1 Research Service, Southern Arizona Veterans Health Care System, and Arizona Respiratory Center, University of Arizona, Tucson, Arizona 85723; and 2 The First Department of Internal Medicine and 3 The Second Department of Surgery, School of Medicine, Shinshu University, Matsumoto, Japan 390-0802
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ABSTRACT |
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Chemotactic chemokines can
be released from lung fibroblasts in response to interleukin (IL)-1
and tumor necrosis factor (TNF)-
. An imbalance between proteases and
antiproteases has been observed at inflammatory sites, and, therefore,
protease inhibitors might modulate fibroblast release of chemotactic
cytokines. To test this hypothesis, serine protease inhibitors (FK-706,
1-antitrypsin, or
N
-p-tosyl-L-lysine chloromethyl
ketone) were evaluated for their capacity to attenuate the release of
neutrophil chemotactic activity (NCA) or monocyte chemotactic activity
(MCA) from human fetal lung fibroblasts (HFL-1). Similarly, the release
of the chemoattractants IL-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, macrophage colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor, from
HFL-1, were evaluated in response to IL-1
and TNF-
. NCA, MCA, and
chemotactic cytokines were attenuated by FK-706. However, matrix
metalloproteinase inhibitors were without effect, and cysteine protease
inhibitors only slightly attenuated chemotactic or cytokine release.
These data suggest that IL-1
and TNF-
may stimulate lung
fibroblasts to release NCA and MCA by a protease-dependent mechanism
and that serine protease inhibitors may attenuate the release.
neutrophil; monocyte; interleukin-8; monocyte chemoattractant protein-1; granulocyte/macrophage colony- stimulating factor
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INTRODUCTION |
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A BROAD SPECTRUM OF INFLAMMATORY lung disorders is characterized by tissue destruction and remodeling, caused by an excess of protease activity, e.g., adult respiratory distress syndrome, pulmonary emphysema, bronchopulmonary dysplasia, and cystic fibrosis (2, 3, 48). Protease inhibitors may protect the lung from detrimental destruction by proteases. However, antiproteases may also modulate neutrophil migration (22, 23, 40). This observation suggests that protease inhibitors not only might act directly on proteolysis but may also attenuate inflammation by inhibiting production of chemokines.
The fibroblast is the principal connective tissue cell involved in the
synthesis of the collagenous and noncollagenous components of the
extracellular matrix. This synthetic activity serves an important
structural function by providing a frame network for organ integrity.
In addition to this traditionally accepted function, recent studies
have demonstrated that fibroblasts may also participate in the
orchestration of acute and chronic inflammation. In this context,
fibroblasts release monocyte chemoattractant protein-1 (MCP-1),
granulocyte/macrophage colony-stimulating factor (GM-CSF), and
transforming growth factor-, in response to inflammatory cytokines
such as interleukin (IL)-1
and tumor necrosis factor (TNF)-
(25, 26, 28, 33). Moreover, fibroblasts secreted a
variety of proteases, including plasmin (10), fibroblast
activation protein (37), tissue-type plasminogen activator
(46), urokinase-type plasminogen activator
(16), and a calcium-dependent serine protease (34). Therefore, the fibroblast, because of its anatomical
location and protease secretion, is in a pivotal position to
participate in and direct communications between interstitial and
vascular events in pulmonary inflammation and fibrosis.
On the basis of the rationale above, the purpose of this study was to demonstrate that protease inhibitors modulate the release of proinflammatory cytokines by HFL (human fetal lung)-1 cells. The results demonstrate that the serine protease inhibitor FK-706 inhibited the release of neutrophil chemotactic activity (NCA) and monocyte chemotactic activity (MCA) from the lung fibroblast cell line, HFL-1. These results suggest that the interaction between HFL-1 and proinflammatory cytokines involves proteolytic mechanism(s) and that protease inhibitors may have the potential for modulating lung inflammation.
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MATERIALS AND METHODS |
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Cell cultures. HFL-1 fibroblasts (lung, diploid, human, passage 14) were purchased from American Type Culture Collection (Rockville, MD). The HFL-1 cells were cultured, according to previously described methods, in Ham's F-12 medium with 10% heat-inactivated fetal bovine serum (24, 35, 36). After 2-4 days in culture, the cells had reached confluence and were then used for experiments.
Protease inhibitors and stimulants.
FK-706
(C26H32F3N4NaO7;
Fujisawa Pharmaceutical, Osaka, Japan) was used as a serine
protease inhibitor (38). HFL-1 cells were exposed to human
recombinant IL-1 (500, 50, 5, and 0.5 pg/ml; Sigma, St. Louis, MO)
or TNF-
(100, 10, 1, and 0.1 ng/ml; Sigma) at 37°C in a humidified
5% CO2 atmosphere for 24 h. In some experiments, HFL-1 cells were pretreated with several concentrations of the serine
protease inhibitors FK-706 (50, 10, and 5 µg/ml),
1-antitrypsin (200, 100, and 10 µg/ml; Sigma), or
N
-p-tosyl-L-lysine chloromethyl ketone (TLCK; 200 and 100 µM; Sigma). In the other experiments, the
cysteine protease inhibitor, leupeptin (200 and 100 µM; Sigma), or a
metalloprotease inhibitor of neutral endopeptidase 24.11, phosphoramidon (200 and 100 µM; Sigma), were used. The concentrations of FK-706 were based on results showing that neutrophil
elastase-induced lung hemorrhage of mice was significantly inhibited by
intratracheal treatment with FK-706 at a dose from 1 to 100 µg
(38). In addition, the concentrations of other protease
inhibitors were based on previous studies (22, 23). In
some cultures, neutrophil elastase (Elastin Products, Owensville, MO)
was used to reverse the effects of FK-706. IL-1
and TNF-
were
tested for LPS contamination, and LPS was shown to be <0.1 ng/ml.
These cytokines did not cause HFL-1 cell injury (no deformity of cell
shape, no detachment from culture dish, and >98% viability by trypan
blue exclusion) after 24 h of incubation at the highest
concentration used. The culture supernatant fluid was harvested and
frozen at
80°C until assay. At least six separate HFL-1 cell
supernatant fluids were harvested from cultures for each experimental condition.
Measurement of cytokines in the supernatant fluids. The concentrations of IL-8, MCP-1, macrophage colony-stimulating factor (M-CSF), granulocyte colony-stimulating factor (G-CSF), and GM-CSF were measured in the cell supernatant fluids using commercially available ELISAs (R&D Systems, Minneapolis, MN), according to the manufacturer's instructions, in duplicate. The minimum concentrations detected by these methods were 10 pg/ml for IL-8, 5.0 pg/ml for MCP-1, 9.0 pg/ml for M-CSF, 20 pg/ml for G-CSF, and 3.0 pg/ml for GM-CSF.
Effects of protease inhibitors on NCA and MCA by HFL-1 supernatant fluids. Polymorphonuclear leukocytes were purified from heparinized normal human blood by the method of Böyum (4). The resulting cell pellet consisted of >96% neutrophils and >98% viable cells as determined by trypan blue and erythrosin exclusion. The cells were suspended in Gey's balanced salt solution (GIBCO, Grand Island, NY) containing 2% bovine serum albumin (BSA; Sigma) at pH 7.2 to give a final concentration of 3.0 × 106 cells/ml. This suspension was used for the neutrophil chemotaxis assay.
Mononuclear cells for the chemotaxis assay were obtained from normal human volunteers by Ficoll-Hypaque density centrifugation to separate red blood cells and neutrophils from mononuclear cells. The preparation routinely consisted of 30% large monocytes and 70% small lymphocytes determined by morphology andEvaluation of mRNA expression.
Cytokine mRNA was analyzed by RT-PCR. HFL-1 cells were incubated with
FK-706 and cytokines for 12 h, and total cellular RNA was
extracted from adherent cells using a modification of the methods of
Chomczynski and Sacchi (7). The RNA was reverse transcribed using a commercially available kit (Promega, Madison, WI).
One microgram of the reverse-transcribed DNA was then mixed with Ready
to Go PCR Beads (Pharmacia, Piscataway, NJ), and the front and back
primers, using a commercially available primer pair (R&D Systems), were
added at 0.3 µM final concentration. PCR was performed in a Perkin
Elmer 480 thermal cycler using 94°C for 2 min and 26 cycles
consisting of 94°C for 45 s, primer annealing at 55°C for
45 s, and primer extension at 72°C for 45 s, followed by
72°C for an additional 7 min. -Actin was used as a "housekeeping gene" with PCR. The DNA was subjected to agarose gel, and the intensity of the bands quantified by densitometry. The results were
expressed as the ratio of intensity to the
-actin.
Statistical analysis. Data were analyzed by Dunnett's one-way analysis of variance with a Fisher's protected least significant differences test. In all cases, P < 0.05 was considered significant. The data are expressed as means ± SD.
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RESULTS |
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Release of NCA and MCA from HFL-1 cells in response to IL-1 and
TNF-
.
IL-1
or TNF-
stimulated the release of NCA and MCA from HFL-1 in
a dose-dependent fashion (Fig. 1, A-D,
n = 6). The release of
NCA and MCA was observed after 24 h of incubation in
response to 100 pg/ml of IL-1
and 1 ng/ml of TNF-
. IL-1
and
TNF-
induced the release of significant NCA at 5 pg/ml and 0.1 ng/ml, and MCA at 0.1 pg/ml and 0.1 ng/ml, respectively.
|
Effects of FK-706 on cytokine production from HFL-1.
HFL-1 spontaneously released IL-8, MCP-1, M-CSF, G-CSF, and GM-CSF, but
the inflammatory cytokines IL-1 and TNF-
stimulated the release
of these cytokines from HFL-1 (Table 1,
n = 4).
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Effects of protease inhibitors on NCA and MCA.
IL-1 or TNF-
stimulated NCA and MCA from HFL-1. FK-706 inhibited,
in a dose-dependent manner, NCA and MCA from HFL-1 stimulated with
IL-1
or TNF-
(Fig. 3, n = 6). FK-706 alone had no effect on
baseline release of NCA and MCA under control conditions
(P > 0.05). The other serine protease inhibitors
1-antitrypsin and TLCK reduced the IL-1
- or
TNF-
-induced NCA and MCA (Fig. 4, n = 6). None of these inhibitors altered
baseline NCA and MCA release (P > 0.05, Fig. 4).
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Effect of elastase on the anti-inflammatory action of FK-706.
Neutrophil elastase attenuated the anti-inflammatory action of FK-706.
In the sample of preincubated FK-706 and 50 µg/ml of neutrophil
elastase, the inhibition for releases of NCA, MCA, and IL-8 in
response to IL-1 decreased compared with FK-706 (Fig. 6,
n = 4). The preincubated
reagents alone had no effect on baseline releases of NCA, MCA, and
IL-8 under control conditions (P > 0.05).
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Effects of FK-706 on mRNA expression from HFL-1.
Semiquantitative RT-PCR was performed to evaluate the effect of FK-706
on cytokine mRNA expression in HFL-1 (n = 3). IL-1- or TNF-
-induced IL-8 and MCP-1 mRNA expressions were suppressed by
pretreatment with FK-706 (Fig. 7).
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DISCUSSION |
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In the present study, we demonstrated that HFL-1 released NCA,
MCA, and cytokines, including IL-8, MCP-1, G-CSF, M-CSF, and GM-CSF, in
response to proinflammatory cytokines. Several structurally different
serine protease inhibitors attenuated the release of NCA and MCA by the
HFL-1 in response to IL-1 or TNF-
. FK-706 suppressed the
expression of these cytokines. These protease inhibitors had no effect
on NCA or MCA by unstimulated HFL-1. Consistent with these results,
FK-706 treatment of HFL-1 also showed the suppressive effect on
cytokine production and expression of IL-8 and MCP-1 mRNA.
These results suggest that HFL-1 interaction with IL-1
or TNF-
may involve proteolytic mechanisms, and serine protease inhibitors may
modulate the interaction between proinflammatory cytokines and HFL-1.
Protease imbalance has been proposed in the pathogenesis of several
acute and chronic inflammatory diseases, including pulmonary emphysema
(5, 12), adult respiratory distress syndrome
(27, 31), cystic fibrosis (17, 32), chronic
bronchitis (29), septic shock (44), and other
inflammatory states (1, 14). Antiproteases have been
reported to modulate neutrophil migration in response to several
stimuli (22, 23, 40). Furthermore, Churg and coworkers
(8) noted that 1-antitrypsin suppressed silica-induced neutrophil influx and MCP-1 gene expression. Kikuchi et
al. (19) reported that secretory leukocyte protease
inhibitor (SLPI) and
1-antitrypsin augmented hepatocyte
growth factor production in human lung fibroblasts. SLPI has also been
suggested to suppress prostaglandin E2 and
metalloproteinase production in monocytes (49). In this
context, protease inhibitors may reduce lung injury directly by
preventing destruction of connective tissue, but also indirectly by
attenuating recruitment of neutrophils and monocytes to sites of
inflammation. Activated inflammatory cells release a variety of
degradative enzymes, oxygen metabolites, and cytokines, which may lead
to further tissue damage.
We investigated the effect of protease inhibitors on HFL-1 because lung
fibroblasts constitute 35-40% of the cells in the interstitium of
the lung and are activated to proliferate and synthesize various
cytokines during inflammation (24). Moreover, fibroblasts
have been reported to produce large amounts of the chemotactic
cytokines, IL-8, MCP-1, G-CSF, and GM-CSF, in response to various
stimuli (41, 42). In the present study, IL-1 or TNF-
stimulated the release of these cytokines and an increase in NCA and
MCA. These observations are consistent with the concept that
fibroblasts may be an important source of neutrophil and monocyte
chemoattractants in lung inflammation.
The present study confirmed that fibroblasts had the potential for contributing to airway inflammation by releasing NCA and MCA and suggested that an imbalance between protease and antiprotease activity in the lower respiratory tract might augment lung inflammation by modulating the responsiveness of fibroblasts. However, a limitation of these studies was that they were done in vitro with a human fibroblast cell line. The effects of protease inhibitors on primary cultures of human airway fibroblasts and demonstrating this phenomenon in vivo are important issues for future research.
In this study we used phosphoramidon as a matrix metalloprotease
inhibitor, but it did not inhibit either NCA or MCA. Other reports
indicate that matrix metalloprotease inhibitors reduce inflammation in
vivo and in vitro (18, 43). Phosphoramidon is a selective
inhibitor of neutral endopeptidase (NEP), a metalloprotease on the
surface membrane of fibroblasts (15). Moreover, NEP
expression from lung fibroblasts was enhanced by IL-1 and TNF-
(21). In contrast, other reports suggest that NEP may
reduce inflammation by enzymatic cleavage of inflammatory substances,
such as bradykinin (45), substance P (39),
and the chemotactic peptide formyl-Met-Leu-Phe (11). These later observations would suggest that matrix
metalloproteinase inhibitors are unlikely to work as
anti-inflammatories by inhibition of NEP, whose activity may reduce inflammation.
FK-706 is a water-soluble, chloromethyl ketone derivative that inhibits
serine proteases (38). The Ki value
for human neutrophil elastase is 4.2 nM. This compound
inhibits human neutrophil elastase activity and porcine pancreatic
elastase activity with respective IC50 values of 83 and 100 nM. FK-706 acted against elastase-induced lung hemorrhage and
elastase-induced skin edema in animal models (38). FK-706 consists of a trifluoromethyl ketone
motif, as an active site, with a molecular mass of 0.59 kDa. Although
it is not fully understood which signaling pathways were stimulated and/or inhibited in response to protease inhibitors, chloromethyl ketone derivatives reduce activation of NF-B, a major nuclear factor
inducing the release of several inflammatory cytokines (6,
20). In this study, we demonstrated that FK-706 blocked the
release of inflammatory cytokines and suppressed the expression of IL-8
and MCP-1 mRNA. These data indicate that FK-706 may attenuate the
response of lung fibroblasts to IL-1
and TNF-
upstream at or
before transcription, possibly through suppression of NF-
B signaling pathway.
Although most serine protease inhibitors cannot penetrate cell
membranes, the present study revealed that protease inhibitors affected
the responses of HFL-1 cells to proinflammatory cytokines. The
mechanisms of antiprotease inhibition of the inflammatory action,
including receptors and signaling pathways, are still unclear. In
recent years, protease-activated receptors have been described that are
proteolysis-activated G protein-coupled receptors (9, 30).
Neutrophil elastase induces IL-8 gene upregulation in bronchial
epithelial cells through an IL-1 receptor-associated kinase
signaling pathway, suggesting that neutrophil elastase stimulates an as
yet unidentified receptor (47). In this study, neutrophil
elastase attenuated the anti-inflammatory action of FK-706. In this
context, FK-706 may act through protease-activated receptors or other
unidentified mechanisms.
In conclusion, a number of protease inhibitors attenuated NCA and MCA in response to proinflammatory cytokines on HFL-1. Therefore, proteolytic activity appears to play a critical role in the release of NCA and MCA. Antiprotease attenuated this activity at the transcriptional level. Thus extracellular protease inhibitors, such as FK-706, may be effective in attenuating inflammatory interaction between HFL-1 and proinflammatory cytokines.
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ACKNOWLEDGEMENTS |
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This work was supported by a Merit Review grant from the Veterans Administration.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. A. Robbins, Research Service Line, Southern Arizona Veterans Health Care System, 3601 S. 6th Ave., Tucson, AZ 85723 (E-mail: Richard.Robbins2{at}med.va.gov).
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.
First published December 13, 2002;10.1152/ajplung.00211.2002
Received 3 July 2002; accepted in final form 10 December 2002.
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