(Journal of Leukocyte Biology. 2001;69:513-521.)
© 2001
by Society for Leukocyte Biology
Chemokines in cutaneous wound healing
Reinhard Gillitzer and
Matthias Goebeler
Department of Dermatology, University of Würzburg Medical School, Würzburg, Germany
Correspondence: Reinhard Gillitzer, M.D., Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. E-mail:
gillitzer-r.derma{at}mail.uni-wuerzburg.de
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ABSTRACT
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Healing of wounds is one of the most complex biological events after
birth as a result of the interplay of different tissue structures and a
large number of resident and infiltrating cell types. The latter are
mainly constituted by leukocyte subsets (neutrophils, macrophages, mast
cells, and lymphocytes), which sequentially infiltrate the wound site
and serve as immunological effector cells but also as sources of
inflammatory and growth-promoting cytokines. Recent data demonstrate
that recruitment of leukocyte subtypes is tightly regulated by
chemokines. Moreover, the presence of chemokine receptors on resident
cells (e.g., keratinocytes, endothelial cells) indicates that
chemokines also contribute to the regulation of epithelialization,
tissue remodeling, and angiogenesis. Thus, chemokines are in an
exclusive position to integrate inflammatory events and reparative
processes and are important modulators of human-skin wound healing.
This review will focus preferentially on the role of chemokines during
skin wound healing and intends to provide an update on the multiple
functions of individual chemokines during the phases of wound
repair.
Key Words: tissue repair • angiogenesis • inflammation • neutrophil migration • keratinocytes
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BIOLOGY OF WOUND HEALING
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Wound healing is an interactive process that involves soluble
mediators, extracellular matrix components, resident cells
(keratinocytes, fibroblasts, endothelial cells, nerve cells), and
infiltrating leukocyte subtypes, which participate differentially in
the classically defined three phases of wound healing: inflammation,
tissue formation, and tissue remodeling [1
,
2
]. Under the assumption of finding efficient, novel,
therapeutic agents for the constantly increasing number of patients
with chronic wounds, major efforts in wound-healing research during the
last two decades have focused on the role of growth factors during the
phase of tissue formation. However, the rather discouraging clinical
results of local application of growth factors made clear that the
biology of wound healing is much more complex than initially assumed
and needs consideration of additional components and mechanisms.
Wound healing, whether sterile or not, is accompanied, for instance, by
an inflammatory reaction, which does not subside with
epithelialization. It rather persists until tissue remodeling, albeit
with a different cellular composition as opposed to the early acute
phase [2
, 3
] and influences catabolic and
anabolic reactions of tissue repair. In skin wound healing—the
standard model of wound healing—the leukocyte subsets, as the cellular
components of inflammation, are not only immunological effector cells
against invading environmental pathogens but are also involved in the
anabolic phase of tissue degradation through production of proteases
and reactive oxygen intermediates and, in particular, in the catabolic
phase of tissue formation through production of growth factors
[4
]. Therefore, understanding the network of wound
healing requires a profound analysis of all soluble mediators and
adhesion factors involved in the recruitment and trafficking of
leukocytes during the inflammatory reaction.
|
INFLAMMATION IN WOUND HEALING
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Tissue injury is associated intimately with the onset of an acute
inflammation and the arrival of polymorphnuclear neutrophil
granulocytes (neutrophils), which at day 1 after tissue injury,
constitute nearly 50% of all cells at the wound site
[5
]. Under physiological wound-healing conditions,
monocytes/macrophages invade into the wound area concomitantly. After
day 2 with wound closure and epithelialization and the consecutive
decline of neutrophil numbers, they represent the most frequent
blood-cell population [5
]. Because of their capacity to
produce inflammatory cytokines and a battery of growth factors,
macrophages are considered to play a central role in wound repair
[4
, 6
]. Notably, lymphocytes are attracted
to the wound site at nearly equal numbers as monocytes and are, after
14 days, the dominating leukocyte subset. Because lymphocytes are not
only effector cells in the antigen-specific limb of the immune system
but also produce growth factors [7
], they may contribute
to tissue remodeling during the late phase of wound healing. Beside
macrophages, neutrophils, and lymphocytes, mast cells are increasingly
considered an important source of mediators during wound healing and
are detected at higher frequencies as opposed to noninjured skin
[8
, 9
]. Because recruitment of leukocyte
subsets is spatially, timely, and differentially regulated, general
leukocyte-attractant mediators detected in the provisional matrix as
fibrinopeptides and fibrin-degradation products—in concert with
factors of the complement cascade (C5a), leukotrienes, formyl methionyl
peptides cleaved from bacterial proteins, and adhesion molecules—may
support but cannot guarantee the selective and regio-specific
chemoattraction of macrophages, neutrophils, and other leukocyte
subtypes. Since 1985, the still-growing supergene family of
chemoattractant cytokines (chemokines), whose predominant
characteristic is the leukocyte subtype-specific chemoattraction, has
emerged (summarized in [10
11
12
]). These chemokines have
the unique potential to activate and selectively guide various
leukocyte subsets to specific microanatomical sites of skin wounds
during the phases of tissue repair. More recently, these inflammatory
mediators have also been considered as angiogenesis-regulating
cytokines [13
]. Therefore, investigating the role of
involved chemokines is an absolute prerequisite for understanding the
dynamic and complex process of wound healing. In the present review, we
first want to discuss the role of chemokines as leukocyte
chemoattractants and then illuminate their role as growth regulators
during wound healing.
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NEUTROPHIL RECRUITMENT
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Because neutrophils are a highly abundant blood-cell population in
the circulation, quite a significant number of neutrophils are
collected passively at the wound site in the blood clot as a result of
blood-vessel disruption with concomitant extravasation of blood
constituents. After the "passive" extravasation of neutrophils,
they migrate immediately to the wound surface together with additional,
actively recruited neutrophils from adjacent blood vessels to form a
dense barrier against invading pathogens. According to our own in
vivo data and the concept of multistep navigation
[5
, 14
], multiple chemoattractants regulate
neutrophil trafficking. The concept of neutrophil recruitment and
migration after skin injury is summarized schematically in Figure 1
. Platelets entrapped and aggregated in the blood clot release,
among growth factors such as platelet-derived growth factor (PDGF), the
chemokine-connective tissue-activating peptide-III
(CTAP-III), which is converted proteolytically into
neutrophil-activating peptide-2 (NAP-2; CXCL7) by neutrophils attached
to the thrombus [15
]. Initially, low concentrations of
NAP-2, which acts as a first-line mediator within minutes through
immediate proteolytic processing, mediate chemoattraction of
neutrophils via the CXC chemokine receptor 2 (CXCR2) over a
considerably wide concentration range (see [15
] for
review). In addition, secretion of growth-related oncogene 
(GRO-) (CXCL1) by vessel-associated cells (endothelial cells
and pericytes) [16
], which in contrast to NAP-2 has to
be newly synthesized, promotes further the process of neutrophil
diapedesis. Notably, in contrast to GRO-, we were unable to detect
interleukin (IL)-8 (CXCL8) mRNA expression in endothelial cells in
neutrophil-rich skin tissue (wound healing, psoriasis)
[5
, 17
], and in situ data from
lipopolysaccharide (LPS)-treated guinea pigs also demonstrated
selective endothelial expression of GRO- but not IL-8
[18
]. The recruitment of neutrophils is further
supported by ENA-78 (CXCL5), which is expressed at lower levels as
compared with GRO- in single mononuclear cells within the
provisional matrix of the wound (unpublished results). All three
chemokines (NAP-2, GRO-, and ENA-78) interact at physiological
concentrations with CXCR2 on neutrophils (see [12
,
19
] for review). It is well-known that chemotactic
responses saturate with increasing concentrations of attractants
specific for one receptor, which is a result of unresponsiveness
(desensitization) and down-regulation of the receptor
[19
]. Therefore, neutrophils would stop moving after
diapedesis and reside diffusely distributed in the blood clot. This
transient unresponsiveness to CXCR2-specific chemokines may be overcome
by the strong and selective expression of IL-8 under the wound surface,
the area of the highest concentration of neutrophil-specific chemokines
(Fig. 2
). Because IL-8 also stimulates the CXCR1 on neutrophils
[19
], they will be able to mount a second response and
migrate to the superficial wound bed. It is interesting that the
induction of the respiratory burst in neutrophils depends on
interaction of IL-8 with exclusively CXCR1 rather than with CXCR2
[20
]; thus, early and deleterious activation of
neutrophils prior to arriving at the wound surface can be avoided. The
band-like colocalization of neutrophils and, to a lesser extent,
macrophages with IL-8 on the denuded wound surface indicates that both
leukocyte subtypes produce IL-8 and attract further neutrophils. This
may be accelerated by GRO-, which is albeit at a lower concentration
coexpressed with IL-8 [5
].
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Figure 1. Model of neutrophil migration in incisional human-skin wounds. After
acute injury, platelets and neutrophils are released passively from
destroyed blood vessels. Platelets not only release growth factors but
also mediators such as CTAP-III, which is processed to NAP-2 by
proteases released from attached neutrophils. NAP-2 stimulates
migration and extravasation of neutrophils via CXCR2. In addition,
vessel-associated cells and endothelial cells produce GRO-, which
supports diapedesis of neutrophils. Further migration of
neutrophils is stimulated by dermal GRO- and ENA-78, expressed by
mononuclear cells in the provisional matrix. Continuous stimulation by
these chemokines via CXCR2 causes transient unresponsiveness of
neutrophils. This may be overcome by interaction of IL-8 with the
neutrophil CXCR1, which is not targeted by GRO- or ENA-78. IL-8,
which is expressed strongly in a band-like pattern by neutrophils
themselves and macrophages immediately below the denuded wound surface,
further mediates the recruitment of large numbers of neutrophils. The
strong expression of IL-8 below the wound surface is induced by
proinflammatory cytokines such as IL-1 and TNF-, bacterial products
(LPS), and hypoxia. In addition, peak levels of IL-8 below the wound
surface may stimulate migration and proliferation of keratinocytes,
which express the CXCR2 at the wound edge. Arrows indicate chemokine
gradients pointing from higher to lower concentrations.
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Figure 2. Strong expression of IL-8 mRNA 24 h after incisional wounding of
human skin. IL-8 mRNA is expressed in a rim of inflammatory cells
(neutrophils and macrophages) exclusively at the denuded wound surface,
whereas expression is quiescent in cells residing in the provisional
matrix below. In situ hybridization with
35S-UTP-labeled IL-8 anti-sense probe. (A,
Bright-field illumination; B, dark-field illumination)._art>
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Moreover, bacterial products, such as lipopolysaccharides,
formyl-methionyl peptides, and
N-acetylmuramyl-L-alanyl-D-isoglutamine
accumulating on the bacterially infected wound surface, accelerate the
directed neutrophil locomotion. During wounding, the classical and
alternative pathways of the complement cascade are activated, leading
to production of C5a, which further enhances neutrophil and monocyte
recruitment. However, C5a is hydrolyzed rapidly and thus may only
contribute to the early wave of leukocyte infiltration. Leukotrienes
released from activated, newly arrived neutrophils exhibit strong
chemoattractant properties to all leukocytes and support their rapid
trafficking. As mentioned previously, these factors do not act
leukocyte subtype-specifically and therefore may not explain their
spatially and temporally different accumulation. However, detailed data
on the interaction of these chemoattractants with chemokines relevant
in the setting of wound healing such as IL-8, GRO-, and MCP-1 (CCL2)
are not available currently and remain speculative.
The concept of multistep neutrophil migration is supported by data from
Ludwig and colleagues [21
], who demonstrated that CXC
receptors, CXCR1 and CXCR2, are involved differentially in the
chemotactic response of neutrophils to NAP-2. Low concentrations of
NAP-2 led to down-regulation of the high-affinity CXCR2, whereas
neutrophils are still responsive to IL-8 or high concentrations of
NAP-2 via CXCR1. NAP-2 may be particularly important in occluded blood
vessels, which are typically seen after an acute injury.
Albeit many resident skin cells and infiltrating leukocyte subsets are
capable of producing IL-8 and/or GRO- when stimulated appropriately
under in vitro conditions, expression in the setting of
cutaneous wound healing is timely and spatially strongly restricted
[5
]. As demonstrated in Figure 2
, IL-8 expression levels
peak at day 1 exclusively in those cells that line the uppermost part
of the wound, namely neutrophils and macrophages, and subside when
wound closure is completed. A similar situation as in skin wounds is
seen in psoriasis where neutrophils migrate to the upper epidermal
layer [22
]. In both conditions, IL-8 is produced by
upper-level neutrophils, whereas within the dermal compartment, only
GRO- and, in the case of wound healing, ENA-78 message is detectable
[5
, 17
, 22
]. Beside direct
induction of chemokines by bacterial products (e.g.,
lipopolysaccharides), the proinflammatory cytokines tumor necrosis
factor (TNF-) and IL-1 are expressed initially and predominantly
by neutrophils within a few hours after wounding and appear to act as
main inducers of chemokines [23
]. This is in accordance
with peak levels of IL-8 detected at day 1 [5
]. At later
stages of the repair process, expression of IL-1 and TNF- is also
seen in macrophages [23
]. The hypoxic situation
immediately below the wound surface may furthermore amplify IL-8
expression [24
]. This situation would resemble that
observed in tumors, where IL-8 is expressed particularly in
hypoxic/necrotic areas by neutrophils and tumor cells
[25
].
The simultaneous expression of several neutrophil-attractant chemokines
in the acute phase of inflammation during wound healing may at first
sight refer to the redundancy and robustness of the chemokine system as
suggested by Mantovani [26
]. The spatially and timely
differential expression of multiple neutrophil-specific chemokines,
however, argues strongly in favor of a sophisticated multistep event,
which enables neutrophils to leave occluded vessels and to bridge a
rather long distance rapidly to the denuded wound surface, which is
severely prone to infections with extrinsic pathogens. It is
interesting that because of the long half-life of IL-8 mRNA
[27
], it persists in neutrophils that are entrapped in
the crust above the newly built epidermis [5
].
Inasmuch as chemokines perpetuate inflammation, several mechanisms
operate to limit and down-regulate this activity. Such mechanisms
include down-regulation of chemokine expression by anti-inflammatory
cytokines such as IL-10 [28
], receptor unresponsiveness,
and down-regulation by high concentrations of ligands
[19
]. Furthermore, proinflammatory cytokines such as
TNF- not only induce IL-8 but may also conversely suppress CXCR2
expression on neutrophils [29
]. Whether
metalloproteinases down-regulate inflammation in wound healing via
cleavage of chemokines, which then act as antagonists as has recently
been shown for gelatinase A and MCP-3 (CCL7) in vitro
[30
], remains to be elucidated in vivo.
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MACROPHAGE AND MAST-CELL RECRUITMENT
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Macrophages are essential for normal wound repair
[31
]. They exhibit immunological functions as
antigen-presenting cells and phagocytes and are in particular an
important source of growth factors [4
, 31
].
With exception to the direct presence of neutrophils through
extravasation after vessel injury and the immediate action of NAP-2,
both leukocyte subtypes migrate equally fast into the injured tissue
[5
]. Among a large set of
monocyte/macrophage-attractant chemokine-anti-sense probes
studied by in situ hybridization [regulated on activation,
normal T expressed and secreted (RANTES; CCL5), macrophage-inflammatory
protein-1 (MIP-1; CCL3) and MIP-1ß (CCL4), I309 (CCL1), and
monocyte chemoattractant protein-1 (MCP-1) and MCP-3], MCP-1 was
almost exclusively found to be expressed during the first week after
wounding (Fig. 3
; [5
] and unpublished results). The multiple
functions of MCP-1 during wound healing are summarized schematically in
Figure 4
. Almost 20% of total cells (resident and infiltrating mononuclear
cells) expressed MCP-1 mRNA 1 day after wounding. Notably, after day 2,
MCP-1 was also expressed by basal keratinocytes at the wound edge,
which are hyperproliferative and the cellular source for migrating
keratinocytes to cover the wound surface. Thus, keratinocytes
contribute significantly to the inflammatory network in wounds. A
comparable MCP-1 expression pattern has been observed in human burn
wounds [32
]. The expression profile of MCP-1 is quite
reminiscent to the situation in psoriasis where basal
hyperproliferative keratinocytes produce MCP-1 and attract macrophages
[33
]. In analogy to neutrophils, it appears most likely
that macrophages also face different chemokine gradients. Considerable
amounts of additional monocyte-attractant chemokines have, at least in
human skin wounds, not been described. In murine skin-wound healing
models, however, MIP-1 and RANTES have, in addition to MCP-1, been
shown to play a critical role in macrophage recruitment
[34
35
36
37
38
]. This strongly indicates that data obtained
from animal models, in particular in mice with a different skin
morphology, are not easily transferable to the human wound-healing
situation. Therefore, murine transgenic and knock-out models may only
be of limited value for understanding wound healing in humans.
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Figure 3. MCP-1 mRNA expression in human skin 2 days after skin wounding. MCP-1
mRNA expression is detected by in situ hybridization with
35S-UTP-labeled MCP-1 anti-sense probe after
removing the artificially blistered epidermis. MCP-1 is expressed by
mononuclear inflammatory cells and in vessel areas within the full
depth of the dermis. (A, Bright-field illumination; B, dark-field
illumination).
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Figure 4. Model of MCP-1 expression and function in human skin wound healing.
MCP-1 is highly produced by resident cells (keratinocytes at the wound
edge, endothelial cells) and inflammatory cells (macrophages) and may
thus participate at different stages of monocyte, mast cell, and
lymphocyte attraction during cutaneous wound healing. Attracted
macrophages and lymphocytes produce regulatory and growth-promoting
factors. Mast cells release IL-4, which may stimulate fibroblast
activities and down-regulate MCP-1 expression. In addition, MCP-1 may
also contribute to endothelial-cell locomotion during angiogenesis.
Arrows indicate MCP-1 gradients pointing from higher to lower
concentrations.
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Although it is tempting to speculate that MCP-1 may also activate
macrophages to produce growth factors, we were unable to detect those
in the supernatant of MCP-1-stimulated cells (unpublished results).
According to available data, it appears that MCP-1 chemoattracts
monocytes/macrophages primarily, which are stimulated by other signals
subsequently to produce growth-promoting cytokines.
Our own data suggest that during wound healing, MCP-1 does not only
attract monocytes but also, at later time points, mast cells
[9
] (Fig. 4)
. The fivefold increase in mast-cell numbers
during wound healing is a result of an increased recruitment rather
than proliferation.
Because these mast cells produce high levels of IL-4, which in turn
stimulates proliferation of fibroblasts [39
], MCP-1 does
stimulate wound healing via recruitment of different leukocyte subsets.
High levels of IL-4 may, as mentioned above, also down-regulate the
expression of chemokines, e.g., MCP-1 and IL-8 [40
],
thus limiting the inflammatory reaction.
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LYMPHOCYTE RECRUITMENT
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In the setting of wound repair, lymphocytes are not only
immunological effector cells but also capable of producing growth
factors [7
]. In the phase of tissue remodeling, when
wound closure has been completed, and local infections are already
overcome, lymphocytes constitute the most frequent leukocyte subset in
human skin wounds [5
]. Whether lymphocytes are
associated intimately with tissue remodeling awaits further studies. As
opposed to the early days of chemokine research, lymphocytes currently
represent the leukocyte subset, which is targeted by the largest set of
specific chemokines (summarized in [10
11
12
]). Among
these chemokines, initially MCP-1 and after day 4,
interferon-
-inducible protein-10 (IP-10) (CXCL10), monokine
induced by interferon- (Mig) (CXCL9), and macrophage-derived
chemokine (MDC) (CCL22) are found to be spatially associated
with lymphocyte accumulation ([5
] and unpublished
results). The expression of all other lymphocyte-specific chemokines
investigated [TARC (CCL17), PARC (CCL18), LARC (CCL20), I-TAC
(CXCL11)] was quiescent or low. Most likely, macrophages are
the major source of these chemokines. Because IP-10 and Mig are induced
selectively by interferons (IFNs) [41
], their strong
expression from day 4 onward reflects a major shift in the cytokine
profile from TNF-/IL-1 to IFN-.
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CHEMOKINES AND REEPITHELIALIZATION
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In addition to their neutrophil-attractant properties, the CXC
chemokines IL-8 and GRO- also elicit responses in nonhematopoietic
cells, namely in keratinocytes and endothelial cells. In
vitro studies have demonstrated that IL-8 is capable of
stimulating human keratinocyte migration and proliferation
[42
43
44
45
]. In healing incisional human wounds, IL-8 is
highly expressed along the denuded wound surface exactly where
keratinocytes migrate from the wound edge to close the epidermal defect
as schematically shown in Figure 1
. Expression of GRO- is
colocalized with IL-8, but GRO- mRNA levels are significantly lower
[5
]. Comparable results regarding GRO- were shown by
Nanney et al. [46
]. Keratinocytes have been
found to express CXCR2, the receptor for IL-8 and GRO-
[42
, 46
, 47
]. When studying
wound healing in CXCR2-/- mice, Devalaraja and colleagues
[48
] observed a severely retarded reepithelization
process in vivo as well as an impaired closure of
"wound" defects in confluent cultures of CXCR2-/- keratinocytes
in vitro. These data suggest that interaction of
keratinocyte CXCR2 with its ligand(s), IL-8 and GRO- in the human
system and MIP-2 and KC (CXCL1) in the murine system, plays a role
during wound repair. Topical application of IL-8 or GRO- to wounds
elicited in mouse skin appears to have a favorable but not overwhelming
effect on reepithelization [45
, 49
].
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ENDOTHELIAL CELLS AND ANGIOGENESIS
|
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Two major roles can be attributed to endothelial cells during the
complex events of wound healing: First, endothelium mediates and
regulates the recruitment of leukocytes from the intraluminal
compartment to tissues, and, second, endothelial cells form new vessels
during wound repair, which arise from the preexisting microvasculature,
a process designated as angiogenesis. In both events, chemokines are of
major importance.
Endothelial cells comprise of a broad repertoire of chemokines, which
may be expressed after appropriate stimulation. These include CC
chemokines such as MCP-1 and RANTES as well as CXC family members like
IL-8, GRO-, IP-10, Mig, and others [16
]. Chemokines,
as e.g., IL-8, may furthermore be presented by endothelial surface
glycosaminoglycans to allow interaction with leukocytes to be recruited
from the intraluminal compartment [50
]. Expression of,
e.g., MCP-1 by endothelial cells contributes to the establishment of a
chemokine gradient, which facilitates subset-specific recruitment of
leukocytes to sites of inflammation [51
]. Under flow
conditions, MCP-1 triggers firm adhesion of rolling monocytes to
E-selectin-expressing vascular endothelium [52
]. During
wound healing, MCP-1 mRNA can be detected in blood vessel areas
especially [5
, 32
]. However, because of the
strong signal intensity and the preponderance of MCP-1-expressing
mononuclear cells, the portion of endothelially expressed MCP-1 cannot
be estimated reliably (Fig. 3)
. Similar observations regarding GRO-
message have been made by Engelhardt et al.
[5
], whereas in another study, GRO- protein could not
be detected [46
]. Endothelial expression of other
proinflammatory, cytokine-inducible chemokines such as IL-8 or RANTES
under the conditions of wound healing has so far not been described.
The process of angiogenesis is closely related to the formation of
granulation tissue. It depends on the concerted action of multiple
factors produced by a variety of cells. These include macrophages and
keratinocytes, which produce angiogenic factors such as vascular
endothelial growth factor (see [6
] and
[53
] for review). In parallel, proteolytic enzymes are
released, which degrade extracellular matrix proteins to allow
endothelial cell migration and formation of new vessels at sites of
injury. Conversely, angiogenesis has to cease when the wound defect is
filled with granulation tissue. These sequential events reflect
temporal changes in the balance between (pro)angiogenic and angiostatic
factors.
Chemokines, especially those of the CXC family, have been attributed to
a role for the regulation of angiogenesis. The work of Strieter and
colleagues (see [13
] for review) demonstrated that CXC
chemokines, which contain a Glu-Leu-Arg (ELR) motif [54
]
adjacent to their first cysteine amino acid in the NH2
terminus, are potent promoters of angiogenesis. This group of
ELR-containing chemokines includes IL-8, GRO-, GRO-ß (CXCL2),
GRO (CXCL3), as well as CTAP-III, ß-thromboglobulin, and
NAP-2 and is described to induce endothelial cell proliferation
in vitro and angiogenesis in vivo (see
[13
] for review). Studying expression of the
ELR-positive chemokines IL-8 (Fig. 2)
and GRO- in a human
wound-healing model, we found strong expression of both during days
1–4 after wounding. The expression levels of IL-8 and GRO-
correlated with an increasing number of vessels. After day 4,
expression of IL-8 and GRO- declined markedly, and vascularization
ceased concomitantly [5
]. Investigating cutaneous wound
repair after burns in humans, Nanney and colleagues [46
]
found strong expression of GRO- at dermal and epidermal sites as
well. In another species, chicken, the CXC chemokine 9E3/CEF4, which is
highly homologous to human IL-8 and GRO-, is strongly up-regulated
within the granulation tissue of wounded areas, especially at sites of
neovascularization [55
]. Furthermore, this avian
chemokine induces chemotaxis of endothelial cells and is angiogenic in
the chorioallantoic membrane assay [56
]. Because all
ELR-positive chemokines bind to the CXCR2, the latter is supposed to be
responsible for mediation of the angiogenic activity
[13
]. However, the detection of CXCR2 chemokine
receptors on endothelial cells is a controversal issue. In contrast to
Nanney et al. [46
], Kulke and colleagues
[47
] could not demonstrate CXCR2 expression by
endothelial cells in nondiseased skin. Similarly, conflicting data
exist regarding the in vitro expression of CXCR2 on
endothelium: Some groups identified CXCR2 expression by cultured
endothelial cells, whereas others could not confirm such data
[19
, 57
58
59
60
]. Investigating wound healing
in CXCR2 knock-out mice, Devalaraja et al.
[48
] not only found decreased recruitment of neutrophils
and reduced keratinocyte migration and proliferation during
epithelialization but also a significant delay in neovascularization.
They postulated that this would be a result of the diminished
angiogenic response toward MIP-2, the functional homologue of IL-8 in
the murine system.
The chemokine SDF-1 (CXCL12) is the only CXC subfamily member that
is angiogenic despite lacking the ELR motif [60
]. It
specifically binds to CXCR4 receptors on endothelial cells, induces
endothelial cell chemotaxis and formation of blood vessels
[60
, 61
], and appears to be important for
vascularization of the gastrointestinal tract [62
].
Whereas the angiogenic capacity of SDF-1-CXCR4 interaction has not
been elucidated yet during wound healing, a model has been proposed in
which vascular endothelial growth factor (VEGF) and basic fibroblast
growth factor (bFGF) up-regulate endothelial CXCR4 expression on
endothelial cells, which subsequently show increased responsiveness to
SDF-1 [60
, 63
]. However, because
SDF-1 and CXCR4 are already found to be strongly expressed by
endothelial and other cells in normal skin [64
], the
impact of these on angiogenesis during wound healing remains illusive.
Beyond direct angiogenic effects of chemokines, indirect mechanisms of
action have been demonstrated. DiPietro et al.
[35
] found that in the murine system, depletion of wound
MIP-1 by a neutralizing anti-serum significantly reduced angiogenic
activity of wound homogenates. MIP-1 does not appear to be a direct
angiogenic factor but promotes recruitment of macrophages to wound
sites, which in turn act as a source of angiogenic cytokines. A rather
similar role may be conceivable for MCP-1 [65
], which is
highly expressed during the course of wound repair [5
,
32
, 34
, 37
]. This indirect
action of MCP-1 has been challenged recently: Weber et al.
[66
] demonstrated expression of the MCP-1 receptor CCR2
by endothelial cells and migration of the latter upon stimulation with
MCP-1. Proliferation of endothelial cells, however, was not altered.
Basically, Salcedo and colleagues [67
] came to similar
results.
CXC chemokines lacking the ELR motif such as the IFN--inducible
cytokines IP-10, Mig, or I-TAC act as efficient inhibitors of
angiogenesis [13
, 54
]: They not only fail
to induce endothelial cell chemotaxis in vitro or corneal
neovascularization in vivo but also act as angiostatic
factors in the presence of ELR-positive chemokines or bFGF. The mode of
angiostatic action, however, is not clear yet. Neither cultured
endothelial cells [59
, 60
] nor endothelium
studied in normal skin or during wound healing in situ
(unpublished results) have been found to express CXCR3, the receptor
for IP-10, Mig, and I-TAC. Therefore, it is possible that the
angiostatic effects of these chemokines are mediated by an as yet
unidentified endothelial receptor or occur in an indirect manner. In
transgenic mice overexpressing IP-10 in the epidermis under control of
a keratin promoter, wound healing was disturbed by a prolonged and
disorganized granulation phase with impaired blood-vessel formation
[68
]. In a human wound-healing model, we detected
maximum levels of IP-10 and Mig expression with the onset of
angiostasis, i.e., cessation of endothelial cell proliferation
[5
].
|
FIBROBLASTS AND CHEMOKINES
|
|---|
Upon appropriate stimulation, fibroblasts are potent producers of
a variety of chemokines [69
70
71
72
]. Because of the lack of
well-established fibroblast-specific antibodies, it is difficult to
evaluate whether fibroblasts contribute to inflammation in wound
healing via production of chemokines under in vivo
conditions. Although dermal fibroblasts produce IL-8 in
vitro [70
], IL-8 mRNA expression by fibroblasts has
not been detected in the setting of wound healing (Fig. 2)
[5
]. Fibroblasts expressing GRO- and, occasionally,
the corresponding receptor CXCR2 have been observed recently in
keloids, benign collagenous tumors that occur during dermal wound
healing in genetically predisposed individuals [72
].
Such an expression pattern, which was probably induced by
proinflammatory cytokines, was not detected in hypertrophic scars or
normal skin by these authors.
Recent data suggest that fibroblasts are not only producers of but also
targets for chemokines. Gharaee-Kermani and colleagues
[73
] showed that exposure of rat fibroblasts to MCP-1
resulted in the expression of transforming growth factor-ß (TGF-ß)
as well as in collagen synthesis. More recent data by Yamamoto and
colleagues [74
] indicated that MCP-1 enhances gene
expression of matrix metalloproteinase-1 (MMP-1) as well as of
metalloproteinase-1 (TIMP-1) tissue inhibitor in primary human dermal
fibroblasts. Thus, MCP-1 may act, at least in vitro, at the
same time as profibrotic as well as collagenolytic mediator. It is not
clear yet whether these paradoxically appearing observations are of
relevance in vivo.
In this context, it is interesting to mention that chemokines such as
IL-8, RANTES, MIP-1, MIP-1ß, and/or MCP-1 induce expression of
metalloproteinases in various leukocyte subtypes
[75
76
77
]. Thus, chemokines not only regulate locomotion
of resident and passenger cells but may also influence tissue
remodeling.
Moreover, IP-10, an ELR-negative CXC chemokine with angiostatic
properties (see above), inhibits epidermal growth factor-induced
motility of fibroblasts [78
]. This in vitro
observation fits very well with our data demonstrating that IP-10 and
Mig are expressed highly in the late phase of normal wound healing
after day 4 [5
], thus limiting recruitment of
fibroblasts and consecutive, excessive scarring. High concentrations of
another ELR-negative CXC chemokine, platelet factor-4 (PF4,
CXCL4)—present at high concentrations within and in close vicinity to
the platelet plug as a result of platelet degranulation immediately
after wounding—might result in the arrest and accumulation of
migrating/infiltrating fibroblasts. In addition, PF4 inhibits the
mitogenic activity of bFGF on fibroblasts [79
], which,
however, appears to be less desirable during early phases of wound
healing. Taken together, these ELR-negative CXC chemokines exhibit
growth-inhibitory functions in the later phase of wound healing and
could possibly provide a therapeutic approach against excessive wound
healing, as seen in hypertrophic scarring or keloid formation
(Table 1).
|
CHEMOKINES IN WOUND HEALING— AN OUTLOOK
|
|---|
Various studies have demonstrated the important role of chemokines
for the accompanying inflammatory reaction as well as for repair
processes during wound healing. However, the importance of chemokines
during pathological wound-healing conditions (non- or slow-healing
wounds) has not been investigated and needs particular attention. It
appears conceivable that chemokines could be exploited therapeutically,
as major adjuvants to stimulate wound healing provided that the timely
and spatially different expression patterns, as detected in
physiological wound healing, are considered adequately. To overcome the
current failure of wound-healing treatments by local application of
single growth factors, the phase-specific, chemokine-mediated
attraction of inflammatory cells, in particular monocytes/macrophages,
with subsequent stimulation of growth-factor release could present an
essential approach for future wound-healing strategies. In addition,
the role of chemokines not only as inflammatory cytokines but also as
positive and negative growth regulators (IL-8, GRO-, Mig, IP-10,
PF4) has to be taken into account. Therefore, the orchestrated
processes of wound healing with respect to treatment certainly require
a highly complex and sophisticated approach and should target
chemokines as important traffic lights for migration of resident and
inflammatory cells as well as essential regulators of repair
mechanisms.
|
ACKNOWLEDGEMENTS
|
|---|
This work was supported by grant No. 95.064.2 from the
Wilhelm-Sander-Stiftung to R. G. and grant No. GO 811/1-3 from the
Deutsche Forschungsgemeinschaft to M. G. The authors thank Atiye
Toksoy and Ariane Voss for assistance and valuable discussion.
Received December 1, 2000;
revised January 8, 2001;
accepted January 16, 2001.
|
REFERENCES
|
|---|
-
Singer, A. J., Clark, R. A. F. (1999) Cutaneous wound healing New Engl. J. Med. 341,738-746[Free Full Text]
-
Clark, R. A. F. (1996) Wound repair: overview and general considerations Clark, R. A. F. eds. The Molecular and Cellular Biology of Wound Repair 2nd ed. ,1-50 Plenum New York, London.
-
Haslett, C., Henson, P. (1996) Resolution of inflammation Clark, R. A. F. eds. The Molecular and Cellular Biology of Wound Repair 2nd ed. ,143-168 Plenum New York, London.
-
Riches, D. W. H. (1996) Macrophage involvement in wound repair, remodeling and fibrosis Clark, R. A. F. eds. The Molecular and Cellular Biology of Wound Repair 2nd ed. ,95-141 Plenum New York, London.
-
Engelhardt, E., Toksoy, A., Goebeler, M., Debus, S., Bröcker, E. B., Gillitzer, R. (1998) Chemokines IL-8, Gro, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing Am. J. Pathol. 153,1849-1860[Abstract/Free Full Text]
-
Sunderkötter, C., Steinbrink, K., Goebeler, M., Bhardwaj, R., Sorg, C. (1994) Macrophages and angiogenesis J. Leukoc. Biol. 55,410-422[Abstract]
-
Blotnik, S., Peoples, G. E., Freeman, M. R., Eberlein, T. J., Klagsbrun, M. (1994) T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4+ and CD8+ T cells Proc. Natl. Acad. Sci. USA 91,2890-2894[Abstract/Free Full Text]
-
Hebda, P. A., Collins, M. A., Tharp, M. D. (1993) Mast cell and myofibroblast in wound healing Dermatol. Clin. 11,685-696[Medline]
-
Trautmann, A., Toksoy, A., Engelhardt, E., Bröcker, E. B., Gillitzer, R. (2000) Mast cell involvement in normal human skin wound healing: expression of monocyte chemoattractant protein-1 is correlated with recruitment of mast cells which synthesize interleukin-4 in vivo J. Pathol. 190,100-106[Medline]
-
Baggiolini, M. (1998) Chemokines and leukocyte traffic Nature 392,565-568[Medline]
-
Luster, A. D. (1998) Chemokines—chemotactic cytokines that mediate inflammation N. Engl. J. Med. 338,436-445[Free Full Text]
-
Rossi, D., Zlotnik, A. (2000) The biology of chemokines and their receptors Annu. Rev. Immunol. 18,217-242[Medline]
-
Belperio, J. A., Keane, M. P., Arenberg, D. A., Addison, C. L., Ehlert, J. E., Burdick, M. D., Strieter, R. M. (2000) CXC chemokines in angiogenesis J. Leukoc. Biol. 68,1-8[Abstract/Free Full Text]
-
Foxman, E. F., Campbell, J. J., Butcher, E. C. (1997) Multistep navigation and the combinatorial control of leukocyte chemotaxis J. Cell Biol. 139,1349-1360[Abstract/Free Full Text]
-
Brandt, E., Petersen, F., Ludwig, A., Ehlert, J. E., Bock, L., Flad, H. D. (2000) The beta-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation J. Leukoc. Biol. 67,471-478[Abstract]
-
Goebeler, M., Yoshimura, T., Toksoy, A., Ritter, U., Bröcker, E. B., Gillitzer, R. (1997) The chemokine repertoire of human dermal microvascular endothelial cells and its regulation by inflammatory cytokines J. Investig. Dermatol. 108,445-451[Medline]
-
Gillitzer, R., Ritter, U., Spandau, U., Goebeler, M., Bröcker, E. B. (1996) Differential expression of Gro and IL-8 mRNA in psoriasis: a model for neutrophil migration and accumulation in vivo J. Investig. Dermatol. 107,778-782[Medline]
-
Yoshimura, T., Takeya, M., Ogata, H., Yamashiro, S., Modi, W. S., Gillitzer, R. (1999) Molecular cloning of the guinea pig GRO- gene and its rapid expression in the tissues of lipopolysaccharide-injected guinea pigs Int. Arch. Allergy Immunol. 119,101-111[Medline]
-
Murdoch, C., Finn, A. (2000) Chemokine receptors and their role in inflammation and infectious diseases Blood 95,3032-3043[Abstract/Free Full Text]
-
Jones, S. A., Wolf, M., Qin, S., Mackay, C. R., Baggiolini, M. (1996) Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NAPDH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2 Proc. Natl. Acad. Sci. USA 93,6682-6686[Abstract/Free Full Text]
-
Ludwig, A., Petersen, F., Zahn, S., Götze, O., Schröder, J. M., Flad, H. D., Brandt, E. (1997) The CXC-chemokine neutrophil-activating peptide-2 induces two distinct optima of neutrophil chemotaxis by differential interaction with interleukin-8 receptors CXCR-1 and CXCR-2 Blood 90,4588-4597[Abstract/Free Full Text]
-
Gillitzer, R., Berger, R., Mielke, V., Müller, W., Wolff, K., Stingl, G. (1991) Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ J. Investig. Dermatol. 97,73-79[Medline]
-
Hübner, G., Brauchle, M., Smola, H., Madlener, M., Fässler, R., Werner, S. (1996) Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice Cytokine 8,548-556[Medline]
-
Metinko, A. P., Kunkel, S. L., Standiford, T. J., Strieter, R. M. (1992) Anoxia-hyperoxia induces monocyte-derived interleukin-8 J. Clin. Invest. 90,791-798
-
Kunz, M., Hartmann, A., Flory, E., Toksoy, A., Koczan, D., Thiesen, H. J., Mukaida, N., Neumann, M., Rapp, U. R., Bröcker, E. B., Gillitzer, R. (1999) Anoxia-induced up-regulation of interleukin-8 in human malignant melanoma. A potential mechanism for high tumor aggressiveness Am. J. Pathol. 155,753-763[Abstract/Free Full Text]
-
Mantovani, A. (1999) The chemokine system: redundancy for robust outputs Immunol. Today 20,254-257[Medline]
-
Vilarete, L. H., Remick, D. G. (1996) Transcriptional and post-transcriptional regulation of interleukin-8 Am. J. Pathol. 149,1685-1693[Abstract]
-
Sato, Y., Ohshima, T., Kondo, T. (1999) Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing Biochem. Biophys. Res. Commun. 265,194-199[Medline]
-
Asagoe, K., Yamamoto, K., Takahashi, A., Suzuki, K., Maeda, A., Nohgawa, M., Harakawa, N., Takano, K., Mukaido, N., Matsushima, K., Okuma, M., Sasada, M. (1998) Down-regulation of CXCR2 expression on human polymorphnuclear leukocytes by TNF- J. Immunol. 160,4518-4525[Abstract/Free Full Text]
-
McQuibban, G. A., Gong, J. H., Tam, E. M., McCulloch, C. A., Clark-Lewis, I., Overall, C. M. (2000) Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 Science 289,1202-1206[Abstract/Free Full Text]
-
DiPietro, L. A. (1995) Wound healing: the role of the macrophage and other immune cells Shock 4,233-240[Medline]
-
Gibran, N. S., Ferguson, M., Heimbach, D. M., Isik, F. F. (1997) Monocyte chemoattractant protein-1 mRNA expression in the human burn wound J. Surg. Res. 70,1-6[Medline]
-
Gillitzer, R., Wolff, K., Tong, D., Müller, C., Yoshimura, T., Hartmann, A. A., Stingl, G., Berger, R. (1993) MCP-1 mRNA expression in basal keratinocytes of psoriatic lesions J. Investig. Dermatol. 101,127-131[Medline]
-
DiPietro, L. A., Polverini, P. J., Rahbe, S. M., Kovacs, E. J. (1995) Modulation of JE/MCP-1 expression in dermal wound repair Am. J. Pathol. 146,868-875[Abstract]
-
DiPietro, L. A., Burdick, M., Low, Q. E., Kunkel, S. L., Strieter, R. M. (1998) MIP-1 as a critical macrophage chemoattractant in murine wound repair J. Clin. Invest. 101,1693-1698[Medline]
-
Jackman, S. H., Yoak, M. B., Keerthy, S., Beaver, B. L. (2000) Differential expression of chemokines in a mouse model of wound healing Ann. Clin. Lab. Sci. 30,201-207[Abstract]
-
Wetzler, C., Kämpfer, H., Stallmeyer, B., Pfeilschifter, J., Frank, S. (2000) Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair J. Investig. Dermatol. 115,245-253[Medline]
-
Frank, S., Kämpfer, H., Wetzler, C., Stallmeyer, B., Pfeilschifter, J. (2000) Large induction of the chemotactic cytokine RANTES during cutaneous wound repair: a regulatory role for nitric oxide in keratinocyte-derived RANTES expression Biochem. J. 347,265-273
-
Trautmann, A., Krohne, G., Bröcker, E. B., Klein, C. E. (1998) Human mast cells augment fibroblast proliferation by heterotypic cell-cell contact and action of IL-4 J. Immunol. 160,5053-5057[Abstract/Free Full Text]
-
Leonard, E. J., Skeel, A., Yoshimura, T., Rankin, J. (1993) Secretion of monocyte chemoattractant protein-1 (MCP-1) by human mononuclear phagocytes Adv. Exp. Med. Biol. 351,55-64[Medline]
-
Farber, J. M. (1997) Mig and IP-10: CXC chemokines that target lymphocytes J. Leukoc. Biol. 61,246-257[Abstract]
-
Michel, G., Kemeny, L., Peter, R. U., Beetz, A., Ried, C., Arenberger, P., Ruzicka, T. (1992) Interleukin-8 receptor-mediated chemotaxis of normal human epidermal cells FEBS Lett 305,241-243[Medline]
-
Gyulai, R., Hunyadi, J., Kenderessy-Szabo, A., Kemeny, L., Dobozy, A. (1994) Chemotaxis of freshly separated and cultured human keratinocytes Clin. Exp. Dermatol. 19,309-311[Medline]
-
Tuschil, A., Lam, C., Haslberger, A., Lindley, I. (1992) Interleukin-8 stimulates calcium transients and promotes epidermal cell proliferation J. Investig. Dermatol. 99,294-298[Medline]
-
Rennekampf, H. O., Hansbrough, J. F., Kiessig, V., Dore, C., Sticherling, M., Schröder, J. M. (2000) Bioactive interleukin-8 is expressed in wound and enhances wound healing J. Surg. Res. 93,41-54[Medline]
-
Nanney, L. B., Mueller, S. G., Bueno, R., Peiper, S. C., Richmond, A. (1995) Distributions of melanoma growth stimulatory activity of growth-regulated gene and the interleukin-8 receptor B in human wound repair Am. J. Pathol. 147,1248-1260[Abstract]
-
Kulke, R., Bornscheuer, E., Schlüter, C., Bartels, J., Röwert, J., Sticherling, M., Christophers, E. (1998) The CXC receptor 2 is overexpressed in psoriatic epidermis J. Investig. Dermatol. 110,90-94[Medline]
-
Devalaraja, R. M., Nanney, L. B., Quian, Q., Du, J., Yu, Y., Devalaraja, M. N., Richmond, A. (2000) Delayed wound healing in CXCR2 knockout mice J. Investig. Dermatol. 115,234-244[Medline]
-
Rennekampff, H. O., Hansbrough, J. F., Woods, V., Dore, C., Kiessig, V., Schröder, J. M. (1997) Role of melanoma growth stimulatory activity (MGSA/gro) on keratinocyte function in wound healing Arch. Dermatol. Res. 289,204-212[Medline]
-
Middleton, J., Neil, S., Wintle, J., Clark-Lewis, I., Moore, H., Lam, C., Auer, M., Hub, E., Rot, A. (1997) Transcytosis and surface presentation of IL-8 by venular endothelial cells Cell 91,385-395[Medline]
-
Randolph, G. J., Furie, M. B. (1995) A soluble gradient of endogenous monocyte chemoattractant protein-1 promotes the transendothelial migration of monocytes in vitro J. Immunol. 155,3610-3618[Abstract]
-
Gerszten, R. E., Garcia-Zepeda, E. A., Lim, Y. C., Yoshida, M., Ding, H. A., Gimbrone, M. A., Luster, A. D., Luscinskas, F. W., Rosenzweig, A. (1999) MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions Nature 398,718-723[Medline]
-
Dvorak, H. F., Brown, L. F., Detmar, M., Dvorak, A. M. (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis Am. J. Pathol. 146,1029-1039[Abstract]
-
Strieter, R. M., Polverini, P. J., Kunkel, S. L., Arenberg, D. A., Burdick, M. D., Kasper, J., Dzuiba, J., Van Damme, J., Walz, A., Marriott, D., Chan, S. Y., Roczniak, S., Shanafelt, A. B. (1995) The functional role of the ELR motif in CXC chemokine-mediated angiogenesis J. Biol. Chem. 270,27348-27357[Abstract/Free Full Text]
-
Martins-Green, M., Bissell, M. J. (1990) Localization of 9E3/CEF-4 in avian tissues: expression is absent in Rous sarcoma virus-induced tumors but is stimulated by injury J. Cell Biol. 110,581-595[Abstract/Free Full Text]
-
Martins-Green, M., Feugate, J. E. (1998) The 9E3/CEF4 gene product is a chemotactic and angiogenic factor that can initiate the wound-healing cascade in vivo Cytokine 10,522-535[Medline]
-
Petzelbauer, P., Watson, C. A., Pfau, S. E., Pober, J. S. (1995) IL-8 and angiogenesis: evidence that human endothelial cells lack receptors and do not respond to IL-8 in vitro Cytokine 7,267-272[Medline]
-
Schönbeck, U., Brandt, E., Petersen, F., Flad, H. D., Loppnow, H. (1995) IL-8 specifically binds to endothelial but not to smooth muscle cells J. Immunol. 154,2375-2383[Abstract]
-
Murdoch, C., Monk, P. N., Finn, A. (1999) CXC chemokine receptor expression on human endothelial cells Cytokine 11,704-712[Medline]
-
Salcedo, R., Wasserman, K., Young, H. A., Grimm, M. C., Howard, O. M. Z., Anver, M. R., Kleinman, H. K., Murphy, W. J., Oppenheim, J. J. (1999) Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells In vivo neovascularization induced by stromal-derived factor-1 Am. J. Pathol. 154,1125-1135[Abstract/Free Full Text]
-
Gupta, S. K., Lysko, P. G., Pillarisetti, K., Ohlstein, E., Stadel, J. M. (1998) Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines J. Biol. Chem. 273,4282-4287[Abstract/Free Full Text]
-
Tachibana, K., Hirota, S., Iizasa, H., Yoshida, H., Kawabata, K., Kataoka, Y., Kitamura, Y., Matsushima, K., Yoshida, N., Nishikawa, S., Kishimoto, T., Nagasawa, T. (1998) The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract Nature 393,591-594[Medline]
-
Feil, C., Augustin, H. G. (1998) Endothelial cells differentially express functional CXC-chemokine receptor-4 (CXCR-4/fusin) under the control of autocrine activity and exogenous cytokines Biochem. Biophys. Res. Commun. 247,38-45[Medline]
-
Pablos, J. L., Amara, A., Bouloc, A., Santiago, B., Caruz, A., Galindo, M., Delaunay, T., Virelizier, J. L., Arenza-Seisdedos, F. (1999) Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin Am. J. Pathol. 155,1577-1586[Abstract/Free Full Text]
-
Goede, V., Brogelli, L., Ziche, M., Augustin, H. G. (1999) Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1 Int. J. Cancer 82,765-770[Medline]
-
Weber, K. S., Nelson, P. J., Grone, H. J., Weber, C. (1999) Expression of CCR2 by endothelial cells: implications for MCP-1 mediated wound injury repair and in vivo inflammatory activation of endothelium Arterioscler. Thromb. Vasc. Biol. 19,2085-2093[Abstract/Free Full Text]
-
Salcedo, R., Ponce, M. L., Young, H. A., Wasserman, K., Ward, J. M., Kleinman, H. K., Oppenheim, J. J., Murphy, W. J. (2000) Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression Blood 96,34-40[Abstract/Free Full Text]
-
Luster, A. D., Cardiff, R. D., MacLean, J. A., Crowe, K., Granstein, R. D. (1998) Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine Proc. Assoc. Am. Phys. 110,183-196[Medline]
-
Larsen, C. G., Zachariae, C. O. C., Oppenheim, J. J., Matsushima, K. (1989) Production of monocyte chemotactic and activating factor (MCAF) by human dermal fibroblasts in response to interleukin 1 or tumor necrosis factor Biochem. Biophys. Res. Commun. 160,1403-1408[Medline]
-
Larsen, C. G., Anderson, A. O., Oppenheim, J. J., Matsushima, K. (1989) Production of interleukin 8 by human dermal fibroblasts and keratinocytes in response to interleukin 1 or tumor necrosis factor Immunology 68,31-36[Medline]
-
Bartels, J., Schlüter, C., Richter, E., Noso, N., Kulke, R., Christophers, E., Schröder, J. M. (1996) Human dermal fibroblasts express eotaxin: molecular cloning, mRNA expression, and identification of eotaxin variants Biochem. Biophys. Res. Commun. 225,1045-1051[Medline]
-
Nirodi, C. S., Devalaraja, R., Nanney, L. B., Arrindell, S., Russell, S., Trupin, J., Richmond, A. (2000) Chemokine and chemokine receptor expression in keloid and normal fibroblasts Wound Repair Regen 8,371-382[Medline]
-
Gharaee-Kermani, M., Denholm, E. M., Phan, S. H. (1996) Costimulation of fibroblast collagen and transforming growth factor ß1 gene expression by monocyte chemoattractant protein-1 via specific receptors J. Biol. Chem. 271,17779-17784[Abstract/Free Full Text]
-
Yamamoto, T., Eckes, B., Mauch, C., Hartmann, K., Krieg, T. (2000) Monocyte chemoattractant protein-1 enhances gene expression and synthesis of matrix metalloproteinase-1 in human fibroblasts by an autocrine IL-1 loop J. Immunol. 164,6174-6179[Abstract/Free Full Text]
-
Xia, M., Leppert, D., Hauser, L., Sreedharan, S. P., Nelson, P. J., Krensky, A. M., Goetzl, E. J. (1996) Stimulus specificity of matrix metalloproteinase dependence of human T cell migration through a model basement membrane J. Immunol. 156,160-167[Abstract]
-
Johnatty, R. N., Taub, D. D., Reeder, S. P., Turcovski-Corrales, S. M., Cottam, D. W., Stephenson, T. J., Rees, R. C. (1997) Cytokine and chemokine regulation of proMMP-9 and TIMP-1 production by human peripheral blood lymphocytes J. Immunol. 158,2327-2333[Abstract]
-
Wu, L., Fan, J., Matsumoto, S., Watanabe, T. (2000) Induction and regulation of matrix metalloproteinase-12 by cytokines and CD40 signaling in monocyte/macrophages Biochem. Biophys. Res. Commun. 269,808-815[Medline]
-
Shiraha, H., Glading, A., Gupta, K., Wells, A. (1999) IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity J. Cell Biol. 146,243-253[Abstract/Free Full Text]
-
Watson, J. B., Getzler, S. B., Mosher, D. F. (1994) Platelet factor 4 modulates the mitogenic activity of basic fibroblast growth factor J. Clin. Invest. 94,261-268
-
Zlotnik, A., Yoshie, O. (2000) Chemokines: a new classification system and their role in immunity Immunity 12,121-127[Medline]
TOP
ABSTRACT
BIOLOGY OF WOUND HEALING
