(Journal of Leukocyte Biology. 2000;68:1-8.)
© 2000
by Society for Leukocyte Biology
CXC chemokines in angiogenesis
John A. Belperio
,
Michael P. Keane
,
Douglas A. Arenberg
,
Christina L. Addison
,
Jan E. Ehlert
,
Marie D. Burdick* and
Robert M. Strieter*
* Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles School of Medicine; and
Department of Internal Medicine, Division of Pulmonary and Critical Medicine, The University of Michigan Medical School, Ann Arbor
Correspondence: Robert M. Strieter, M.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCLA School of Medicine, Room 37-131B, CHS, Box 951690, 10833 Le Conte Ave., Los Angeles, CA 90095-1690. E-mail: rstrieter{at}mednet.ucla.edu
 |
ABSTRACT
|
|---|
A variety of factors have been identified that regulate angiogenesis,
including the CXC chemokine family. The CXC chemokines are a unique
family of cytokines for their ability to behave in a disparate manner
in the regulation of angiogenesis. CXC chemokines have four highly
conserved cysteine amino acid residues, with the first two cysteine
amino acid residues separated by one non-conserved amino acid residue
(i.e., CXC). A second structural domain within this family determines
their angiogenic potential. The NH2 terminus of the
majority of the CXC chemokines contains three amino acid residues
(Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino
acid residue of the primary structure of these cytokines. Members that
contain the ELR motif (ELR+) are potent promoters of
angiogenesis. In contrast, members that are inducible by interferons
and lack the ELR motif (ELR-) are potent inhibitors of
angiogenesis. This difference in angiogenic activity may impact on the
pathogenesis of a variety of disorders.
Key Words: cytokines neovascularization wound repair tumorigenesis tumor metastasis
 |
INTRODUCTION
|
|---|
Angiogenesis is the formation of new blood vessels from
preexisting microvasculature. Angiogenesis is a biological process that
is critical to both physiological and pathological processes
[1
2
3
4
5
6
7
8
9
10
11
]. The regulation of angiogenesis depends on a
dual, yet opposing balance of angiogenic and angiostatic factors that
promote or inhibit neovascularization, respectively. For example, under
homeostatic conditions the rate of normal capillary endothelial cell
turnover is measured in months or years [12
,
13
], suggesting a balance in the biological effect of
angiogenic and angiostatic factors. During wound repair the formation
of granulation tissue is associated with a shift in the balance
favoring the predominance of angiogenic factors that supports the
development of new functioning capillaries within days
[8
]. In contrast, the latter phases of wound repair are
associated with a marked decline of angiogenesis. This event correlates
with the involution of granulation tissue that is concomitant with
re-epithelialization. These events suggest that angiogenesis of wound
repair is tightly controlled and temporally related to the imbalance of
expression of angiogenic and angiostatic factors that ultimately
regulates angiogenesis. The temporal imbalance in angiogenic and
angiostatic factors in granulation tissue can either represent a marked
reduction in the elaboration of angiogenic factors and/or a
simultaneous increase in factors that inhibit neovascularization
[14
]. In contrast to the precise regulation of
angiogenesis in wound repair, aberrant angiogenesis can lead to an
imbalance in the relationship of angiogenic and angiostatic factors
that favors persistent angiogenesis. This type of environment can
contribute to the pathogenesis of tumor growth and metastases, and the
promotion of chronic fibroproliferative disorders. The complement of
angiogenic and angiostatic factors may vary among different
physiological and pathological settings. However, the recognition of
this dual mechanism of control is critical in order to gain insight
into this complex process and understand aberrant angiogenesis
associated with a variety of pathological conditions. The CXC
chemokines are a unique family of cytokines that can regulate
angiogenesis in a disparate manner and will be the subject of this
review.
 |
CHEMOKINES, CXC CHEMOKINE RECEPTORS, AND ANGIOGENESIS
|
|---|
CXC chemokines are characteristically heparin binding proteins. On
a structural level, they have four highly conserved cysteine amino acid
residues, with the first two cysteines separated by one nonconserved
amino acid residue [15
16
17
18
19
20
21
22
23
24
25
26
27
]. Although the CXC motif
distinguishes this family from other chemokine families, a second
structural domain dictates their angiogenic activity. The
NH2 terminus of the majority of the CXC chemokines contain
a three-amino-acid motif (Glu-Leu-Arg: the ELR motif), which precedes
the first cysteine amino acid of the primary structure of these
cytokines [15
16
17
18
19
20
21
22
23
24
25
26
27
]. The family members that contain the
ELR motif (ELR+) are potent promoters of angiogenesis
[23
] (Table 1
).In contrast, members that are induced by interferons and lack the ELR
motif (ELR-) are potent inhibitors of angiogenesis
[23
, 28
29
30
] (Table 1) . Therefore, on a
structural/functional level, members of the CXC chemokine family can
either promote or inhibit angiogenesis, and the imbalance of the local
expression of these chemokines may be important in the regulation of
angiogenesis under both physiological and pathological conditions.
Angiogenic (ELR+) CXC chemokines
Members of the CXC chemokine family that behave as angiogenic
factors include interleukin-8 (IL-8), epithelial neutrophil activating
protein-78 (ENA-78), growth-related genes (GRO-
, -ß, and -
),
granulocyte chemotactic protein-2 (GCP-2), and NH2-terminal
truncated forms of platelet basic protein (PBP), which include
connective tissue activating protein-III (CTAP-III),
beta-thromboglobulin (ß-TG), and neutrophil activating protein-2
(NAP-2) [23
, 31
32
33
] (Table 1)
.
ELR+ CXC chemokines directly induce endothelial cell
chemotactic and proliferative activity in vitro, and
angiogenesis in vivo in the absence of preceding
inflammation [23
, 32
33
34
35
]. Their angiogenic
activity is distinct from their ability to induce inflammation.
Although a specific CXC chemokine receptor(s) that mediates the
angiogenic activity of these cytokines remains to be determined, the
candidate CXC chemokine receptors for this effect are CXCR1 and/or
CXCR2. Only IL-8 and GCP-2 specifically bind to CXCR1, whereas all
ELR+ CXC chemokines bind to CXCR2 [15
16
17
18
19
20
21
22
23
24
25
26
27
].
The ability of ELR+ CXC chemokine ligands to bind to CXCR2
supports the notion that this represents the receptor for the mediation
of angiogenic activity by ELR+ CXC chemokines. This is
further supported by the fact that CXCR2 has the greatest sequence
homology with the recently described human Kaposis sarcoma herpes
virus-G protein-coupled receptor (KSHV-GPCR; ORF 74)
[36
37
38
39
40
].
The KSHV-GPCR demonstrates constitutive activation with the ability to
cause oncogenic transformation of NIH 3T3 cells and to promote
angiogenesis in vivo [36
, 40
].
Infection of primary endothelial cells with KSHV and expression of
KSHV-GPCR leads to enhanced proliferation and long-term survival
[38
]. The CXC chemokine ligands, IL-8 and GRO-
, can
act as agonists for KSHV-GPCR, and further augment the signaling of
this receptor [41
, 42
]. It is interesting
that introducing a single point mutation in wild-type CXCR2 and
transfection of NIH 3T3 cells results in oncogenic transformation in a
similar manner as KSHV-GPCR [36
]. Moreover, wild-type
CXCR2 expression in these cells results in cellular transformation
related to autocrine stimulation by an ELR+ CXC chemokine
[36
]. However, oncogenic transformation was not induced
with either mutated CXCR1 or wild-type CXCR1 [36
]. These
data suggest that either constitutive activation or persistent
autocrine stimulation of CXCR2 causes cellular transformation similar
to KSHV-GPCR. Thus, the potential expression of CXCR2 on endothelial
cells in the presence of persistent autocrine (endothelium), juxtacrine
(endothelium), and paracrine (tumor cells or other activated stromal
cells) stimulation with ELR? CXC chemokines has important implications
in promoting angiogenesis. Future studies will delineate whether CXCR2
is the putative receptor for mediating ELR+ CXC chemokine
angiogenic activity.
Angiostatic (ELR-) CXC chemokines
The angiostatic members of the CXC chemokine family include PF4,
monokine induced by interferon-
(MIG), and interferon-
-inducible
protein (IP-10) [43
44
45
46
47
48
] (Table 1)
. Although stromal
cell-derived factor (SDF-1) is another ELR- CXC chemokine,
it remains unclear whether this ELR- CXC chemokine
inhibits or promotes angiogenesis. SDF-1 has been found to induce
in vitro migration of human umbilical vein endothelial cells
[49
, 50
]. Mice with targeted disruption of
the SDF-1 gene perinatally die [51
]. This appears to be
multi-factorial and includes defects in B cell and myeloid progenitors,
suggesting that SDF-1 is involved in lymphopoiesis and myelopoiesis. In
addition, these mice demonstrate cardiac ventricular septal defects
[51
]. Recently, targeted disruption of the receptor for
SDF-1, CXCR4, has demonstrated that this CXC chemokine receptor is
essential for vascularization of the gastrointestinal tract,
hematopoiesis, and cerebellar development in these mice
[52
, 53
]. In contrast to these findings,
SDF-1 can attenuate the angiogenic activity of ELR+ CXC
chemokines, bFGF, or VEGF [54
]. Thus, the role of SDF-1
in modulating angiogenesis in the context of tumorigenesis or chronic
fibroproliferative disorders awaits further study.
All three interferons (IFN-
, -ß, and -
) stimulate the
expression of IP-10 [15
, 43
44
45
46
47
48
]. MIG is
induced only by IFN-
[15
, 43
44
45
46
47
48
].
Recently, a new ELR- member of the CXC chemokine family,
IFN-inducible T cell alpha chemoattractant (I-TAC), has been cloned,
and is induced primarily by IFN-
[55
]. I-TAC, similar
to IP-10 and MIG, inhibits neovascularization in the rat corneal
micropocket (CMP) assay of angiogenesis in response to either
ELR+ CXC chemokines or VEGF (unpublished observation).
These findings suggest that all interferon-inducible ELR-
CXC chemokines are potent inhibitors of angiogenesis. Moreover, this
interrelationship of interferon and interferon-inducible
ELR- CXC chemokines and their biological function are
directly relevant to the function of IL-18 and IL-12. The capability of
IL-18 and IL-12 to induce IFN-
and subsequent interferon-inducible
ELR- CXC chemokines explains their ability to inhibit
angiogenesis [56
]. Therefore, IL-12 and IL-18, via the
induction of IFN-
, will have a profound effect on the production of
IP-10, MIG, and I-TAC. The subsequent expression of
interferon-inducible ELR- CXC chemokines may represent the
final common pathway and explain the mechanism for the attenuation of
angiogenesis related to interferons. Although all three IFN-inducible
ELR- CXC chemokines specifically bind to the CXC chemokine
receptor, CXCR3 [55
, 57
], and the
expression of CXCR3 mRNA has been associated with endothelial cells
[58
], it remains to be determined whether CXCR3 is the
putative receptor for interferon-inducible ELR- CXC
chemokine inhibition of angiogenesis.
Recently, eloquent studies have delineated potential mechanisms for the
ELR- CXC chemokine, PF4, and its ability to inhibit
angiogenesis that may be relevant to interferon-inducible
ELR- CXC chemokines. The ability of PF4 to bind to
glycosaminoglycans (GAG; heparin and heparan sulfate) with high
affinity appears to be important to several of its biological
functions. PF4 inhibits endothelial cell migration, proliferation, and
in vivo angiogenesis in response to bFGF or VEGF
[59
, 60
]. Moreover, fluorescein
isothiocyanate (FITC)-labeled PF4 injected systemically, selectively
binds to the endothelium only in areas of active angiogenesis
[61
, 62
]. This suggests that the
microvasculature is the major target for the biological effects of PF4
during angiogenesis. PF4 has been shown to inhibit bFGF and
VEGF165 binding to their respective receptors
[63
64
65
]. One mechanism for this effect is related to
the generation of PF4-bFGF or PF4-VEGF165 heterodimeric
complexes, which impairs bFGF or VEGF165 binding to their
respective receptors [64
65
66
]. bFGF must undergo
dimerization in the presence of endogenous heparin in order to bind to
its receptor [65
, 66
]. PF4 complexes to
bFGF and prevents bFGF dimerization followed by impaired receptor
binding and internalization [65
]. VEGF165
possesses heparin binding ability similar to bFGF. PF4 impairs
VEGF165 binding to its receptors on endothelium via a
mechanism similar to what has been reported for its ability to inhibit
bFGF [64
]. Although the ability of PF4 to form
heterodimers with bFGF and VEGF165 is one potential
mechanism to inhibit bFGF and VEGF165 biological activity,
it appears that PF4 may inhibit angiogenesis through additional
mechanisms.
Although PF4 inhibits specific VEGF165 binding, it does not
inhibit VEGF121 binding to VEGF receptors on endothelial
cells. In contrast to VEGF165, VEGF121 is not a
heparin-binding protein [64
, 67
,
68
]. PF4 neither forms heterodimers with
VEGF121 nor competitively interferes with
VEGF121 binding to its receptor. However, PF4 directly
inhibits VEGF121-induced endothelial cell proliferation
[64
]. These findings suggest that other mechanisms must
be operative for PF4 inhibition of mitogen stimulation of endothelial
cells, perhaps mediated through its own independent biological signal.
Although a specific receptor for PF4 on endothelium has not yet been
discovered, studies have suggested that PF4 inhibits endothelial cell
cycle by preventing cell entry into S phase [60
]. In a
model system of endothelial cell stimulation independent of interaction
with cell-surface GAGs, PF4 inhibits epidermal growth factor
(EGF)-stimulated endothelial cell proliferation by causing a decrease
in cyclin E-cyclin-dependent kinase 2 (cdk2) activity that results in
attenuation of retinoblastoma protein (pRb) phosphorylation
[69
]. The mechanism is related to PF4-dependent
sustained increase in the levels and binding of the cyclin-dependent
kinase inhibitor (CKI), p21Cip1/WAF1, to the cyclin E-cdk2
complex. This inhibits cell cycle progression by preventing the
down-regulation of p21Cip1/WAF1 leading to inhibition of
both cyclin E-cdk2 activity and phosphorylation of pRb
[69
]. These studies suggest that PF4 can inhibit a
variety of endothelial cell mitogens at multiple levels. These events
may be relevant to interferon-inducible ELR- CXC
chemokines because IP-10 has been shown to compete with PF4 for
binding, and inhibition of endothelial cell proliferation that may be
related to inhibition of the cell cycle [29
]. This
supports the notion that interferon-inducible ELR- CXC
chemokines may have similar mechanisms for their inhibition of bFGF,
VEGF, EGF, and ELR+ CXC chemokine-induced angiogenesis.
ELR+ CXC chemokines promote angiogenesis associated
with tumorigenesis
The ELR+ CXC chemokines are important mediators of
tumorigenesis related to their angiogenic properties. Although GRO-ß
has been recently reported to inhibit angiogenesis [70
],
the concentration used in this study was 1000-fold higher (110 µM)
than what was found for its angiogenic activity (110 nM)
[23
, 54
]. This would suggest that
superphysiological concentrations of GRO-ß can desensitize the
angiogenic response. Moreover, studies in melanoma tumors support that
all GROs play a significant role in mediating tumorigenesis related to
both their mitogenic and angiogenic activities. For example, GRO-
,
-ß, and -
have all been found to be highly expressed in human
melanoma [71
]. To determine the biological significance
of the presence of these ELR+ CXC chemokines in melanoma,
human GRO-
, -ß, and -
genes have been transfected into
immortalized murine melanocytes [71
, 72
].
The persistent expression of GROs in these cells transforms their
phenotype to one with anchorage-independent growth in vitro
and the ability to form tumors in vivo in nude and SCID mice
[71
, 72
]. The tumors are highly vascular
and similar to the vascularity of B16 melanoma controls
[71
, 72
]. When tumors are depleted of GROs
there is a marked reduction of tumor-derived angiogenesis directly
related to inhibition of tumor growth [71
,
72
]. These findings support the notion that the
ELR+ CXC chemokines, such as GRO-
, -ß, and -
, have
the ability to act both as autocrine growth factors for melanoma and as
potent paracrine mediators of angiogenesis to promote tumorigenesis and
metastases.
The progression and growth of ovarian carcinoma is also dependent on
successful angiogenesis, and IL-8 has been determined to play a
significant role in mediating human ovarian carcinoma-derived
angiogenesis and tumorigenesis [73
]. The expression of
IL-8, bFGF, and VEGF was examined in five different human ovarian
carcinoma cell lines [73
]. All cell lines in
vitro expressed similar levels of bFGF, however, these cells
expressed either high or low levels of IL-8 or VEGF. When implanted
into the peritoneum of nude mice, the high-expressing IL-8 tumors were
associated with all animals dying in <51 days [73
]. The
expression of IL-8 was directly correlated with neovascularization and
inversely correlated with survival, whereas VEGF expression was only
correlated with production of ascites [73
]. No
correlation was found for bFGF with either tumor neovascularization or
survival [73
]. This study has been substantiated in
patients with ovarian cancer, where ascites fluid demonstrates
angiogenic activity directly correlated to IL-8 [74
].
These findings support the notion that antigenic ELR+ CXC
chemokines play a greater role than bFGF and VEGF in mediating
angiogenesis associated with ovarian cancer.
IL-8 is markedly elevated and contributes to overall angiogenic
activity of non-small-cell lung cancer (NSCLC) [75
].
Extending these studies to an in vivo model system of human
tumorigenesis (i.e., human NSCLC/SCID mouse chimera)
[76
], tumor-derived IL-8 was found to be directly
correlated with tumorigenesis [76
]. Tumor-bearing
animals depleted of IL-8 demonstrated a >40% reduction in tumor
growth and a reduction in spontaneous metastases [76
].
The attenuation of tumor growth and metastases was directly correlated
to reduced angiogenesis. These findings have been further corroborated
through the use of several human NSCLC cell lines grown in nude mice.
NSCLC cell lines that constitutively express IL-8 display greater
tumorigenicity that is directly correlated to angiogenesis
[77
].
Although IL-8 was the first angiogenic CXC chemokine to be discovered
in NSCLC, ENA-78 was found to be highly correlated with NSCLC-derived
angiogenesis [78
]. Surgical specimens of NSCLC tumors
demonstrate a direct correlation of ENA-78 with tumor angiogenesis.
These studies were extended to a SCID mouse model of human NSCLC
tumorigenesis. ENA-78 expression was directly correlated with tumor
growth. Moreover, when NSCLC tumor-bearing animals were depleted of
ENA-78, both tumor growth and spontaneous metastases were markedly
attenuated [78
]. The reduction angiogenesis is also
accompanied by an increase in tumor cell apoptosis, consistent with the
previous observation that inhibition of tumor-derived angiogenesis is
associated with increased tumor cell apoptosis [79
,
80
]. Similarly, in vivo and in
vitro proliferation of NSCLC cells was unaffected by the presence
of ENA-78. Although a significant correlation of ENA-78 exists with
tumor-derived angiogenesis, tumor growth, and metastases, ENA-78
depletion does not completely inhibit tumor growth. This reflects that
the angiogenic activity of NSCLC tumors is related to many overlapping
and potentially redundant factors acting in a parallel or serial
manner.
Prostate cancer tumorigenesis and metastasis is dependent on
angiogenesis [81
, 82
]. Serum levels of IL-8
have been found to be markedly elevated in patients with prostate
cancer. These levels are highly correlated with the stage of the
disease and have been determined to be an independent variable from the
ratio of free/total prostate specific antigen (PSA)
[83
]. In fact, the combined use of free/total PSA and
IL-8 levels were more effective in distinguishing prostate cancer from
benign prostatic hypertrophy. This suggests that an ELR+
CXC chemokine may be playing an important role in mediating prostate
cancer-derived angiogenesis in support of tumorigenesis and metastases.
This observation in patients has been substantiated in human/SCID mice
chimeras of human prostate cancer tumorigenesis [84
].
Three human prostate cancer cell lines were examined for constitutive
production of angiogenic ELR+ CXC chemokines
[84
]. Tumorigenesis of the human prostate cancer cell
line, PC-3, was shown to be attributable, in part, to the production of
the angiogenic CXC chemokine, IL-8. Depletion of endogenous IL-8
inhibited PC-3 tumor growth in SCID mice, that was entirely
attributable to inhibition of PC-3 tumor-derived angiogenesis. In
contrast, the human prostate cancer cell line, Du145, was found to
utilize a different angiogenic CXC chemokine, GRO-
, to mediate
tumor-derived angiogenesis. Depletion of endogenous GRO-
, but not
anti-IL-8, reduced tumor growth that was directly related to attenuated
angiogenic activity. Thus, prostate cancer cell lines can utilize
distinct CXC chemokines to mediate their tumorigenic potential. Similar
findings have been shown in gastric carcinoma [85
,
86
]. The findings for the redundancy of ELR+
CXC chemokines in human tumors provides the unique opportunity to
target a putative receptor for ELR+ CXC chemokine-mediated
angiogenesis.
ELR- CXC chemokines attenuate angiogenesis associated
with tumorigenesis
ELR- CXC chemokines have been shown to inhibit
angiogenesis in several model systems. For example, Burkitts lymphoma
cell lines form tumors in nude mice [87
]. Angiogenesis
is essential for tumorigenesis of these lymphomas, analogous to
carcinomas. The expression of IP-10 and MIG was found to be higher in
tumors that demonstrated spontaneous regression, and was directly
related to impaired angiogenesis [88
]. To determine
whether this effect was attributable to IP-10 or MIG, more virulent
Burkitts lymphoma cell lines were grown in nude mice and subjected to
intra-tumor inoculation with either IP-10 or MIG. Both conditions
resulted in marked reduction in tumor-associated angiogenesis
[30
, 89
]. Although both IP-10 and MIG have
been demonstrated to induce mononuclear cell recruitment via the
interaction with their putative CXC chemokine receptor (CXCR3)
[15
16
17
18
, 44
], the ability of both of these
ELR- CXC chemokines to inhibit angiogenesis and induce
lymphoma regression in nude mice support that these chemokines mediate
their effects in a T cell-independent manner.
To examine the role of IP-10 in the regulation of angiogenesis in a
carcinoma, the level of IP-10 from human surgical NSCLC tumor specimens
was examined and found to be significantly higher in the tumor
specimens than in normal adjacent lung tissue [90
]. The
increase in IP-10 from human NSCLC tissue was entirely attributable to
the higher levels of IP-10 present in squamous cell carcinoma (SCCA)
compared with adenocarcinoma. Moreover, depletion of IP-10 from SCCA
surgical specimens resulted in augmented angiogenic activity
[90
]. The marked difference in the levels and
bioactivity of IP-10 in SCCA and adenocarcinoma is clinically and
pathophysiologically relevant, and represents a possible mechanism for
the biological differences of these two cell types of NSCLC. Patient
survival is lower, metastatic potential is higher, and evidence of
angiogenesis is greater for adenocarcinoma, compared with SCCA of the
lung [91
92
93
]. These studies were extended to a SCID
mouse system to examine the effect of IP-10 on human NSCLC cell line
tumor growth in a T- and B cell-independent manner. SCID mice were
inoculated with either adenocarcinoma or SCCA cell lines
[90
]. The production of IP-10 from adenocarcinoma and
SCCA tumors was inversely correlated with tumor growth
[90
]. However, IP-10 levels were significantly higher in
the SCCA, compared with adenocarcinoma tumors. The appearance of
spontaneous lung metastases in SCID mice bearing adenocarcinoma tumors
occurred after IP-10 levels from either the primary tumor or plasma had
reached a nadir. In subsequent experiments, SCID mice bearing SCCA
tumors were treated with either neutralizing anti-IP-10 antibodies,
whereas animals bearing adenocarcinoma tumors were treated with
intra-tumor IP-10. Depletion of IP-10 in SCCA tumors resulted in a
twofold increase in their size. In contrast, reconstitution of
intra-tumor IP-10 in adenocarcinoma tumors reduced both their size and
metastatic potential, which was unrelated to infiltrating neutrophils
or mononuclear cells (i.e., macrophages or NK cells) and directly
attributable to a reduction in tumor-associated angiogenesis.
The role of angiogenic (ELR+) and angiostatic
IFN-inducible (ELR-) CXC chemokines in the regulation of
angiogenesis associated with chronic fibroproliferative disorders
Angiogenesis is increasingly being recognized for its role in
promoting the pathogenesis of chronic inflammatory/fibroproliferative
disorders. For example, rheumatoid arthritis is associated with the
unrestrained proliferation of fibroblasts and capillary blood vessels
that leads to the formation of the pannus and destruction of joint
spaces. Macrophages isolated from rheumatoid synovium produce
pro-angiogenic factors [94
]. Psoriasis is a well-known
angiogenesis-dependent skin disorder that is characterized by marked
dermal neovascularization. Keratinocytes isolated from psoriatic
plaques demonstrate a greater production of angiogenic activity. It is
interesting that this angiogenic phenotype is due, in part, to a
combined defect in the overexpression of the angiogenic cytokine IL-8,
and a deficiency in the production of the angiogenesis inhibitor,
thrombospondin-1, resulting in a pro-angiogenic environment
[95
].
Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal
pulmonary fibroproliferative disorder. The pathogenesis of IPF that
ultimately leads to end-stage fibrosis demonstrates features of
dysregulated/abnormal repair with exaggerated
neovascularization/vascular remodeling, fibroproliferation, and
deposition of extracellular matrix, leading to progressive fibrosis and
loss of lung function. Although numerous eloquent studies have examined
the biology of fibroblast proliferation and deposition of extracellular
matrix (ECM) in interstitial lung disease, few studies have examined
the role of angiogenesis/vascular remodeling that may support
fibroplasia and deposition of ECM in these disorders.
The existence of neovascularization in IPF was originally identified by
Turner-Warwick, who examined the lungs of patients with widespread
interstitial fibrosis and demonstrated neovascularization leading to
anastomoses between the systemic and pulmonary microvasculatures and
evidence of extensive vascular remodeling in areas of fibrosis
[96
]. These findings have been further substantiated
with evidence of extensive neovascularization during the pathogenesis
of pulmonary fibrosis in bleomycin-induced pulmonary fibrosis
[97
].
Recently, studies have corroborated the findings of Turner-Warwick, and
have shown that the bronchoalveolar lavage fluid and lung tissue from
patients with IPF have marked angiogenic activity that is almost
entirely attributable to the imbalance in the overexpression of the
angiogenic ELR+ CXC chemokine, IL-8, compared with the
relative down-regulation of the angiostatic IFN-inducible CXC
chemokine, IP-10 [98
]. To determine whether the
imbalance in the expression of these CXC chemokines were relevant to
the pathogenesis of pulmonary fibrosis, studies were extended to a
murine model system of bleomycin-induced pulmonary fibrosis. In this
model system, the expression and biological activity of murine
macrophage inflammatory protein-2 (MIP-2; an angiogenic
ELR+ CXC chemokine homologous to human GRO-ß/
) and the
angiostatic CXC chemokine, IP-10, were correlated to the magnitude of
lung fibrosis during bleomycin-induced pulmonary fibrosis
[99
, 100
]. MIP-2 and IP-10 were measured
during bleomycin-induced pulmonary fibrosis from bronchoalviolar lavage
and whole lung tissue homogenates, and were found to be directly and
inversely correlated, respectively, with total lung hydroxyproline
levels, a measure of lung collagen deposition [99
,
100
]. Moreover, if either endogenous MIP-2 was depleted
or exogenous IP-10 (intramuscular) was administered to the animals
during bleomycin exposure, both treatment strategies resulted in marked
attenuation of pulmonary fibrosis that was entirely attributable to a
reduction in angiogenesis in the lung [99
,
100
]. These findings support the notion that angiogenesis
is critical to promote fibroplasia and deposition of ECM during
pulmonary fibrosis, and that angiogenic and angiostatic factors, such
as ELR+ and interferon-inducible ELR- CXC
chemokines play an important role in the pathogenesis of this process.
Furthermore, with the recent demonstration of the efficacy of IFN-
treatment of IPF patients [101
, 102
], the
above studies substantiate that IFN-
treatment of IPF may mediate
its effect, in part, by shifting the imbalance of the expression of
angiogenic ELR+ and angiostatic interferon-inducible
ELR- CXC chemokines to favor an angiostatic environment
leading to inhibition of dysregulated neovascularization/vascular
remodeling, fibroproliferation, and deposition of extracellular matrix
in IPF patients.
 |
CONCLUSION
|
|---|
Angiogenesis is regulated by an opposing balance of
angiogenic and angiostatic factors. CXC chemokines are a unique
cytokine family that contains members that exhibit on a
structural/functional basis either angiogenic or angiostatic biological
activity. The above studies have demonstrated that, as a family, the
CXC chemokines appear to be important in the regulation of angiogenesis
associated with both tumorigenesis and the pathogenesis of chronic
inflammatory/fibroproliferative disorders. These findings support the
notion that therapy directed at either inhibition of angiogenic or
augmentation of angiostatic CXC chemokines may be a novel approach in
the treatment of solid tumors and chronic fibroproliferative disorders.
 |
ACKNOWLEDGEMENTS
|
|---|
This work was supported in part by National Institutes of Health
Grants P50 HL60289 and CA87879 (R. M. S.), CA72543 (D. A. A.), and HL03906 (M. P. K.).
 |
FOOTNOTES
|
|---|
Present address for JAB and MPK: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, CA 90095.
Received January 1, 2000;
revised January 15, 2000;
accepted January 18, 2000.
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R. M. Strieter
Out of the Shadows: CXC Chemokines in Promoting Aberrant Lung Cancer Angiogenesis
Cancer Prevention Research,
October 1, 2008;
1(5):
305 - 307.
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E. D. Karagiannis and A. S. Popel
A systematic methodology for proteome-wide identification of peptides inhibiting the proliferation and migration of endothelial cells
PNAS,
September 16, 2008;
105(37):
13775 - 13780.
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I. V. Nesmelova, Y. Sham, J. Gao, and K. H. Mayo
CXC and CC Chemokines Form Mixed Heterodimers: ASSOCIATION FREE ENERGIES FROM MOLECULAR DYNAMICS SIMULATIONS AND EXPERIMENTAL CORRELATIONS
J. Biol. Chem.,
August 29, 2008;
283(35):
24155 - 24166.
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J. A Belperio and A. Ardehali
Chemokines and Transplant Vasculopathy
Circ. Res.,
August 29, 2008;
103(5):
454 - 466.
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Y. Yu, Y. Su, S. R. Opalenik, T. Sobolik-Delmaire, N. F. Neel, S. Zaja-Milatovic, S. T. Short, J. Sai, and A. Richmond
Short tail with skin lesion phenotype occurs in transgenic mice with keratin-14 promoter-directed expression of mutant CXCR2
J. Leukoc. Biol.,
August 1, 2008;
84(2):
406 - 419.
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