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Chemokine and cytokine processing by matrix
metalloproteinases and its effect on leukocyte migration
and inflammation
Philippe Van Lint
1
and Claude Libert
2
Departments of Molecular Biomedical Research, VIB, and Molecular Biology, Ghent University, Ghent, Belgium
Abstract: The action of matrix metalloprotein-
ases (MMPs) was originally believed to be restricted
to degradation of the extracellular matrix; how-
ever, in recent years, it has become evident that
these proteases can modify many nonmatrix sub-
strates, such as cytokines and chemokines. The use
of MMP-deficient animals has revealed that these
proteases can indeed influence the progression of
various inflammatory processes. This review aims
to provide the reader with a concise overview of
these novel MMP functions in relation to leukocyte
migration. J. Leukoc. Biol. 82: 000 – 000; 2007.
Key Words: extracellular matrix 䡠ELR
INTRODUCTION
Matrix metalloproteinases (MMPs) form a family of closely
related, zinc-dependent endoproteinases. The first report about
MMPs dates back to 1962, when Gross and Lapiere [1], while
attempting to establish how a tadpole loses its tail during
metamorphosis, discovered the first member of this family
(MMP-1). Since then, the family has expanded gradually; the
latest member discovered is MMP-28 [2], which gives a total of
23 human MMPs. As their name suggests, MMPs were char-
acterized initially as matrix-degrading proteases. Indeed, col-
lectively, these enzymes can degrade all components of the
extracellular matrix (ECM), thereby influencing many impor-
tant processes, such as cell proliferation, differentiation, mi-
gration, and death, as well as cell– cell interactions [3]. It is
therefore not surprising that MMPs play a crucial role in many
physiological processes, e.g., bone morphogenesis, the men-
strual cycle, and development and also, in many pathological
conditions, such as cancer invasion, arthritis, and atheroscle-
rosis. The story has been made even more complex by the
increasing number of studies revealing many nonmatrix sub-
strates for MMPs, such as chemokines, growth factors, and
receptors, indicating that MMPs influence an even wider array
of physiological and pathological processes [4].
Inflammatory conditions are almost always characterized by
deregulated, often increased MMP activities [5]. The central
question is whether these MMPs can influence the outcome of
inflammation and if so, how they do so. Only by understanding
the mechanism by which MMPs exert their function can they
develop into effective drug targets. Indeed, ignorance of the
relevant in vivo substrates is one of the main reasons for the
disappointing and often unexpected results of trials using MMP
inhibitors. Identifying the functions of specific MMPs in spe-
cific pathologies should therefore become a major goal. Ini-
tially, knowledge of MMP substrates was based on in vitro
experiments, in which purified, activated MMPs were incu-
bated with specific substrates. Although these data can be
informative, the question remains whether processing of a
purified substrate under optimal conditions implies that the
same protein is a physiologically relevant MMP substrate in
vivo. In this respect, the use of transgene and knockout tech-
nologies has meant a giant leap forward, as it enables the
testing of MMP functions in vivo.
Apart from occasional, subtle developmental differences,
such as a transient delay in myelination observed in MMP-9
and MMP-12 knockout mice [6], all MMP-deficient animals
have an overall normal development and are viable. A notable
exception is the MT1-MMP (MMP-14) knockout, which dis-
plays severe skeletal deformations and dies shortly after birth
[7, 8]. However, many MMP knockouts challenged by injury,
inflammatory stimulus, infection, or cancer reveal interesting
phenotypes. Indeed, numerous studies have reported that
MMPs play roles in modulating inflammatory reactions by
acting at different levels: leukocyte recruitment, alteration of
the functions of cytokines and proteases, and clearance of the
pathogen [5].
MMPs AND LEUKOCYTE RECRUITMENT
Leukocyte recruitment to the site of injury or infection is a
complex process, which is regulated tightly by the interplay
between endothelial cells and leukocytes, a process in which
chemokines play a central role. These chemotactic cytokines
together help attract leukocytes to the site of infection or
injury, thereby influencing the outcome of an inflammatory
response. They are divided into four structural groups: CC
chemokines (or -chemokines) have two adjacent cysteines
1
Current address: General Hospital Sint-Augustinus, Clinical Laboratory,
Wilrijk, Belgium.
2
Correspondence: VIB, Ghent University, Technologiepark 927, Ghent (Zwi-
jnaarde), East-Flanders 9052, Belgium. E-mail: Claude.Libert@dmbr.Ugent.be
Received June 1, 2007; revised July 19, 2007; accepted July 20, 2007.
doi: 10.1189/jlb.0607338
0741-5400/07/0082-0001 © Society for Leukocyte Biology Journal of Leukocyte Biology Volume 82, December 2007 1
Uncorrected Version. Published on August 20, 2007 as DOI:10.1189/jlb.0607338
Copyright 2007 by The Society for Leukocyte Biology.
near the N terminus; CXC chemokines (or ␣-chemokines), in
which the cysteines are separated by a variable amino acid;
CX
3
C chemokines (or ␦-chemokines) have three variable
amino acids between the two cysteines; and C chemokines (or
␥-chemokines) have only one cysteine at the N terminus [9].
Another important structural property of chemokines is the
presence or absence of a specific tripeptide sequence Glu-Leu-
Arg (ELR), which is important in the interaction with CXCR1
and CXCR2 [10].
Chemokine processing by MMPs
As shown in Table 1, MMP-mediated proteolysis of chemo-
kines is one way by which MMPs can influence leukocyte
trafficking. MMP proteolysis can affect the biological functions
of chemokines in different ways. First, the proteolysis might
inactivate the chemokine. Second, processing might generate
antagonistic derivatives, which can still bind to the chemokine
receptor but cannot promote chemotaxis. Third, the truncated
chemokine is a more powerful chemotactic agent. Whatever the
outcome, chemokine processing undoubtedly affects the pro-
gression of an inflammatory reaction and influences the type of
cells, which are recruited and activated.
It was shown that MMP-2 can cleave CXCL12 (also known
as stromal cell-derived factor-1) to produce a truncated pro-
tein, which appeared to be highly neurotoxic, although it did
not affect chemotaxis directly [11]. CXCL12 inactivation is not
restricted to MMP-2, as MMP-1, MMP-3, MMP-9, MMP-13,
and MMP-14 have been shown to inactivate this chemokine
[12]. MMP-2 was also found to shed the plasma membrane-
associated chemokine CX
3
CL1 (fractalkine) to generate a
soluble chemokine; however, an additional MMP-2-medi-
ated cleavage at the N terminus of the protein inactivates
the chemokine, converting it into a potent, functional an-
tagonist [13].
MMP-9 also inactivates CXCL chemokines. For instance,
CXCL4 (platelet factor 4), a ELR-negative CXC chemokine,
and CXCL1 (growth-related oncogene-␣), a ELR motif contain-
ing CXC chemokine [14], are proteolytically inactivated by
MMP-9. This MMP also degraded CTAPIII, which is the NH2-
terminally extended, inactive precursor of CXCL7 (neutrophil-
activating peptide-2 [14]). CXCL5 [epithelial-derived neutro-
phil-activating factor-78 (ENA-78)] is also cleaved by gelati-
nase B at different sites, resulting in transient potentiation of
this chemokine, but eventually leading to its inactivation [15].
Finally, CXCL9 (monokine induced by IFN-␥) and CXCL10
(IFN-inducible protein 10) are processed C-terminally by
MMP-8 and MMP-9 [16]. At least in the case of CXCL9, this
decreases chemotactic ability drastically and might intervene
with association with the ECM [17].
As mentioned earlier, several inactivated chemokines are
still capable of binding to their receptors and therefore, act as
functional antagonists, preventing the activity of other non-
cleaved chemokines. MMP-2, for instance, was shown to pro-
cess CCL7 (also known as MCP-3) into an antagonistic form
[18]. Other MMPs are also capable of cleaving MCPs to gen-
erate chemotactic antagonists. In addition to MMP-2, CCL7 is
cleaved efficiently by MMP-1, MMP-3, MMP-13, and MMP-14.
The closely related chemokines CCL2 (MCP-1) and CCL13
(MCP-4) could also be cleaved by MMP-1 and MMP-3, the
latter of which also cleaved CCL8 (MCP-2) [19]. Finally,
MMP-8 also processed CCL2, although inefficiently. It is in-
teresting that all the truncated forms generated were shown to
function as inflammatory antagonists when administered in
vivo. This means that MMPs can have anti-inflammatory effects
by dampening the action of chemokines.
In contrast to these examples, MMPs have also been shown
to increase the biological activity of chemokines. Indeed,
MMP-9 was shown to process CXCL8 (IL-8), which led to a
significant increase in its chemotactic activity [14]. MMP-8,
MMP-13, and MMP-14 were later also shown to generate a
truncated IL-8 species with increased activity [20, 21]. More-
over, another human CXCR2 ligand, CXCL5 (ENA-78), was
found recently to be activated by MMP-8 cleavage [21].
The rodent chemokine LIX, which is considered to be the
sole murine counterpart of two closely related human chemo-
kines, namely CXCL5 (ENA-78) and CXCL6 [granulocyte che-
motactic protein 2 (GCP-2)], was found to be processed N-
terminally by MMP-9, with a consequent twofold increase in its
biological activity [15]. MMP-8 was later shown to cleave LIX
N- and C-terminally, generating truncated forms with in-
creased chemotactic activities [22]. Recently, MMP-1, MMP-2,
and MMP-13 were also shown to enhance the biological func-
tion of LIX by processing it N-terminally [21]. These observa-
tions of MMP-mediated LIX activation can have a serious
impact on the course of several neutrophil-driven pathologies,
as mouse LIX is believed to play the same role as IL-8 in
TABLE 1. Chemokine Processing by MMPs and Its Effect on Chemotactic Capacity
LIX CX3CL1 CXCL1 CXCL4 CXCL5 CXCL6
CTAPIII
(CXCL7) CXCL8 CXCL9 CXCL10 CXCL12 CCL2 CCL7 CCL8 CCL13
MMP-1 ⫹⫹⫹ ??—⫺⫺⫺ ⫺⫺⫺ ⫺⫺⫺
MMP-2 ⫹⫹⫹ ⫺⫺⫺ —⫺⫺⫺
MMP-3 —⫺⫺⫺ ⫺⫺⫺ ⫺⫺⫺ ⫺⫺⫺
MMP-8 ⫹⫹⫹ ⫹⫹⫹ 0⫹⫹⫹ —? ⫺⫺⫺
MMP-9 ⫹⫹⫹ ——— 0 —⫹⫹⫹ —? —
MMP-13 ⫹⫹⫹ ⫹⫹⫹ —⫺⫺⫺
MMP-14 ⫹⫹⫹ —⫺⫺⫺
Proteolytic modification of chemokines by MMPs can have different consequences for the chemokines biological activity. For some chemokines, the effect of
proteolysis on their chemotactic capacity was not reported (?), and other chemokines have been shown to become inactivated (–) or transformed into an antagonist
(⫺⫺⫺). Proteolysis can also lead to an increase in chemotactic potency of the chemotactic protein (⫹⫹⫹) or have no effect on chemokine activity (0). Gray boxes
indicate that proteolysis has not been reported. LIX, LPS-induced CXC chemokine; CTAPIII, connective tissue-activating peptide III.
2 Journal of Leukocyte Biology Volume 82, December 2007 http://www.jleukbio.org
humans. Indeed, compared with humans, rodents have few
chemokines. For instance, the mouse has only four ELR-
containing CXC chemokines, which specifically target poly-
morphonuclear cells: LIX, keratinocyte-derived chemokine
(KC), dendritic cell (DC) inflammatory protein-1, and MIP-2, of
which only LIX was found to be processed by MMPs [21].
Finally, it is noteworthy that cleavage does not always alter
the activities of chemokines. An example of this is the N-
terminal cleavage of CXCL6 (GCP-2) by MMP-8 and MMP-9,
which does not affect its biological activity [15].
MMPs modulating chemokine gradients
In vivo, however, instead of being presented to proteases as
soluble proteins, chemokines are immobilized mostly on the
ECM or cell surface by binding to glycosaminoglycans (GAGs)
through positively charged domains. This binding to GAGs
seems to be important for chemokines to exert their role
effectively. IL-8 binding to heparan sulfate leads to structural
stabilization of the dimeric form of the chemokine, resulting in
an extended biological activity and enhanced neutrophil re-
sponses [23]. Some chemokines with mutations in the GAG-
binding sites lose the ability to recruit cells in vivo, but they
retain receptor-signaling activity in vitro [24]. This might mean
that MMPs mediate the function of chemokines indirectly by
releasing chemokines bound to the cell surface or ECM.
The best example of this comes from a study describing the
role of MMP-7 in a bleomycin-induced model of lung inflam-
mation [25]. In response to the mucosal damage, epithelial
cells release KC, which upon secretion, binds to syndecan-1, a
cell-bound heparan sulfate proteoglycan (HSPG). It was al-
ready known that a tissue inhibitor of metalloproteinase 3
(TIMP-3)-sensitive protease could mediate the cleavage of the
intact syndecan-1 and syndecan-4 ectodomains (shedding),
thereby converting the cell-surface molecules into soluble ef-
fectors [26]. Indeed, together with CXCL1, MMP-7 is produced
by these epithelial cells and cleaves the ectodomain of synde-
can-1, thereby releasing the syndecan-1/KC complex. This
creates a chemokine gradient, which triggers neutrophil infil-
tration into the alveolar space. As seen after bleomycin injury,
neutrophils of the MMP-7-deficient animals do extravasate, but
in contrast to their wild-type counterparts, they do not enter the
lumen of the lung. Instead, they are confined to an expanded
perivascular space. As a consequence, survival of MMP-7
knockouts was much better than that of the wild-types. It is
likely that MMP-7 itself first binds to syndecan-1, as MMP-7
has been known to interact with GAGs, which markedly en-
hanced the activity of MMP-7 [27]. Therefore, interaction with
the GAG side-chains of syndecan-1 would make it easier for
MMP-7 to cleave the core protein of this HSPG.
Other experiments have confirmed that MMP-7 is indeed
needed to generate a chemokine gradient, rather than being
indispensable for neutrophil migration as such. Instillation of a
bacterial chemotactic protein in the lungs of MMP-7-deficient
mice did trigger neutrophils to infiltrate the luminal tissue, and
the outcome was worse in these animals than in their wild-type
counterparts [25].
Syndecan shedding is not restricted to MMP-7 and can be
performed by various proteases, including other MMPs.
MMP-9 can shed syndecan-1 and syndecan-4 [28], and MT1-
MMP and MT3-MMP can release the ectodomain of synde-
can-1 [29]. As chemokines, as well as many cytokines and
antimicrobial substances, have the ability to bind to GAGs, this
protease-controlled release of syndecans can affect the pro-
gression of different pathologies.
Besides the study describing the involvement of MMP-7 in
generating a CXCL1 chemokine gradient, other studies report
involvement of MMPs in establishing chemokine gradients.
Our own research has shown that in the liver, following TNF-
induced hepatitis, MMP-8 appears to be indispensable for the
release of yet another neutrophil chemoattractant, LIX [30]. As
a result, neutrophil influx is seriously impaired in mice lacking
a functional Mmp8 gene, which improves survival dramatically.
Moreover, in a model of allergen-induced asthma, leukocytes
accumulated massively in the lung parenchyma but in contrast
to wild-type animals, failed to reach the airway lumen in
MMP-2-deficient animals [31]. This was accompanied by a
large reduction in the levels of CCL11 (eotaxin), a potent
eosinophil chemoattractant, in bronchoalveolar lavage (BAL)
fluids of MMP-2 knockouts. The same group extended the
study by applying the model to MMP-9 knockouts and MMP-
2/9 double-knockouts [32]. In contrast to the results obtained
with the MMP-2 knockouts, in which the reduction in luminal
leukocytes could be attributed entirely to reduced eosinophil
numbers, MMP-9- and MMP-2/9-deficient animals had fewer
eosinophils and neutrophils in their BAL. Furthermore, al-
though absence of MMP-2 affected only CCL11 levels, lack of
MMP-9 led to significantly lower levels of CCL11, CCL7
(MCP-3), and CCL17 (thymus and activation-regulated chemo-
kine). Unfortunately, the mechanism by which both gelatinases
modulate levels of these chemokines in BAL is still unclear.
The fact that MMP-9 seems to promote neutrophil migration in
this model is interesting in view of another study by Ste-
fanidakis et al. [33]. They found that MMP-9 forms a complex
with the ␣
M

2
integrin in the intracellular granules of neutro-
phils and that this complex becomes localized to the cell
surface upon cellular activation. Furthermore, blocking the
interaction between MMP-9 and ␣
M

2
inhibits leukocyte mi-
gration in vitro as in vivo, suggesting that integrin association
might help MMPs in promoting cell migration. Another study,
using a similar asthma model, also showed a marked reduction
in CCL17 BAL levels in MMP-9 knockout mice [34]. However,
this study did not report a difference in the number of recruited
eosinophils and neutrophils [35] but did show fewer DCs
migrating into the airway lumen in the absence of MMP-9 [34].
Furthermore, chondrocyte-derived MMP-3 generated an un-
identified macrophage chemotactic factor, which was required
for disc degradation in a model of herniated disc resorption
[36]. MMP-3-deficient mice also showed reduced neutrophil
recruitment to the airway lumen in a model of IgG-induced
acute lung injury, as well as decreased lung injury [37]. The
mechanism by which MMP-3 influences neutrophil migration
is unknown. However, as neutrophils are not known to produce
MMP-3, it is likely that this protease facilitates neutrophil
migration indirectly, for instance, by generating a chemokine
gradient.
MMP-12, which is predominantly a macrophage protease, is
required for the influx of these cells in a model of smoke-
induced emphysema [38]. As additional instillation of CCL2
Van Lint and Libert Matrix metalloproteinases in inflammation 3
resulted in macrophage migration comparable with that in-
duced in wild-type animals by exposure to cigarette smoke
alone, MMP-12 seems important in establishing a chemotactic
gradient, rather than in macrophage migration as such. Later,
the chemotactic proteins responsible for this phenotype were
identified as being elastin fragments (EFs) [39]. Although it has
been long known that EFs are chemotactic for monocytes in
vitro [40, 41], the study by Houghton et al. [39] is the first
report that shows that MMP-generated elastin fragments can
drive the progression of a disease. Furthermore, neutrophil
migration too seems to be driven partially by the release of
cryptic ECM fragments. Recently, it was shown that pulmonary
ECM proteolysis, following exposure to a bacterial component,
gives rise to a tripeptide chemoattractant, which promotes
neutrophil recruitment [42].
These studies are important, as they show that ECM break-
down can promote chemotaxis, not only by releasing ECM-
bound chemotactic factors but also by exposing cryptic ECM
sites possessing chemotactic properties. Indeed, after so many
chemotactic chemokine family members had been identified,
the chemotactic properties of several ECM-derived fragments
were believed to be, at best, of minimal importance in vivo.
Therefore, these data might ask for a re-evaluation of the in
vivo relevance of cryptic sites of several ECM components,
such as fibronectin, collagen, and laminin [43– 46].
Finally, nonmatrix proteins too, following proteolysis, can
give rise to unexpected chemotaxis-promoting fragments. An
example of this is the MMP-12-mediated cleavage of the ␣1-
proteinase inhibitor, a serine proteinase inhibitor processed by
several MMPs, which generates a fragment that promotes che-
motaxis of neutrophils [47].
MMPs and mobilization of hematopoietic
progenitor cells (HPCs)
The influence of MMPs on leukocyte migration is not limited to
the fate of mature circulating leukocytes but also affects the
trafficking of HPCs from the bone marrow into circulation.
Administrating anti-MMP-9 antibodies to rhesus monkeys to-
tally inhibited the IL-8-induced mobilization of HPCs [48].
Although a similar role for MMP-9 in IL-8-mediated HPC
release could not be shown in mice [49], MMP-9 was shown to
be involved in hematopoietic recovery after depletion of hema-
topoietic cells [50]. This could be explained by the role MMP-9
plays in shedding of the membrane-bound kit ligand, also
known as the stem cell factor. Another study indicated a
possible role for MMP-2 in releasing proteoglycan-bound
CXCL12 from the surface of bone marrow stromal cells,
thereby promoting pro-B cell migration [51].
It should be noted, however, that the influence of MMPs on
leukocyte trafficking is not merely restricted to chemokine
processing and release. Indeed, by degrading a variety of
proteins, which constitute interstitial ECMs, MMPs help leu-
kocytes cross otherwise impassable basement membranes,
such as the blood-brain barrier. For instance, MMP-2 and
MMP-9 were shown to degrade dystroglycan, a critical compo-
nent of the blood-brain barrier, thereby compromising its in-
tegrity and allowing leukocyte trafficking into the CNS during
experimental autoimmune encephalomyelitis [52].
CYTOKINE PROCESSING BY MMPs
The influence of MMPs on the progression of inflammatory
processes is not limited to leukocyte migration, as they process
not only chemokines but also a variety of cytokines. Indeed, as
with chemokines, cytokine proteolysis often leads to altered
bioavailability and activity. Shedding of the proinflammatory
cytokine TNF is one example of how MMPs might influence an
inflammatory reaction by modulating cytokines. TNF is pro-
duced as a trimeric membrane-anchored precursor and re-
leased from the cell surface by a regulated proteolytic step
[53]. In vivo studies have shown that most of the biological
functions of TNF require its shedding and release as a soluble
mediator. Indeed, mice carrying in their pro-TNF sequence a
mutation, which blocks effective release of the membrane-
anchored protein, have defective leukocyte migration [54]. A
disintegrin and metalloproteinase 17 (ADAM-17) is, as its
alternate name TNF-␣-converting enzyme (TACE) suggests,
the main TNF sheddase. The release of active TNF is reduced
by 90% in cells from ADAM-17 knockouts, indicating that
ADAM-17 is the main TACE in vivo [55]. However, it seems
that in specific cellular settings, ADAM-17-independent re-
lease of TNF can become important. In a model of macrophage-
mediated herniated disc resorption, macrophage MMP-7 was
found to be indispensable for TNF shedding [56]. As a result,
MMP-7-deficient macrophages were unable to infiltrate the
disc. Apart from MMP-7, also MMP-1, MMP-2, MMP-3,
MMP-9, MMP-12, MMP-14, and MMP-17 were shown to re-
lease active TNF from the cell surface by a mechanism similar
to that of ADAM-17-mediated TNF release [20, 57, 58].
Another cytokine, IL-1, is produced as an inactive precur-
sor protein, which is activated by proteolytic removal of the
N-terminal part. Caspase-1, also known as IL-1-converting
enzyme (ICE), is an intracellular cysteine protease, which has
been identified as the primary IL-1activator. However, there
is evidence that IL-1can be activated in a caspase-1-inde-
pendent manner in vitro and in vivo. For instance, in response
to turpentine injection, the levels of mature IL-1were not
diminished in ICE⫺/⫺mice [59]. Furthermore, human kera-
tinocytes, which express IL-1, but not active ICE, were
capable of producing mature IL-1[60]. Some MMPs, namely
MMP-2, MMP-3, and MMP-9, were found to activate pro-IL-
1, but MMP-1 could not [61]. This study also showed that
further proteolytic degradation during prolonged incubation
with MMP-3 could eventually inactivate mature IL-1. Indeed,
MMP-mediated IL-1degradation had been reported already a
few years earlier by Ito et al. [62], who found that 4-amino-
phenyl mercuric acetate-activated, conditioned medium from
uterine cervical fibroblasts could degrade mature IL-1and
that this activity could be inhibited by adding TIMP-1 to the
reaction. Using purified MMP extracts, MMP-1, MMP-2,
MMP-3, and MMP-9 were shown to diminish the biological
activity of IL-1. As MMPs and IL-1 often colocalize during
inflammatory conditions, MMPs might influence positively and
negatively the inflammatory process, by activating pro-IL-1or
inactivating the mature form of this cytokine, respectively.
TGF-is an anti-inflammatory cytokine, known to restrain
the mononuclear inflammation, whose activity is tightly regu-
lated. TGF-is produced initially as a precursor protein,
4 Journal of Leukocyte Biology Volume 82, December 2007 http://www.jleukbio.org
which is cleaved in the endoplasmic reticulum by furins into an
amino-terminal fragment, called latency-associated protein,
and a shorter, carboxy-terminal fragment, which is the mature
cytokine. These fragments are assembled as a double-ho-
modimer, called the small latent complex, which is modified
further by disulfide linkage to so-called latent TGF--binding
proteins (LTBPs), thereby forming the large latent complex.
After secretion, this latent TGF-complex is cross-linked to
the ECM, forming a reservoir of latent TGF-in the extracel-
lular environment [63]. Several mechanisms, including MMP
proteolysis, have been implicated in the release of mature
TGF-from the latent complex. MMP-2 and MMP-9 [64] as
well as MMP-3 [65] and MMP-14 [66] have been identified as
TGF-activators. Moreover, MMPs have also been implicated
in the cleavage of LTBPs, thereby releasing TGF-from the
ECM [67]. MMPs can also cause release of TGF-by degrad-
ing decorin, a small, collagen-associated proteoglycan, known
to act as a depot for TGF-in the ECM [68]. If shown that these
pathways of MMP-mediated TGF-activation would be rele-
vant in vivo, this might be another mechanism by which MMP
activity restrains rather than augments inflammation. In con-
trast, MMP activity might also down-regulate TGF-signaling.
MT1-MMP was shown to shed -glycan [69], which is a mem-
brane-bound protein, functioning as a coreceptor for TGF-
and regulating the access of TGF-to its signaling receptors.
However, if released from the cell surface, at least in vitro,
-glycan functions as a TGF-inhibitor by blocking the in-
teraction between TGF-and its cell surface receptors [70].
Finally, processing and subsequent inactivation of IFN-by
MMP-9 offer another example of how MMP-mediated cytokine
proteolysis might influence the progression of an inflammatory
reaction [71].
MMPs might alter the biological activity of cytokines, not
only by direct proteolytic processing but also by shedding their
receptors. Some data suggest that MMPs contribute to the
shedding of soluble Type II IL-1 decoy receptor (sIL-1RII)
from the cell surface, as this shedding was blocked by BB-94,
a broad-spectrum MMP inhibitor [72]. The soluble receptor, by
retaining its ability to interact with IL-1, neutralizes the
biological effects of this cytokine. Thus, MMP release of sIL-
1RII offers another mechanism of how MMPs might dampen
inflammation. In contrast, other data indicate that MMPs can
degrade and therefore inactivate this soluble receptor [73].
This would mean that MMPs support rather than inhibit IL-
1-driven inflammation, but all these data have to be verified
in vivo. Other in vitro studies showed that MMP-9 cleaves
IL-2R␣and thereby, down-regulates the proliferative capabil-
ity of activated T cells by generating antagonistic, sIL-2R␣
chains [74]. The release of the receptor of a structurally related
cytokine, namely sIL-15R␣, could also be blocked by using a
broad-spectrum MMP inhibitor; however, the specific MMPs
responsible remain to be identified [75].
CONCLUSION
During the last decade, it has become clear that MMPs can
influence the progression of various inflammatory conditions.
Some of the phenotypes of MMP-deficient mice could be ex-
plained by the proteolytic activities that these proteases exer-
cise in modulating the activities of various cytokines and
chemokines, as has been shown in vitro. However, although
several substrates have been identified as possible MMP tar-
gets, further identification of relevant in vivo targets is needed
for proceeding with the development of MMPs into effective
drug targets.
ACKNOWLEDGMENTS
The Institute for the Promotion of Innovation through Science
and Technology in Flanders (IWT-Vlaanderen) supported re-
search in the authors’ laboratory. The authors thank Dr. Amin
Bredan for editing this review, as well as all investigators
working in the field for their contributions.
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