First Department of Internal Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan
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ABSTRACT |
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In this study, we
determined whether the proinflammatory cytokines tumor necrosis factor
(TNF)- and interleukin-1
contribute to the regulation of matrix
metalloproteinase (MMP)-9 in human bronchial epithelial cells and
whether the induction of MMP-9 is regulated by the transcription factor
nuclear factor (NF)-
B. We demonstrated that TNF-
induced MMP-9 at
both the protein and mRNA levels in human bronchial epithelial cells
and that interleukin-1
did not. In contrast, induction of the tissue
inhibitor of metalloproteinase-1 by TNF-
was less than that of
interleukin-1
. Increased expression of MMP-9 and NF-
B activation
induced by TNF-
were inhibited by pyrrolidine dithiocarbamate and
N-acetyl-L-cysteine but were not inhibited by
curcumin. These results suggest that TNF-
induces the expression of
MMP-9 in human bronchial epithelial cells and that this induction is
mediated via the NF-
B-mediated pathway.
matrix metalloproteinase-2; matrix metalloproteinase-9; tumor
necrosis factor-; nuclear factor-
B; proinflammatory cytokine; airway inflammation
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INTRODUCTION |
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A RECENT STUDY (39) has reported that human bronchial epithelial cells are capable of expressing matrix metalloproteinase-2 and matrix metalloproteinase-9 under basal conditions. Matrix metalloproteinases are a family of extracellular matrix-degrading enzymes and are induced by different stimuli including growth factors, cytokines, and tumor promoters. Matrix metalloproteinases play important roles in inflammation, tissue remodeling, angiogenesis, wound healing, tumor invasion, and metastatic progression (22, 24). Recent evidence (23) suggests that matrix metalloproteinase-9 is induced by airway inflammation. Matrix metalloproteinases are thought to be secreted in physical association with their specific inhibitor tissue inhibitor of metalloproteinase (TIMP-1, TIMP-2, TIMP-3, or TIMP-4). Matrix metalloproteinase-9 activity is inhibited by forming a 1:1 complex with TIMP-1 (3, 7, 12, 18).
Tumor necrosis factor (TNF)- and interleukin-1
are increased in
the lungs of patients with asthma pathophysiologically (4, 15) and may be key cytokines in airway inflammation.
Their effects on the expression of matrix metalloproteinases and TIMPs
have been studied in various cell lines (6, 8, 36, 38),
and these cytokines induce matrix metalloproteinases. It has been demonstrated that TNF-
exerts its effects via nuclear factor-
B, a
transcription factor of diametric complex, in various cell types. TNF-
-induced nuclear factor-
B activation has been suggested to be
mediated by reactive oxygen intermediates such as hydrogen peroxide
because antioxidants such as pyrrolidine dithiocarbamate and
N-acetyl-L-cysteine inhibit nuclear factor-
B
activation (30, 31, 34). Several studies have shown that a
conserved proximal activator protein (AP)-1 binding site is required in
the induction of matrix metalloproteinase-9 (1, 11, 29,
41), and analysis of the matrix metalloproteinase-9 promoter has
identified an essential proximal AP-1 element and an upstream nuclear
factor-
B site (29).
We hypothesized that the inflammatory cytokines TNF- and
interleukin-1
induce matrix metalloproteinase-9 in human bronchial epithelial cells and that these are induced via nuclear factor-
B activation. To investigate the expression and activity of matrix metalloproteinase-9 in human bronchial epithelial cells, we performed Northern blotting and gelatin zymography and examined the expression of
TIMP-1 by enzyme-linked immunosorbent assay (ELISA). The effects of
nuclear factor-
B activation on the expression of metalloproteinase-9 induced by TNF-
were investigated by electrophoretic mobility shift assay.
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MATERIALS AND METHODS |
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Cell culture.
Normal human bronchial epithelial cells (passage 1) were
purchased from Clonetics (San Diego, CA). Human bronchial epithelial cells were grown as monolayers in tissue culture flasks or dishes at
100% humidity and 5% CO2 at 37°C in serum-free modified
LHC-9 medium (Clonetics) supplemented with 7.5 mg/ml of bovine
pituitary extract, 0.5 mg/ml of hydrocortisone, 0.5 µg/ml of human
recombinant epidermal growth factor, 0.5 mg/ml of epinephrine, 10 mg/ml
of transferrin, 5 mg/ml of insulin, 0.1 µg/ml of retinoic acid, 6.5 µg/ml of triiodothyronine, 50 mg/ml of bovine serum albumin, fatty acid free, and 50 mg/ml of gentamicin sulfate-amphotericin B
(Clonetics). For subculturing, the cells from the monolayers were
harvested with trypsin (0.025%) and EDTA (0.01%) in HEPES-buffered
saline solution, centrifuged at low speed (800 rpm for 5 min), and
resuspended in fresh medium before they were grown on 60-mm plastic
culture dishes. The cells were grown to confluence over 7-10 days.
Human bronchial epithelial cells grown to 80% confluence were
incubated in growth factor-free medium for 24 h. These confluent
cells were incubated with interleukin-1 or TNF-
for the indicated
times. To investigate the relationship between matrix
metalloproteinase-9 and nuclear factor-
B, pyrrolidine
dithiocarbamate and N-acetyl-L-cysteine were
added 1.5 h before stimulation with interleukin-1
and TNF-
.
Northern blot analysis. Total cellular RNA was extracted from human bronchial epithelial cells with ISOGEN (Nippon Gene, Tokyo, Japan). RNA samples were applied to a 1% denaturing agarose gel, electrophoresed, and blotted onto a Hybond-N filter. The blotted filters were hybridized with 32P-labeled human matrix metalloproteinase-9 cDNA probe generated by random priming with a multiprime DNA labeling system (Amersham International).
After hybridization, the filters were washed twice with 1× saline-sodium citrate (SSC)-1% sodium dodecyl sulfate (SDS) at 65°C for 20 min and once with 1× SSC-0.1% SDS at 65°C for 20 min. The filters were exposed to an imaging plate (BAS 2, Fuji Xerox, Tokyo, Japan) for 2 h at room temperature. The relative intensities of signals were determined by an autoimage analyzer (BAS 2000, Fuji Xerox). Equal RNA loading was confirmed by ethidium bromide staining of 28S and 18S rRNA.Zymography.
The human bronchial epithelial cell culture medium was harvested and
stored at 20°C until used. Aliquots of each sample were subjected
to SDS-PAGE in 10% polyacrylamide gels containing 1 mg/ml of gelatin.
The method of Laemmli (17) was followed, excluding any reducing agents or boiling products. After electrophoresis, the
gels were washed twice in 2.5% Triton X-100 at room temperature for 20 min to remove SDS. The gel was then incubated in reaction buffer [100
mM Tris · HCl (pH 7.5), 10 mM CaCl2, and 1 mM Brij 35] overnight at 37°C and stained with Coomassie brilliant blue R-250. The positions of matrix metalloproteinases that contained gelatinolytic activity appeared as clear bands. Molecular
masses of gelatinolytic bands were estimated with prestained
molecular mass markers (Bio-Rad Laboratories). For detection of
zymogen, samples were incubated for 4 h at 37°C with 1 mM
aminophenylmercuric acetate (Sigma) before undergoing SDS-PAGE. To
determine the inhibition profile of the enzymatic activities, we also
used incubation in reaction buffer containing 10 mM EDTA, a
metalloproteinase inhibitor, and 2 mM phenylmethylsulfonyl fluoride
(Sigma), a serine proteinase inhibitor. Gelatinolytic activity was
measured on zymography-digitalized images with NIH Image shareware
V.1.55 as described in a recent work by Shan et al.
(33).
Quantification of TIMP-1 protein by ELISA. TIMP-1 protein concentrations in human bronchial epithelial cell culture medium were measured with a human TIMP-1 sandwich ELISA kit (Amersham). The assays were performed in triplicate following instructions of the manufacturer.
Cell fractionation and preparation of nuclear extracts.
Nuclear extracts were prepared with a modified version of the method of
Schreiber et al. (32). Confluent human bronchial epithelial cells in a 60-mm dish were washed with ice-cold
phosphate-buffered saline (PBS), harvested by scraping into 1 ml of
PBS, and centrifuged in a 1.5-ml microtube at 5,000 rpm for 1 min. The
pellet was resuspended in 400 µl of cold hypotonic buffer [10 mM
HEPES buffer (pH 7.8) containing 10 mM KCl, 0.1 mM EDTA, 0.1% Nonidet
P-40, 1 mM dithiothreitol, 0.5 mM phenylmethylsulfonyl fluoride, 2 µg/ml of aprotinin, 2 µg/ml of pepstatin, and 2 µg/ml of
leupeptin] and pelleted at 5,000 rpm for 1 min. Then the pellet was
resuspended in 100 µl of hypertonic buffer [50 mM HEPES-saline
buffer (pH 7.8) containing 420 mM KCl, 0.1 mM EDTA, 5 mM
MgCl2, 20% glycerol, 1 mM dithiothreitol, 0.5 mM
phenylmethylsulfonyl fluoride, 2 µg/ml of aprotinin, 2 µg/ml of
pepstatin, and 2 µg/ml of leupeptin] and incubated for 30 min at
4°C. The nuclear pellet was isolated by centrifugation at 15,000 rpm
for 15 min. The supernatant was the nuclear extract. Protein
concentrations were determined with the method of Bradford (5). The extracts were then stored at 80°C.
Electrophoretic mobility shift assay.
Nuclear extracts (2 µg of protein) were incubated with 60,000 counts/min of a 25-bp oligonucleotide containing the nuclear factor-B consensus sequence 5'-T CGA CAG AGG GAC TTT CCG
A-3' that was prelabeled with 32P by random priming with a
multiprime DNA labeling system (Amersham). Incubation was performed for
15 min at room temperature in the presence of 2 µg of poly(dI-dC) as
a nonspecific competitor and 4 mM Tris · HCl (pH 7.9)
containing 12 mM HEPES (pH 7.9), 60 mM KCl, 1 mM EDTA, 12% glycerol, 1 mM phenylmethylsulfonyl fluoride, 1 mM dithiothreitol, and 4.5 mg/ml of
nuclease-free bovine serum albumin. For competition studies, unlabeled
wild-type oligonucleotides were added to the binding reaction before
addition of the radiolabeled probe. To examine specific binding,
anti-p50 nuclear factor-
B antibody (Transduction Laboratories) was
preincubated with nuclear extracts for 2 h. All incubation
mixtures were subjected to electrophoresis on gels containing 25 mM
Tris, 52.6 mM glycine, 1.3 mM EDTA, 4% acrylamide, 0.05%
bis-acrylamide, and 2.5% glycerol, which were subsequently dried and
exposed to an imaging plate (BAS 2, Fuji Xerox) for 1 h at
room temperature. The relative intensities of signals were determined
with an autoimage analyzer (BAS 2000, Fuji Xerox).
Reagents.
TNF-, pyrrolidine dithiocarbamate,
N-acetyl-L-cysteine, Brij 35, aminophenylmercuric acetate, and phenylmethylsulfonyl fluoride were
purchased from Sigma (St. Louis, MO). Interleukin-1
was purchased
from Immugenex. The matrix metalloproteinase-9 probe was kindly
provided by Dr. K. Tryggvason (Biocenter and Department of
Biochemistry, University of Oulu, Oulu, Finland).
Data and statistical analysis. Data are expressed as means ± SE. Statistical evaluation of the data was performed with Student's t-test for unpaired observations with StatView 4.5 (Abacus Concepts, Berkeley, CA) for Macintosh.
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RESULTS |
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TNF- induced production of matrix metalloproteinase-9 by human
bronchial epithelial cells.
After stimulation with TNF-
(10 ng/ml) or interleukin-1
(10 ng/ml), total RNAs of human bronchial epithelial cells were collected
at each time point (0, 8, 24, 36, and 48 h) and the expression of
matrix metalloproteinase-9 was analyzed by Northern blot analysis. The
level of matrix metalloproteinase-9 mRNA was increased in a
time-dependent manner and the expression peaked at 24 h,
indicating a 11.9 ± 0.15-fold increase compared with the control
value (n = 3 experiments; Fig.
1, A and E).
However, interleukin-1
did not consistently increase the
expression of matrix metalloproteinase-9 mRNA compared with TNF-
(1.93 ± 0.67-fold increase compared with the control value;
n = 3 experiments; Fig. 1, B and
E).
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TIMP-1 production by human bronchial epithelial cells.
TNF- or interleukin-1
stimulation increased TIMP-1 production in
a time-dependent manner (Fig.
5A). However, TNF-
did not increase induction compared with interleukin-1
. To determine whether
this induction was in a dose-dependent manner, human bronchial epithelial cells were incubated for 24 h with TNF-
and
interleukin-1
at concentrations from 0.1 to 20 ng/ml. These
inductions were increased statistically but not in a dose-responsive
manner (Fig. 5, B and C).
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Matrix metalloproteinase-9 production by TNF--stimulated human
bronchial epithelial cells was inhibited by pyrrolidine dithiocarbamate
or N-acetyl-L-cysteine.
The intracellular redox state of the lung cells may have a key role in
the regulation of the inflammatory immune responses in many
inflammatory lung diseases (28). To examine the
contribution of nuclear factor-
B, human bronchial epithelial cells
were treated with antioxidants such as
N-acetyl-L-cysteine or pyrrolidine
dithiocarbamate before TNF-
stimulation. In Northern blotting,
N-acetyl-L-cysteine or pyrrolidine
dithiocarbamate showed a dose-dependent inhibition of TNF-
-induced
matrix metalloproteinase-9 mRNA expression (Fig. 6, A and B). As a
control, 28S rRNA levels were not altered by pyrrolidine
dithiocarbamate and N-acetyl-L-cysteine.
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TNF- induced nuclear factor-
B activation in human bronchial
epithelial cells.
To examine whether TNF-
induced nuclear factor-
B activation in
human bronchial epithelial cells, we performed an electrophoretic mobility shift assay with a nuclear factor-
B oligonucleotide (25 bp). The nuclear factor-
B oligonucleotide prelabeled with 32P was incubated with the nuclear extracts prepared from
human bronchial epithelial cells (Fig.
7A). Stimulation of human
bronchial epithelial cells with TNF-
induced the expression
of nuclear factor-
B (3.5 ± 1.9-fold; Fig. 7A,
lane 2). Pyrrolidine dithiocarbamate treatment before
stimulation with TNF-
showed inhibition of nuclear factor-
B
activation in nuclear extracts (P < 0.05; Fig.
7A, lane 3), and
N-acetyl-L-cysteine treatment before stimulation
with TNF-
partially inhibited nuclear factor-
B activation (Fig.
7A, lane 5). Pyrrolidine dithiocarbamate
alone inhibited nuclear factor-
B activation compared with that in
control cells (P < 0.001; Fig. 7A,
lane 4), but N-acetyl-L-cysteine
alone did not change nuclear factor-
B activation (Fig.
7A, lane 6). To elucidate that this activation is
specific for the nuclear factor-
B pathway, anti-p50 nuclear
factor-
B antibody was preincubated with nuclear extracts before
binding with nuclear factor-
B oligonucleotides (Fig. 7B). Supershift assay showed that the binding of anti-p50 antibody with a
nuclear factor-
B element induced by TNF-
caused an upward shift
(Fig. 7B, lane 3) from the baseline (Fig.
7B, lane 2) and was inhibited by pyrrolidine
dithiocarbamate (Fig. 7B, lane 4). N-acetyl-L-cysteine showed partial inhibition of
the upper shift caused by TNF-
treatment (Fig. 7B,
lane 5). However, the AP-1 inhibitor curcumin did not
inhibit this reaction (Fig, 7B, lane 8). To
explore the relationship with protein kinase C activity, the
nonselective inhibitors calphostin C, H-7, and staurosporine were
added. Calphostin C (data not shown) and H-7 (Fig. 7, lane 6) partially inhibited nuclear factor-
B expression induced by TNF-
, whereas staurosporine totally inhibited it (Fig. 7, lane 7).
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DISCUSSION |
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In this study, we demonstrated that TNF- induced an increase in
matrix metalloproteinase-9 expression and nuclear factor-
B activation in human bronchial epithelial cells and that these inductions were inhibited by pyrrolidine dithiocarbamate and
N-acetyl-L-cysteine. On the other hand,
interleukin-1
did not consistently induce matrix metalloproteinase-9 expression.
Matrix metalloproteinases and their inhibitors are implicated in the
degradation of extracellular matrix components and hence in the
mechanism of cellular migration (20, 25, 37). Inflammatory cytokines, particularly interleukin-1 and TNF-
, induce the
production of matrix metalloproteinase-9 in normal human fibroblasts
(38) and osteosarcoma and fibrosarcoma cell lines
(27). It is well known that interleukin-1
and TNF-
play a central role in acute inflammation in the lung. Our data
indicated that TNF-
increased matrix metalloproteinase-9 expression
at both the protein and mRNA levels in human bronchial epithelial
cells. Yao et al. (39) demonstrated matrix
metalloproteinase-9 production and activation induced by
lipopolysaccharide and supported the fact that matrix metalloproteinase-9 may be involved in inflammatory pulmonary processes. These data suggest that acute inflammation increases production of matrix metalloproteinase-9 in human bronchial epithelial cells and that matrix metalloproteinase-9 production may contribute to
the pathogenesis of several inflammatory diseases in the human airway.
Recent studies have indicated that matrix metalloproteinase-9 is
increased in bronchoalveolar lavage fluid (23) and
bronchial tissues (26) in patients with bronchial asthma,
suggesting that matrix metalloproteinase-9 may play an important role
in bronchial asthma. In addition, a recent study by Shan et al.
(33) demonstrated that the expression and release of
matrix metalloproteinase-9 in human bronchial epithelial cells were
stimulated by platelet-activating factor, which plays a role as a
mediator in pathological states of asthma. In contrast, matrix
metalloproteinase-2 was not significantly increased after stimulation
by TNF-, interleukin-1
, and platelet-activating factor in the
present or in the recent study by Shan et al. These data indicate that
matrix metalloproteinase-2 expression induced by these inflammatory
cytokines is constitutive at a low level compared with matrix
metalloproteinase-9 expression. Previous studies have demonstrated that
the source of matrix metalloproteinase-9 in airway inflammation is
eosinophils (14, 26), neutrophils (19), and
bronchial epithelial cells (39, 40). This study also shows
that the source of matrix metalloproteinase-9 is bronchial epithelial
cells in an inflammatory model in vitro.
TIMP-1 expression in human bronchial epithelial cells did not increase
after TNF- treatment compared with interleukin-1
treatment. These
data suggest that human bronchial epithelial cells produce matrix
metalloproteinase-9 and TIMP-1 in the basal condition. However, the
expression of matrix metalloproteinase-9 induced by TNF-
was higher
than that of TIMP-1. These results correspond with a previous report
(40) that TNF-
and interleukin-1
induced an increase
in the latent form of 92-kDa gelatinase production and mRNA level,
whereas TIMP-1 production and mRNA level were unchanged in the presence
of interleukin-1
and that these were decreased in the presence of
TNF-
. An imbalance between matrix metalloproteinase and TIMP
activities has been reported under various conditions. In patients with
asthma, matrix metalloproteinase-9 and TIMP-1 immunoreactivities were
significantly increased in both the epithelium and submucosa and the
expression of matrix metalloproteinase-9 was stronger than that of
TIMP-1 in the submucosa (14), suggesting that the
increased expression of matrix metalloproteinase-9 may be produced by
eosinophils in chronic asthmatic patients. However, our investigation
indicated that matrix metalloproteinase-9 and TIMP-1 were produced by
bronchial epithelial cells in an inflammation model in vitro. Because
matrix metalloproteinase-9 activity is inhibited by forming a 1:1
complex with TIMP-1, our data suggest that inflammatory changes induce
both matrix metalloproteinase-9 activation and TIMP-1 secretion and
that the overflow of matrix metalloproteinase-9 may cause cell
invasion, matrix degradation, and tissue remodeling.
A previous study (29) indicated that analysis of the
matrix metalloproteinase-9 promoter has identified an essential
proximal AP-1 element and an upstream nuclear factor-B site. We
hypothesized that nuclear factor-
B may mediate the induction of
matrix metalloproteinase-9 in human bronchial epithelial cells
stimulated by TNF-
. Because a recent study (13)
demonstrated the presence of activated nuclear factor-
B in asthmatic
airways and inflammatory cells and that nuclear factor-
B is
responsible for the regulation of a number of cytokines (interleukin-1,
interleukin-2, interleukin-6, interleukin-8, granulocyte-macrophage
colony-stimulating factor, regulated on activation normal T cell
expressed and secreted, and TNF-
), nuclear factor-
B may play a
role in airway inflammation. It has been demonstrated that TNF-
exerts its effects via nuclear factor-
B. Nuclear factor-
B
activation may be regulated at several potential points, including
signal transduction, I
B degradation, and nuclear translocation of
nuclear factor-
B. Although antioxidants inhibit nuclear
factor-
B-mediated cytokine production in some cell lines, the role
of nuclear factor-
B in airway epithelial cells has not yet been
determined (9, 21). Our data showed that TNF-
increased nuclear factor-
B activation in human bronchial epithelial cells and
that this expression is inhibited by the antioxidants pyrrolidine dithiocarbamate and N-acetyl-L-cysteine. In
addition, the expression of matrix metalloproteinase-9 induced by
TNF-
was inhibited by pyrrolidine dithiocarbamate and
N-acetyl-L-cysteine. However, an AP-1 inhibitor, curcumin,
did not show the inhibitory effect of nuclear factor-
B activation.
These data suggest that activation of nuclear factor-
B induces an
increase in the expression of matrix metalloproteinase-9 after
stimulation of TNF-
in human bronchial epithelial cells, although we
could not show where the point of nuclear factor-
B activation is
regulated. In airway epithelial cells from the human lung carcinoma
cell line A549, TNF-
induces I
B degradation, nuclear factor-
B
activation, and interleukin-8 gene transcription (10).
Moreover, in primary rabbit and human dermal fibroblasts, matrix
metalloproteinase-9 mRNA expression induced by interleukin-1
and
platelet-derived growth factor is inhibited by I
B-
overexpression
(2). Recently, it has been reported (16) that
protein kinase C activation stimulated by TNF-
induces I
B kinase
activation and I
B degradation. Our data showed that treatment with a
nonselective protein kinase C inhibitor inhibited the nuclear
factor-
B activation induced by TNF-
. Therefore, matrix
metalloproteinase-9 may be expressed via activation of nuclear
factor-
B through protein kinase C activation.
Although these data indicated that activation of nuclear factor-B
induces expression of matrix metalloproteinase-9 after treatment with
TNF-
, we should examine the possibility that the antioxidants
pyrrolidine dithiocarbamate and
N-acetyl-L-cysteine affected other transcription
factors and signal transduction systems. In bacteria and eukaryotic
cells, oxidative stress-responsive transcription factors unrelated to
nuclear factor-
B are likely to exist (35). Their
activation should also be suppressed by pyrrolidine dithiocarbamate and
N-acetyl-L-cysteine. Although our data showed
that the AP-1 inhibitor did not decrease matrix metalloproteinase-9
secretion by TNF-
, further studies will be required to explain the
pathway of expression of matrix metalloproteinase-9 in detail after
stimulation with TNF-
.
In conclusion, TNF- increased the expression of matrix
metalloproteinase-9 and induced an imbalance between matrix
metalloproteinase-9 and TIMP-1 in human bronchial epithelial cells. The
nuclear factor-
B-mediated pathway plays a role in matrix
metalloproteinase-9 expression induced by TNF-
in human bronchial
epithelial cells.
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ACKNOWLEDGEMENTS |
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We thank Dr. Karl Tryggvason (Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden) for providing the matrix metalloproteinase-9 cDNA probe. We also thank Dr. T. Ishida and Dr. T. Takahashi (First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan) for teaching us the methods of investigation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y. Nishimura, First Dept. of Internal Medicine, Kobe Univ. School of Medicine, 7-5-1 Kusunoki-cho, Chuo-Ku, Kobe 650-0017, Japan (E-mail: nishiy{at}med.kobe-u.ac.jp).
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.
Received 28 July 2000; accepted in final form 14 August 2001.
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