Wy-14643 treatment inhibited the induction of
IL-6 mRNA levels by IL-1
as described previously (21).
Similarly, when incubations were done with fenofibric acid, another
PPAR
ligand, I
B
mRNA was significantly induced (Fig.
1B). This induction occurred rapidly with a maximum reached after 1 h. I
B
mRNA levels declined thereafter but
remained elevated to increase again at 24 h (Fig. 2B).
Moreover, Wy-14643 increased I
B
mRNA levels in a
dose-dependent manner (Fig. 2C). Results from
actinomycin D transcription inhibition experiments demonstrated that
fibrates induce I
B
expression at the transcriptional level (data
not shown). In HASMC, Wy-14643 also increased I
B
protein with a
maximum of induction reached after 24 h of treatment (2.25 ± 0.19-fold; p < 0.05), demonstrating that the induction
of I
B
gene expression results in increased
protein levels (Fig. 2D).

View larger version (45K):
[in a new window]
Fig. 2.
PPAR
activators
induce I
B
mRNA
and protein levels in human aortic SMC. A, human aortic SMC
(80% confluence) were incubated for 2 h in standard medium with
Wy-14643 (250 µM) or vehicle (Me2SO, 0.1%)
and were subsequently stimulated with IL-1
(10 ng/ml) for 3 h.
IL-6, I
B
, and 36B4 mRNA were measured by Northern blot
analysis. B, SMC were cultured in standard medium with
fenofibric acid (100 µM) for different times as
indicated. RNA (10 µg) was extracted, separated on a 1%
agarose-formaldehyde gel, transferred to a nylon membrane, and analyzed
by hybridization to I
B
and 36B4 cDNA probes. C,
SMC were cultured in standard medium with increasing concentrations of
Wy-14643 for 1 h. RNA (10 µg) was extracted, separated on a 1%
agarose-formaldehyde gel, transferred to a nylon membrane, and analyzed
by hybridization to I
B
and 36B4 cDNA probes. D,
human aortic SMC were cultured in standard medium with Wy-14643 (100 µM) or vehicle (Me2SO, 0.1%) for different
lengths of time (h). Protein extracts were prepared, and 30 µg of
each extract were separated by SDS-PAGE, transferred to Hybond
membrane, and probed with antibodies to I
B
and
-actin.
To determine whether this induction of I
B
expression by fibrates occurs in other PPAR
- expressing cell types,
I
B
regulation was next studied in the liver, where PPAR
is
highly expressed (29, 30). In line with previous studies (31), human
primary hepatocytes express I
B
mRNA under basal conditions
(Fig. 3A). Interestingly,
treatment with Wy-14643 increased I
B
mRNA (approximately 3-fold)(Fig. 3A), indicating that PPAR
ligands regulate
I
B
expression also in human primary hepatocytes. Western blot
analysis confirmed that Wy-14643 treatment led to I
B
protein
induction in human primary hepatocytes (Fig. 3C). To
determine whether I
B
mRNA induction by fibrates in liver is
mediated by PPAR
, further studies were performed in PPAR
-null
mice (32). In livers of PPAR
wild-type mice, treatment with the
PPAR
agonist ciprofibrate resulted in a significant increase
(>4-fold) of I
B
mRNA, whereas in PPAR
null mice no
induction was observed (Fig. 3B). This result indicates that
fibrates regulate I
B
in liver in a PPAR
-dependent manner. Because the liver constitutes a major organ implicated in the
synthesis of numerous acute phase proteins such as cytokines and
hemostatic factors, whose transcription is under the control of NF-
B
transcription factors (33, 34), we next studied NF-
B target gene
regulation by fibrates in human primary hepatocytes. Primary human
hepatocytes express basal COX-2 protein levels, which were modestly
induced by IL-1
(Fig. 3D). Fibrate treatment dose-dependently inhibited COX-2 expression similarly as
described previously in human aortic SMC (14), suggesting a similar
role for PPAR
in the control of the hepatic inflammatory
response.
|
After I
B
degradation, p50/p65 dimers translocate to the nucleus
and activate gene transcription. To explore the functional consequences
of I
B
up-regulation, EMSAs, using a NF-
B consensus site probe,
were performed. Extracts from non-activated SMC contained a basal
NF-
B binding activity, which was inhibited by fibrate treatment
(Fig. 4A). The presence of
NF-
B proteins in the complex was verified by shifting the complex
using an anti-p65 antibody (data not shown). Treatment with IL-1
resulted in a drastic increase of NF-
B binding, which was reduced by
Wy-14643 treatment for 2 h and completely abolished after 24-h
fibrate pretreatment, whereas binding of OCT1 proteins to their
respective consensus site was unaffected (Fig. 4A). As a
control, Western blot analysis demonstrated that PPAR
activators do
not affect either p50 or p65 protein levels (Fig. 4B and
data not shown). Poynter and Daynes (35) and Marx et al.
(22) showed that PPAR
activators significantly reduced NF-
B DNA
binding activities in aged murine splenocytes and in TNF
-stimulated
endothelial cells, respectively. Therefore, our data are in line with
the findings of these studies and suggest that the inhibition of
NF-
B DNA binding activities depends on the time of PPAR
agonist
exposure.
|
In resting cells, I
B
sequesters p50/p65 heterodimers in a
cytoplasmic inactive complex. To determine whether I
B
induction modulates NF-
B protein translocation, nuclear and cytoplasmic extracts from cultured SMC were isolated. IL-1
induced a rapid but
transient p65 translocation to the nucleus (Fig. 4B).
Surprisingly, fenofibric acid treatment did not inhibit IL-1
-induced
p65 translocation suggesting that I
B
up-regulation by fibrates
does not result in an increased sequestration of NF-
B in the
cytoplasm (Fig. 4B). This result constitutes a major
difference between fibrates and glucocorticoids, which were reported to
induce I
B
in T cells and to block p65 translocation (36, 37).
Because newly synthesized I
B
protein accumulates not only in the
cytoplasm but also in the nucleus reducing thereby NF-
B binding (38,
39), I
B
protein localization was analyzed in cytoplasmic and
nuclear extracts from human aortic SMC after fibrate treatment by
Western blot analysis using a monoclonal anti-I
B
antibody. As a
control, fibrate treatment resulted in an increase of the I
B
cytoplasmic content (Fig. 4D), which is consistent with our
findings in Fig. 2D. Surprisingly, in non-stimulated cells,
I
B
protein was also present in the nucleus but its levels were
not affected by fibrate treatment (Fig. 4C). IL-1
treatment for 1 h did not result in an increased nuclear content
of I
B
. This finding is in line with a previous study
demonstrating that newly synthesized I
B
protein is only
detectable in the nucleus after 2 h of IL-1
or TNF
exposure
in HeLa S3 cells (39). Interestingly, fibrate treatment in the presence
of IL-1
for 1 h led to an increase of nuclear I
B
protein
content (Fig. 4C), which occurs concomitantly with the loss
of NF-
B DNA binding activity observed in IL-1
treated cells (Fig.
4A).
Several concurring mechanisms may explain the overall anti-inflammatory
activities of PPAR
ligands. First, PPARs have been shown to
down-regulate inflammatory response genes by negatively interfering
with the STAT, AP-1, and NF-
B transcriptional pathways (14, 18, 21,
40). Direct protein-protein interactions between PPAR
and AP-1 and
NF-
B proteins have been invoked as mechanisms of transrepression
(21). Second, by regulating anti-oxidant enzyme activities such as
catalase (41), PPAR
activators reduce the oxidative stress, and, as
such, may inhibit NF-
B activation. Finally, the results of the
present study provide an additional mechanism through which PPAR
activators may antagonize NF-
B activation (Fig.
5). Induction of I
B
mRNA by
fibrates may contribute to the inhibition of inflammatory gene
activation such as COX-2 or IL-6. The induction
of I
B
by fibrates in cytokine-activated cells should result in an
acceleration of NF-
B nuclear desactivation. This is consistent with
a previous report in which PPAR
ligands were shown to affect the
duration of the inflammatory response in a
PPAR
-dependent manner (42). Consistent with this
observation, the increase of I
B
protein after treatment with
PPAR
activators would lead to a halt in p65-mediated gene activation
thereby reducing the duration of the inflammatory response.
|
The I
B
promoter contains several regulatory regions among which
are sites for NF-
B (43, 44). The results using the PPAR
-deficient
mice indicate that I
B
activation by fibrates occurs in a
PPAR
-dependent manner. Our EMSA experiments indicate that PPAR
activators do not activate I
B
transcription in a NF-
B-dependent manner because basal NF-
B binding
activity present in SMC was not increased by Wy-14643 but was
conversely lowered. Furthermore, I
B
mRNA appeared to be
synergistically induced by fibrates in the presence of IL-1
(Fig.
2A) suggesting that PPAR
activators regulate
I
B
gene expression via a distinct signaling
pathway. In addition, PPAR
was reported to play a major role in the
control of the cellular redox status (35). Klucis et al.
(41) reported that administration of PPAR
activators results in a
drastic increase in the activity of catalase, an anti-oxidant enzyme.
This induction occurs in the absence of oxidative stress as
demonstrated by the absence of increase of F2-isoprostanes after
Wy-14643 treatment (45). Taken together, these observations allow us to
exclude that PPAR
activators induce an oxidative stress resulting in
NF-
B activation and induction of I
B
.
In conclusion, the demonstration that PPAR
activators modulate
NF-
B activation by inducing I
B
provides an additional, complementary action mechanism contributing to the overall
anti-inflammatory properties of PPAR
agonists.
| |
ACKNOWLEDGEMENTS |
|---|
We thank O. Vidal, B. Derudas, and P. Poulain
for technical contributions. We thank Dr. Frank Gonzalez for providing
us the PPAR
-null mice and Dr. Alain Israël (Pasteur Institute,
Paris) who provided us the materials necessary to perform IKK assays.
| |
FOOTNOTES |
|---|
* This work was supported in part by grants from the Institut Pasteur de Lille, INSERM, ARCOL, Laboratoires Fournier, and the Région Nord-Pas-de-Calais/Feder.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. Section 1734 solely to indicate this fact.
Supported by a grant from the Région Nord-Pas-de-Calais.
§ To whom correspondence should be addressed. Tel.: 33-3-2087-7388; Fax: 33-3-2087-7360; E-mail: Bart.Staels@pasteur-lille.fr.
Published, JBC Papers in Press, September 8, 2000, DOI 10.1074/jbc.M004045200
| |
ABBREVIATIONS |
|---|
The abbreviations used are:
IKK, I
B kinase;
SMC, smooth muscle cells;
PPAR, peroxisome proliferator-activated
receptors;
PPRE, PPAR response element;
IL, interleukin;
GST, glutathione S-transferase;
EMSA, electrophoretic mobility
shift assay;
HASMC, human aortic SMC;
STAT, signal transducers and
activators of transcription;
PAGE, polyacrylamide gel
electrophoresis.
| |
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