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From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Many MMPs share similar promoter structures and are co-regulated in vitro and in vivo.8-10 However, MMP expression may also be selective; for example, tumor necrosis factor (TNF) and interleukin (IL)-1 selectively induce MMP-9 in human macrophages.11,12 In fibroblasts, transcription of MMP-1 is dependent on an upstream -72 AP-1 site; neighboring this is a PEA-3 site that is also implicated in control of MMP-1 gene expression.13 Promoter deletion studies in monocytic cell lines indicate that regulation of MMP-1 requires the -72 AP-1 site but this site is not sufficient for MMP-1 expression.14
Almost all cells are subjected to mechanical stresses in their environment. Most studies of mechanotransduction at the cellular level have focused on differentiated cells with clear mechanical roles, such as osteoblasts, vascular smooth muscle cells, and cardiac myocytes. These studies indicate that multiple transduction pathways may participate in converting mechanical signals into biochemical signals, including stretch-activated ion channels, paracrine growth factors, G proteins, mitogen-activated protein (MAP) kinases, integrins, tyrosine kinases, and phospholipid metabolism.15-17 Rapid mechanotransduction signals such as tyrosine kinase activation are followed by other events over the ensuing minutes, including immediate-early gene induction. Transcription of c-fos, c-jun, and egr-1 is rapidly induced in many cell types. These events are followed by cell-specific responses that may include cell migration, changes in cell proliferation rate, and changes in extracellular matrix metabolism.18-20
Once a monocyte infiltrates a tissue, it establishes extracellular matrix contacts and may be subjected to deformation through those contacts. Although the monocyte/macrophage participates in the wound response, remarkably little is known about how these cells respond to mechanical stimuli. Martin et al21 hypothesized that changes in morphology are a common feature of macrophage activation and that stretch-activated ion channels may play a role. They identified an outwardly rectifying potassium channel that is inactive at rest but activated by adhesion of cells or stretch of the membrane. Thus, macrophages, like smooth muscle cells,22 have stretch-activated channels which can transduce mechanical signals. Mastsumoto et al23 studied morphology of the monocyte-like cell line U-937 and rat peritoneal macrophages and suggested that cyclic stretch inhibits the differentiation to vacuolized cells and facilitates the differentiation to spindle cells.
These studies support the hypothesis that monocytes/macrophages are indeed mechanoresponsive. However, little is known about specific gene expression changes in monocytes/macrophages subject to deformation, particularly genes relevant to extracellular matrix degradation. Therefore, we tested the hypothesis that human monocytes/macrophages respond to controlled deformation with relevant molecular responses by studying MMP regulation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RPMI 1640 (Dulbecco’s modified Eagle’s medium) was obtained from
BioWhittaker (Walkersville, MD). Human serum was from ICN
Pharmaceuticals, Costa Mesa, CA. Dulbecco’s phosphate-buffered
saline (PBS) solution, Hanks’ balanced salt solution, fibronectin,
laminin, trypsin, phorbol 12-myristate 13-acetate (PMA), recombinant
human IL-1
, TNF-, and other materials required for tissue culture
were purchased from Life Technologies, Inc. (Gaithersburg, MD).
Lipopolysaccharide (LPS), N-acetyl-L-cysteine,
Tris, glycine, sodium chloride, and sodium dodecyl sulfate were
obtained from Sigma Chemical Co. (St. Louis, MO). Prestained low
molecular weight markers and acrylamide gel buffer were purchased from
Bio-Rad. [ -32P]dCTP (3000 Ci/mmol) was
purchased from Dupont-NEN (Boston, MA).
Monocyte Isolation
Monocytes were isolated from human peripheral blood mononuclear cells by the Histopaque-Ficoll gradient method.24 White cell packs from platelet donors were obtained from Brigham and Women’s Hospital Blood Donor bank. Aliquots of 15 ml of human peripheral blood mononuclear cells were gently layered on 15 ml of Histopaque solution (Sigma Co.). RPMI 1640 (10 ml) with 1% penicillin and streptomycin sulfate was supplemented with 10% human serum and added. After centrifugation for 20 minutes at 25°C, the cell layer was harvested and mixed with fresh RPMI 1640 medium and centrifuged at 400 g for 5 minutes. Precipitated pellets were resuspended with RPMI 1640 medium containing 10% human serum and plated in a T-150 flask for 2 hours. Lymphocytes were removed after extrinsic washing three times with Hanks’ Ca2+, Mg2+ solution and adhered monocytes were maintained with RPMI- 1640 medium supplemented with 10% human serum at 37°C, 5% CO2. The isolated monocytes have undergone adhesion during isolation and we refer to these cells as monocytes/macrophages.
Mechanical Strain
Mechanical deformation was applied to a thin and transparent membrane on which cells were cultured, an approach which produces controlled cellular strain as well as visualization of cells. This device provides a nearly homogeneous biaxial strain profile; that is, strains that are equal at all locations on the membrane and in all directions.25 An advantage of this device over some commonly used systems is that it eliminates locations on the substrate which have very high strains (20 to 30%) in one direction. In our device, at the extreme perimeter of the dish, strains in the circumferential direction are reduced.26 However, very few cells grow at the extreme periphery of the well, as commonly found in all culture dishes. We have previously measured membrane strains with a high-resolution video device;26 the cams used for this study gave strains of 1.0 ± 0.1%, 4.2 ± 0.1%, and 9.5 ± 0.1% (n = 18 different locations for each). For the preparation of monocytes/macrophages to be subjected to mechanical strain, autoclaved membrane dishes were coated with 2 µg/ml of fibronectin in 13 ml of Hanks’ Ca2+, Mg2+solution for 6 to 12 hours at 4°C and then washed twice with 10 ml of PBS. Monocytes/macrophages were plated on the coated membrane at a density of 1,000,000 cells/dish in 13 ml of RPMI 1640 containing 10% human serum and incubated for 4 to 5 days. For culturing monocytes/macrophages on laminin, 1 µg/ml of laminin was used. Before mechanical strain or mitogen stimulation, media was replaced with 10 ml of fresh medium. Mechanical strain was then applied at 1 Hz and control dishes were treated identically but received no mechanical strain. In some experiments, LPS (1 µg/ml) or phorbol myristate acetate (162 µmol/L) was used.
Northern Analysis and Gel-Shift Assay
Total RNA was isolated by the guanidinium isothiocyanate
and phenol chloroform method.27
The full-length 1.47-kb
MMP-1 (interstitial collagenase-1), full-length 1.5-kb MMP-3
(stromelysin), and 652 bp of TIMP-1 cDNAs were used as probes (gift
of Merck Research Laboratories, West Point, PA). The full-length
c-jun probe was obtained from Dr. Peter Libby and the
cDNA for c-fms was obtained from Dr. D. Tenen (both of
Harvard Medical School). For the preparation of the
c-fos probe, human vascular smooth muscle cells were
stimulated with PMA (162 µmol/L) for 1 hour after 48 hours serum
deprivation. Purified RNA (2 µg) was used for the synthesis of cDNA
by Moloney murine leukemia virus reverse transcriptase with a reverse
transcriptase-polymerase chain reaction (PCR) system (Stratagene, La
Jolla, CA). Synthesis of the c-fos cDNA was performed by PCR
reaction with Taq polymerase (Perkin Elmer, Foster City,
CA). The primer set for the synthesis of c-fos was
5'-CTA-CGA-GGC-GTC-ATC-CTC-CCG-3'-sense and
5'-TAC-GGC-GTT-GGC-CTC-CTC-CCT-CGA-3'-antisense oligonucleotides,
yielding a 431-bp cDNA. We used a 438-bp 5'-coding region probe for
human PU.1 (gift of Dr. Francoise Moreau-Gachelin, Institut
Curie, Paris, France) which lacks the 3' ets binding sequence to
avoid hybridization to other ets families.28
The cDNA
probe for MMP-9 (92-kd gelatinase) was synthesized by PCR with the
primer set: sense 5'-GGC-GCT-CAT-GTA-CCC-TAT-GT-3' and antisense
5'-TCA-AAG-ACC-GAG-TCC-AGC-TT-3' to generate a 468-bp PCR product. The
probes were radiolabeled by the random priming method with
[-32P]dCTP and the Klenow fragment of DNA
polymerase (Stratagene). For Northern blotting, 15 µg of RNA was
loaded on a 1.0% agarose-formaldehyde gel (2.0 mol/L), transferred to
a nylon membrane (Amersham Life Science, Arlington Heights, IL)
and UV crosslinked with a UV Stratalinker (Stratagene). The probe was
hybridized with ExpressHyb solution (Clontech, Palo Alto, CA) at 68°C
for 1 hour. The membrane was washed with a 2x SSC, 0.05% sodium
dodecyl sulfate (SDS) solution for 30 to 40 minutes, three times at the
room temperature and 0.1x SSC, 0.1% SDS solution with continuous
shaking at 50°C for 40 minutes. The membrane was exposed to X-ray
film at -80°C. Quantitation of western analyses was performed by
scanning densitometry using the Optimas 5.2 software package (Optimas
Corp., Bothell, Washington). Electrophoretic mobility shift assays were
performed as previously described by Pierce et al,14
using
the identical oligonucleotide with the MMP-1 AP-1 site.
Western Analysis
Conditioned media were concentrated by Centricon 10 miniconcentrators (Millipore, Bedford, MA). Samples were loaded on a 10% SDS-polyacrylamide gel and transferred to a nitrocellulose membrane in 25 mmol/L Tris base (pH 8.5), 0.2 mol/L glycine, 20% methanol. The nitrocellulose membrane was blocked by 5% nonfat-dried milk in Tris-buffered saline (TBS) washing buffer containing 20 mmol/L Tris base (pH 7.6), 137 mmol/L NaCl, 0.1% Tween 20 for 2 hours. For the detection of MMP-1, the membrane was incubated with 1:2000 diluted rabbit anti-human MMP-1 polyclonal antibody (gift of Merck Research Laboratories) for 1 hour at 37°C and washed with TBS washing buffer for 30 minutes. The secondary antibody, goat anti-rabbit IgG coupled to peroxidase, was diluted 1:4000 and incubated with membrane for 30 minutes. After washing with TBS washing buffer for 30 minutes, the membrane was developed with the enhanced chemiluminescent method (Amersham Life Science).
Gelatin Zymography
Conditioned media were loaded on a 10% SDS-polyacrylamide gel containing 1 mg/ml of gelatin. Electrophoresis was performed in Tris-glycine buffer for 4 hours and the gel was then incubated in 2.5% Triton X-100 solution for 15 minutes twice to remove SDS. To detect gelatinase activity, the gel was incubated in reaction buffer containing 50 mmol/L Tris-HCl (pH 7.4), 10 mmol/L CaCl2, and 0.05% Brij 35 overnight at 37°C. The gelatinolytic activity was shown by staining with 0.1% (w/v) Coomassie brilliant blue R-250, 10% (v/v) glacial acetic acid, and 30% (v/v) methanol and destained with 10% (v/v) acetic acid and 30% (v/v) methanol.
All experiments presented were performed at least twice with representative data shown. Quantitative data are presented as the mean ± SD from at least three independent experiments, and comparisons were made by a two-sided Student’s t-test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study the effect of deformation on the regulation of MMP-1
expression, human monocytes/macrophages were subjected to 4%
mechanical strain at 1 Hz for 24 hours. Total RNA was isolated and
analyzed by Northern blotting (Figure 1)
.
Mechanical strain alone did not induce MMP-1 expression by human
monocytes/macrophages. PMA induced MMP-1 expression, and strain
augmented MMP-1 expression induced by PMA by (5.1 ± 0.7-fold,
n = 4, P < 0.05). No apparent
morphological changes were caused by strain at applied 4% amplitude at
1 Hz; we have observed evidence of monocyte cellular injury or
detachment only at strains of at least 14% (data not shown). We then
studied the effect of deformation on the regulation of MMP-3
expression. Co-expression of MMP-1 with MMP-3 level has been observed
in vivo10
and the promoters of MMP-1 and MMP-3
have similar structures.8
Mechanical strain alone did not
induce MMP-3 expression by human monocytes/macrophages, similar to the
findings with MMP-1. PMA induced MMP-3 expression, and strain augmented
MMP-3 expression induced by PMA by (1.6 ± 0.1-fold,
n = 4, P < 0.05). TIMP-1 was induced
by PMA, and this was minimally augmented by strain by (1.3 ±
0.1-fold, n = 4, P < 0.05).
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. Strain of
4% or greater induced MMP-1 gene expression in monocytes/macrophages.
Time course experiments showed that the enhanced MMP-1 gene expression
occurred at 24 hours (and not at 6 hours or earlier), and
cycloheximide (10 µmol/L) inhibited the enhanced expression of
MMP-1 by strain (see Figure 4B
).
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. As observed
at the steady-state mRNA level, strain augmented MMP-1 synthesis in the
media induced by PMA. No MMP-1 protein was detectable in lysates of the
cell monolayer (data not shown). We have previously reported that
strain (applied in an identical manner as used in this study)
suppressed MMP-1 expression by human vascular smooth muscle
cells.29
Thus, deformation may have dramatic cell-specific
effects on MMP-1 expression.
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We then studied the effect of strain on MMP-9 (92-kd gelatinase) expression. Although many MMPs have similar promoter structures, expression of gelatinases may diverge from MMP-1 and MMP-3 and also can be tissue specific.30,31 Northern analysis demonstrated that MMP-9 expression was constitutive and not influenced by PMA or LPS, even in the presence of strain (data not shown). We also analyzed MMP-9 and MMP-2 by gelatin zymography. MMP-9 (92-kd gelatinase) was the major gelatinolytic activity in monocytes/macrophages and was not changed by mechanical strain. MMP-2 (72-kd gelatinase) activity was trivial compared with MMP-9 activity and unchanged by strain (data not shown). These results demonstrated that the strain effect on MMPs in monocytes is specific for MMP-1 and MMP-3 expression.
Strain Regulates Immediate Early Gene Expression
Transcriptional regulation of MMP-1 requires a -72 AP-1 site in
the 5'-flanking region; this site is necessary, but not sufficient, for
PMA induction of the MMP-1 gene.13,14
It is likely that
the induction of MMP-1 by strain is regulated by transcription factors
that interact with these sites. We studied regulation of
c-fos and ets-1 expression in
monocytes/macrophages by mechanical deformation. Induction of
c-fos was observed at 30 minutes after strain (Figure 4A)
and was not observed in controls with
simple media exchange. We have previously reported that mechanical
deformation down-regulates ets-1, a transcription factor
that interacts with PEA-3 sites, in vascular smooth muscle cells; we
did not detect ets-1 expression in monocytes/macrophages in
the presence or absence of mechanical deformation (data not shown).
We also studied regulation of PU.1, a transcriptional factor
of the ets family, and c-jun by mechanical deformation,
because a negative regulatory role of PU.1 interacting with
c-jun on MMP-1 expression has been reported in
fibroblasts.32
In monocytes/macrophages, we observed
PU.1 expression in unstrained cells, but both
PU.1 and c-jun expression increased at 30 minutes
after strain (Figure 4B)
. Induction of these immediate early genes in
monocytes by strain demonstrates mechanoresponsiveness of
monocytes/macrophages; these transcriptional factors may participate in
not only MMP-1 regulation but also possibly in differentiation of
monocytes/macrophages.
Although mechanical induction of c-fos and c-jun
was observed in the absence of PMA, MMP-1 induction was only observed
in the presence of PMA. This observation suggests that induction of
MMP-1 in the presence of PMA is not simply due to c-fos and
c-jun increases. To explore this, monocytes/macrophages were
cultured in the presence of PMA and subjected to strain (Figure 5A)
. When PMA was added at the same time
as strain, dramatic increases of c-fos and c-jun
were observed. A similar induction of jun-B was observed,
although induction of fos-B was not observed (data not
shown). However, when PMA was added 2 hours before initiation of
strain, c-fos and c-jun were noted to be
increased in the absence of strain, such that further induction by
strain was barely apparent. Because MMP-1 expression was measured over
24 hours, it is therefore possible that induction of c-fos
and c-jun by strain is unrelated to induction of MMP-1 by
strain in the presence of PMA, as PMA itself induces these factors. We
also performed electrophoretic mobility shift assays using an
oligonucleotide that contained the MMP-1 -72 AP-1
site.14
Although PMA induced binding of nuclear extract to
the AP-1 site, strain alone did not induce this activity. Strain only
modestly induced further binding, suggesting that enhanced activation
of the -72 AP-1 site alone does not explain the augmentation of MMP-1
synthesis by strain (Figure 5B)
.
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). This induction was rapid (within 30
minutes), occurring at the same time as induction of PU.1.
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To study potential factors mediating MMP-1 induction by strain, we
measured the concentration of IL-1ß released in conditioned medium by
enzyme-linked immunosorbent assay assay. Strain at 4% did not induce
IL-1ß release; we have detected IL-1ß release by deformed
monocytes/macrophages, but only at strains of at least 14% (data not
shown). We also studied MMP-1 regulation in direct response to
exogenous recombinant human IL-1 and TNF- (both 10 ng/ml added at
the initiation of strain), because TNF- is induced by
PMA.33
Northern analysis showed that neither IL-1 nor
TNF- at high concentrations (10 ng/ml) induced MMP-1 expression in
the presence or absence of strain, whereas parallel experiments with
the same cytokines demonstrated induction of MMP-1 in cultured human
aortic smooth muscle cells (data not shown). Thus, these findings
indicate that the effect of strain on the regulation of MMP-1 is not
mediated by paracrine IL-1 or TNF- release.
Several recent studies indicate that reactive oxygen species may
participate in mechanotransduction.34-36
In addition,
Galis et al37
showed that LPS and PMA induced MMP-9
expression via a reactive oxygen species mechanism. To test the
hypothesis that MMP-1 induction by mechanical strain is mediated by
reactive oxygen species, human monocytes/macrophages were pretreated
with 10 mmol/L N-acetyl cysteine for 30 minutes. Northern analysis
indicated that the effect of strain on the regulation of MMP-1 is not
mediated by reactive oxygen species (Figure 7)
.
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The extracellular matrix can strongly influence both
mechanoresponsiveness and MMP-1 regulation.38,39
We
studied mechanoresponsiveness of MMP-1 regulation by
monocytes/macrophages cultured on laminin (1 µg/ml) compared to
fibronectin (we have been unable to attach monocytes/macrophages to the
membrane by type I collagen). We observed the same efficiency of
cellular adherence of human monocytes/macrophages to laminin compared
to fibronectin, and morphological differences were not observed. After
deformation, total mRNA was isolated and analyzed by Northern blotting
(Figure 8)
. Similar to
monocytes/macrophages on fibronectin, monocytes/macrophages deformed on
laminin augmented MMP-1 expression with negligible changes in TIMP-1
expression. However, on laminin, LPS alone did not induce MMP-1, but
strain in the presence of LPS induced MMP-1 expression. This result
shows that MMP-1 regulation by mechanical deformation is matrix
dependent.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several lines of evidence indicate that mechanical events modulate MMP expression. Werb and colleagues41,42 showed that expression of interstitial collagenase (MMP-1) and stromelysin (MMP-3) by rabbit synovial fibroblasts depended on alteration of cellular morphology through the cytoskeleton. In addition, MMP-1 can be induced in a monolayer culture of vascular smooth muscle cells by mechanical injury of the monolayer.43 We recently reported that highly controlled deformation of vascular smooth muscle cells can, in fact, suppress MMP-1 expression.29
We hypothesized that mechanical strain may regulate expression of MMPs
by monocytes/macrophages. In this study, we found that mechanical
strain induced MMP-1, MMP-3, and TIMP-1 expression in the presence of
PMA, whereas MMP-9 expression was not changed. These data show that the
effect of deformation on the regulation of MMPs is selective. Cytokines
secreted by macrophages are known to play an important role in
expression of MMPs.44,45
In our study, exogenous TNF-
and IL-1 did not induce MMPs in the same manner that strain and PMA
did, suggesting that these cytokines were not responsible. However, we
cannot exclude the possibility that other cytokines are involved. In
addition, PMA can cause changes in cell shape and spreading; in this
study, after cells were cultured and spread for 4 to 5 days, we noted
no changes in cell morphology after treatment with PMA.
Induction of c-fos and c-jun could potentially activate AP-1 sites and promote MMP-1 expression. In contrast, PU.1 may function as a negative regulator of MMP-1 expression. In this study, both PU.1 and MMP-1 were induced by deformation, suggesting that PU.1 was not functioning as a suppressor of MMP-1 expression. PU.1 is an essential gene for monocyte differentiation.46-48 Interaction between PU.1 and c-jun in the activation of the promoter of macrosialin, a murine transmembrane protein associated with macrophage differentiation, has been reported.49 We have also shown the induction of the gene for the MCSF receptor. This raises the intriguing possibility that mechanical deformation may promote monocyte to macrophage differentiation.
Contact with specific extracellular matrix components potently regulates mechanotransduction.38 To test the hypothesis that MMP-1 regulation by mechanical deformation depends on matrix composition, we cultured monocytes/macrophages on laminin. We found that mechanical strain induced MMP-1 expression treated with PMA in the same manner as fibronectin. Interestingly, we also observed induction of MMP-1 by mechanical strain in cells treated with LPS on laminin, an effect not seen on fibronectin. It is possible that interactions with specific integrin subunits matrix may explain the differences between fibronectin and laminin in LPS-treated monocytes/macrophages. Because membranes coated with poly-L-lysine did not support adhesion of the cells, we were unable to determine whether adhesion without integrins changed the mechanostimulation effect.
It is important to note that all cell monolayer deformation devices will have shear forces caused by movement of fluid over the membrane, and we cannot exclude an effect of shear stress. In fact, in our device shear stresses are not uniform because the device has been designed to provide uniform strains rather than uniform shear stress. Preliminary results using computational fluid mechanic methods indicate that these shear stresses are extremely low and dependent on depth of media and frequency (Thomas Brown, personal communication). Furthermore, increases in expression of MMP-1 with strain were paralleled by increases in TIMP-1. In repeated experiments we found using a fluorescent MMP-1 substrate that the net activity of MMP-1 remained zero in the culture supernatants, possibly due to concomitant expression of TIMP-1, expression of other TIMPs, or inadequate activation of pro-MMP-1 (data not shown). Thus, our in vitro observations should not be extrapolated directly to the assumption that strain of a tissue with macrophages will increase collagen degradation.
Mechanical activation of monocytes/macrophages could have implications for wound repair. One particular circumstance where this effect could participate in human pathophysiology is the atherosclerotic lesion. In unstable atherosclerotic lesions, regions of high mechanical stress are frequently infiltrated with monocytes/macrophages overexpressing MMP-1. Degradation of collagen fibrils in this location may be an important factor in destabilizing the lesion. Our data suggest that mechanical factors may participate in promoting MMP synthesis in these locations.
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Footnotes |
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Supported in part by a Grant-in-Aid from the American Heart Association, and National Heart Lung and Blood Institute grants HL-54759 and HL-61794.
Accepted for publication January 24, 2000.
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