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Departments of
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Medical Biochemistry and
Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4 integrin subunit. These findings suggest that
angiogenesis dependent on IL-4 and IL-13 is mainly mediated through a
soluble VCAM-1/4 integrin
pathway. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-8, soluble E-selectin, and soluble VCAM-1 (sVCAM-1)
(2). Inhibitors include IFN-, IFN-ß, IL-12, TGF-ß,
platelet factor-4, prolactin fragment, thrombospondins, angiostatin,
and endostatin (3). Angiogenesis-related activities by members of the lymphokine IL-4 superfamily, IL-4 and IL-13, have been reported. Tumors expressing IL-4 have a reduced level of vascular density (4). IL-4 blocked the induction of corneal neovascularization by bFGF in rats (5). Chemotaxis of vascular endothelial cells is stimulated only when small amounts (0.01 ng/ml) of IL-4 are present, but is inhibited when higher doses of IL-4 are present (5). These studies suggest antiangiogenic properties of IL-4 under certain conditions. In contrast, IL-4 induces various activities associated with angiogenesis. IL-4 increases the expression of urokinase-type plasminogen activator (6) and VCAM-1 (7) and induces changes in the morphology of HUVEC (8). IL-4 is a potent mitogen for microvascular endothelial cells (9). We previously reported that angiogenesis is induced in vitro and in vivo in response to IL-4 (10).
Another cytokine derived from T lymphocyte, IL-13, shows about 25%
homology to IL-4 and also shares many of the IL-4 activities
(11). Their common effects have been explained by using
shared receptor subunits consisting of IL-4R and IL-13R
(12). Both IL-4 and IL-13 down-regulate the function of
monocytes by inhibiting the secretion of the inflammatory cytokine
IL-6, TNF-, and IL-12 (11) and by inducing the
production of IL-1R antagonists (13). Regardless of their
predominant anti-inflammatory activities, IL-4 and IL-13
considerably increase the expression of VCAM-1 on the surface of
vascular endothelial cells, causing adhesion of T cells
(7). In addition, IL-4 and IL-13 induce the synthesis of
monocyte chemoattractant protein-1 in endothelial cells
(14), and IL-13 is chemotactic for both HUVEC and dermal
microvascular endothelial cells (15), suggesting a novel
role for IL-13 as a proinflammatory and proangiogenic cytokine. IL-4
and IL-13 thus appear to promote transendothelial migration of
leukocytes and act proangiogenically under certain conditions.
In this study, we asked whether IL-13 can induce angiogenesis together with IL-4 through interaction with common receptor molecules on the cell surface of vascular endothelial cells. We examined the angiogenic activity of IL-13 and IL-4 in vitro and in vivo and showed that sVCAM-1 is markedly up-regulated when vascular endothelial cells are treated with IL-4 and IL-13. How IL-4- and IL-13-mediated angiogenesis is controlled is discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human rIL-4 was a gift from Ono Pharmaceutical (Osaka, Japan).
Human rEGF was purchased from PeproTech (London, U.K.). Human rbFGF was
purchased from Intergen (Purchase, NY). Bovine rbFGF, rat rIL-4, human
rIL-13, murine rIL-13, and anti-human IL-4 soluble receptor
neutralizing Ab were all purchased from R&D Systems (Minneapolis, MN).
Anti-human VCAM-1 Ab was purchased from Upstate Biotechnology (Lake
Placid, NY), and anti-rat 4 Ab was
purchased from Seikagaku (Tokyo, Japan). Anti-STAT6 Ab was purchased
from Santa Cruz Biotechnology (Santa Cruz, CA), and
anti-phospho-STAT6 Ab was purchased from New England Biolabs
(Beverly, MA).
Cell culture
Bovine aortic endothelial cells were isolated and cultured as previously described (16, 17). Human microvascular endothelial cells were isolated from normal omental tissue that was removed during surgery as previously described (18). Because the responsiveness of the endothelial cells to angiogenic factors decreases during serial cultivation, we used cells at passages 5–10 (19).
Quantitative analysis of tube formation in endothelial cells on type I collagen gel
The tube formation assay was made as described previously (16, 20, 21). In brief, bovine aortic endothelial cells or human microvascular endothelial cells were plated onto type I collagen gel in a medium containing 10% FBS. When the cells reached confluence, that medium was replaced with a medium that contained 1% FBS, with or without the various factors, and the cells were incubated for an additional 72 h. On the third day, phase-contrast micrographs (magnification, x200) were recorded using a still video camera recorder (R5000H, Fuji, Tokyo, Japan). The total length of the tube-like structures for each field was measured using a Cosmozone image analyzer (Nikon, Tokyo, Japan). Eight random fields were measured for each dish, and the total length for each field was calculated.
Corneal pocket assay
The corneal pocket assay was made essentially as previously described (22). In brief, 5 µl of Hydron pellets (IFN Sciences, New Brunswick, NJ) containing 250 ng of rat rIL-4, 250 ng of murine rIL-13, or 100 ng of bovine bFGF were prepared and implanted in the corneas of male Sprague Dawley rats (300–500 g). Abs (2 µg/pellet) were added directly to the cytokine/Hydron solution. After 7 days, the animals were killed, and the corneal vessels were photographed.
Western blot analysis
Human microvascular endothelial cells were grown in medium 199 containing 10% FBS, followed by incubation in medium 199 containing 1% FBS for 24 h. Then, the cells were incubated with anti-IL-4R Ab for 1 h at 37°C and were treated with 50 ng/ml of IL-4 or IL-13 for 15 min. The cells were harvested and then lysed in ice-cold lysis buffer containing 10 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1% Nonidet P-40, 1% sodium deoxycholate, 0.1% SDS, 1 mM PMSF, 10 ng/ml aprotinin, 10 ng/ml leupeptin, and 0.2 mM sodium orthovanadate. After centrifugation, cleared supernatants were collected, electrophoresed by SDS-PAGE on 8% polyacrylamide gel, and blotted onto nitrocellulose filters. The nitrocellulose filters were developed by chemiluminescence according to the enhanced chemiluminescence protocol of Amersham (Piscataway, NJ) (21).
ELISA for VCAM-1
The concentration of soluble VCAM-1 in the conditioned medium and whole-cell lysate of human microvascular endothelial cells was measured using ELISA kits obtained from BioSource (Camarillo, CA) according to the manufacturer’s instructions.
Statistical analysis
Statistical comparisons were performed using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first examined whether IL-13 can increase the formation of
tube-like structures by human microvascular endothelial cells. Previous
reports showed that human microvascular endothelial cells cultured on
the surface of three-dimensional type I collagen gel show a
cobblestone-like appearance in the absence of the angiogenic factor,
and they form tube-like structures when treated with EGF or IL-4
(10, 20). Human microvascular endothelial cells treated
with human IL-13 induced formation of tube-like structures (Fig. 1
). To examine the effects of various
doses of IL-13 on the formation of tube-like structures by vascular
endothelial cells, a quantitative analysis was made to determine the
structures’ total length. The total length was 211 ± 45 mm in
the absence of treatment and 157 ± 6, 349 ± 69, 457 ±
65, and 462 ± 92 mm after the cells were exposed to 1, 10, 50,
and 250 ng/ml of IL-13, respectively. IL-13 at 10–250 ng/ml
significantly stimulated the tubulogenesis, but any stimulatory or
inhibitory effect was observed at the concentration of 1 ng/ml. The
total length was 419 ± 112 mm at 20 ng/ml EGF (Fig. 2A).
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B). Thus, IL-13 induced
tubular morphogenesis of human and bovine endothelial cells in
vitro. IL-13 induces angiogenesis in rat corneas
We also examined whether IL-13 can induce angiogenesis in vivo. We
implanted a pellet of Hydron that had been impregnated with murine
IL-13 into the corneas of eight rats. Administration of 250 ng of IL-13
induced an angiogenic response in all eight corneas, while
contralateral corneas treated with Hydron alone showed no angiogenic
response (Fig. 3). Administration of 250
ng of IL-13 caused a much greater angiogenic response than did
administration of 50 ng of IL-13 (data not shown). Consistent with our
previous study (10), administration of 250 ng of rat IL-4
or 100 ng of bovine bFGF also induced angiogenesis in the rat cornea.
IL-13 thus shows angiogenic activity in vivo as well as in vitro.
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Anti-IL-4R Ab inhibits STAT6 phosphorylation and tubulogenesis in response to IL-13
The endothelial receptor for IL-13 and IL-4 is a heterodimeric
complex of IL-13R and IL-4R (23). We previously
reported that formation of tube-like structures mediated by IL-4 was
blocked by coadministration with anti-IL-4R Ab (10).
We thus examined whether IL-4R is also involved in the
IL-13-mediated angiogenesis in vitro and found that pretreatment of
human microvascular endothelial cells with anti-IL-4R Ab almost
completely nullified tubulogenesis induced by IL-13 (Fig. 4). By contrast, EGF-dependent tubular
morphogenesis was not inhibited by pretreatment with
anti-IL-4R Ab.
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and IL-13R, is mediated through activating STAT6
(24). In this study we examined whether STAT6 was
activated in vascular endothelial cells treated with IL-4 or IL-13.
Human microvascular endothelial cells treated with IL-4 or IL-13
rapidly stimulated STAT6 phosphorylation, as shown by immunoblotting
cellular extracts with Ab specific for the tyrosine-phosphorylated form
of STAT6 (Fig. 5). Pretreatment of
endothelial cells with anti-IL-4R Ab almost completely nullified
STAT6 phosphorylation induced by IL-13 and IL-4 (Fig. 5).
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We previously showed that human microvascular endothelial cells,
monocytes, and tumor cells treated with TNF- increase their
production of potent angiogenic factors such as VEGF, bFGF, and IL-8,
and also that these angiogenic factors acting in an autocrine/paracrine
way result in angiogenesis (25, 26, 27). To learn whether
such autocrine/paracrine control by angiogenic factors is involved in
angiogenesis induced by IL-4 and IL-13, we determined the expression of
various angiogenic mediators, including growth factors, cytokines,
proteinases, and adhesion molecules, when treated with IL-4 or IL-13.
Administration of IL-4 or IL-13 to vascular endothelial cells did not
increase the expression of VEGF, bFGF, IL-8, plasminogen activators,
matrix metalloproteinase-2 or -9, ICAM-1, or E-selectin (data not
shown). In contrast, and consistent with previous studies
(7), vascular endothelial cells treated with IL-4 or IL-13
resulted in increased mRNA expression of VCAM-1 by 13- and 12-fold over
controls, respectively (data not shown).
We next examined whether the expression of either membrane-bound VCAM-1
or sVCAM-1 is increased in the presence of IL-4/IL-13 using
VCAM-1-specific ELISA. Human microvascular endothelial cells from the
omentum constitutively expressed VCAM-1. Vascular endothelial cells
treated with IL-4 or IL-13 increased the expression of sVCAM-1 in the
conditioned medium by 8-fold over the controls in a time-dependent
manner (Fig. 6). We found sVCAM-1 to be
present at a level of 7.0 ng/ml in the absence of treatment. The levels
of sVCAM-1 were 13.8, 53.6, and 54.3 ng/ml after the cells were exposed
for 28 h to 20 ng/ml of EGF, 50 ng/ml of IL-4, and 50 ng/ml of
IL-13, respectively. VCAM-1 protein levels in the cellular fraction
also increased up to 4-fold over the controls after 20 h of
stimulation and then decreased by an additional 8 h of incubation,
suggesting that the membrane-bound form of VCAM-1 is converted to the
soluble form and is secreted into the conditioned medium.
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4 integrin inhibits
angiogenesis induced by IL-4 and IL-13
Because sVCAM-1 promotes angiogenesis (2), we
examined whether the formation of tube-like structures induced by IL-4
or IL-13 is mediated through sVCAM-1 and its counter-receptor integrin
4ß1. Vascular
endothelial cells were exposed to 50 ng/ml of IL-4 and IL-13 with or
without anti-VCAM-1 Ab that could block adhesion to integrin
4ß1. Adding
anti-VCAM-1 Ab did not inhibit tubular morphogenesis dependent on
EGF. However, coadministration of the anti-VCAM-1 Ab almost
completely inhibited the formation of tube-like structures dependent on
IL-4 and IL-13 (Fig. 7).
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4ß1, we implanted a
pellet of Hydron that had been impregnated with cytokines and either
anti-rat 4 integrin mAb or IgG control
into rat corneas. Adding anti-4 Ab (2
µg) almost completely inhibited the angiogenic response induced by
rat IL-4 in all three corneas tested (zero of three corneas were
positive), while control IgG had a negligible effect on the angiogenic
response in the contralateral corneas (three of three corneas were
positive) (Fig. 8). Angiogenesis induced
by murine IL-13 was also inhibited by the addition of
anti-4 Ab (zero of three corneas were
positive). However, anti-4 Ab did not
inhibit the angiogenic response induced by bFGF (three of three corneas
were positive).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
IL-13R (12). We previously reported the angiogenic
activity of IL-4 in vitro and in vivo (10). In this study
we showed that IL-13 also has angiogenic activity in vitro and in vivo.
As an Ab against IL-4R blocked the formation of tube-like structures
in collagen gel by microvascular endothelial cells in response to IL-4
(10) and IL-13, angiogenesis by IL-4 or IL-13 was mediated
through common heterodimeric IL-4R/IL-13R. Moreover, both IL-4
and IL-13 phosphorylated STAT6, and coadministration of
anti-IL-4R Ab blocked STAT6 phosphorylation. IL-4 and IL-13 thus
exerted their shared signaling pathways on angiogenesis through the
common receptor on vascular endothelial cells.
Consistent with our previous report (10), IL-4 could
induce neovascularization in both in vitro and in vivo (rat cornea)
angiogenesis models. Toi et al. (9) previously reported
that IL-4 was a potent mitogen for capillary endothelial cells.
Moreover, expression of urokinase-type plasminogen activator was
enhanced in vascular endothelial cells by the exogenous addition of
IL-4 (6) as well as potent angiogenic factors, VEGF, bFGF,
and TNF- (17, 30, 31). Urokinase-type plasminogen
activator is well known to facilitate proteolysis of extracellular
matrix and cell migration by vascular endothelial cells (32, 33). In contrast, Saleh et al. (4) reported that
vessel density in tumors was halved when tumor cells secreted IL-4,
suggesting that IL-4 might inhibit neovascularization in tumors. The
antiangiogenic effect by IL-4-producing tumor cells (4)
might be mainly due to local eosinophil influx into the tumor,
resulting in tumor regression and decreased production of various
angiogenic factors from the tumor.
Volpert et al. (5) have reported that administration of human or mouse IL-4 blocks bFGF-induced angiogenesis in rat cornea. In their study human IL-4 (1–100 pg) or mouse IL-4 (1 ng) inhibited bFGF (1 ng)-induced angiogenesis in rat corneas (5). Moreover, cell migration by vascular endothelial cells was enhanced in response to a low concentration (10 pg/ml) of mouse or human IL-4, but was inhibited in the presence of higher concentrations of IL-4 (5). However, we observed no apparent inhibition of bFGF (100 ng)-induced angiogenesis in rat cornea when 1–1000 ng of human IL-4 was coadministered, and angiogenesis was weakly induced in rat cornea when 1000 ng of human IL-4 was administered (data not shown). In addition, we did not observe any apparent inhibition of cell migration of bovine or human vascular endothelial cells by human, rat, or mouse IL-4 at 0.1–100 ng/ml when assayed by a wound cell migration system (data not shown). Because the concentrations of bFGF and IL-4 employed for the in vivo assays by Volpert et al. (5) were much lower than those employed in our assays, it is possible that an antiangiogenic effect of IL-4 in vivo might be observed only when IL-4 and bFGF are used at very low concentrations. In our previous report (10) and our present study we used rat IL-4 for angiogenesis assay with rat corneas. The species specificity of cytokine and angiogenesis models could also be the basis of the discrepancy between the study by Volpert et al. (5) and our study. Understanding why IL-4 induces such dual effects of stimulation and inhibition of angiogenesis under different experimental conditions will require additional studies.
Both IL-4 and IL-13 induce the up-regulation of VCAM-1 in human
vascular endothelial cells (7). VCAM-1 mediates adhesion
between endothelial cells and activated leukocytes expressing
4ß1 integrin
(7) and is closely associated with inflammation and
angiogenesis. In human coronary atherosclerotic plaques, endothelial
cells express VCAM-1 mainly in areas of neovascularization
(34). Soluble VCAM-1 is chemotactic for vascular
endothelial cells and is angiogenic in rat cornea (2), and
the sVCAM-1/4 integrin pathway plays a key
role in angiogenesis induced by TNF- (35). Consistent
with these previous studies, we observed that human microvascular
endothelial cells treated with IL-4 or IL-13 resulted in a significant
up-regulation of VCAM-1 mRNA (data not shown), and a significant
accumulation of sVCAM-1 proteins at a level of 50–55 ng/ml in cultured
medium for vascular endothelial cells treated with cytokine.
Anti-VCAM-1 Ab administered together with IL-4 or IL-13 almost
completely blocked tubular morphogenesis by microvascular endothelial
cells, and anti-4 integrin Ab blocked the
angiogenic response in rat corneas induced by IL-4 or IL-13. The
sVCAM-1/4 integrin pathway thus appeared to be
closely involved in angiogenesis dependent on IL-4 and IL-13. For
example, rheumatoid arthritis is characterized not only by infiltration
of inflammatory cells, but also by proliferation and neovascularization
of the synovium. Increased levels of IL-4 and IL-13 and sVCAM-1 have
been detected in the synovial fluid and synovium of persons with
rheumatoid arthritis compared with levels in persons with
osteoarthritis (36, 37). Therefore, IL-4/IL-13 might be
responsible for angiogenic states in rheumatoid arthritis, possibly
together with increased expression of sVCAM-1.
The conditioned media from activated macrophages or mast cells
stimulate cell migration and tube formation by vascular endothelial
cells in vitro (38, 39). Infiltration of activated
macrophages is often associated with angiogenesis in tumors such as
breast cancers, gliomas, and melanomas (27, 40, 41, 42).
TNF- and IL-1 are representative cytokines produced from monocytes
and macrophages. TNF- or IL-1 that shows angiogenic activity in
vitro and in vivo also increases the production of the potent
angiogenic factors, VEGF, bFGF, and IL-8, from vascular endothelial
cells and tumor cells, indicating autocrine and/or paracrine control of
angiogenesis (23, 26, 27, 43). However, vascular
endothelial cells treated with IL-4 and IL-13 did not increase the
production of the angiogenic factors, VEGF, bFGF, and IL-8.
Angiogenesis caused by IL-4 and IL-13 appears to be specifically
mediated by sVCAM-1 rather than by angiogenic factors such as VEGF,
bFGF, and IL-8.
Increased expression of VCAM-1 by IL-4 and IL-13 in vascular endothelial cells is closely associated with adhesion of monocytes, lymphocytes, eosinophils, and basophils (44, 45, 46). IL-4 and IL-13 are chemoattractive for monocytes (47) and also increase the expression of monocyte chemoattractant protein-1 in vascular endothelial cells (14). Monocytes in blood thus should have an increased affinity to vascular endothelial cells, resulting in movement to the angiogenic foci, such as tumor or inflammatory loci, when IL-4 and IL-13 are present. In fact, a profound level of macrophage infiltration is observed in the IL-4-expressing tumors (48). In the angiogenic foci, infiltrating activated macrophages exert their angiogenic signaling by producing angiogenic factors and proteases (41, 42, 43, 49). Further study is needed if such an angiogenesis model together with blood cells is to be used for various diseases related to angiogenesis.
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Footnotes |
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2 Abbreviations used in this paper: VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; EGF, epidermal growth factor; sVCAM-1, soluble VCAM-1.
Received for publication February 1, 2000. Accepted for publication June 19, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Stat6 phosphorylation. Immunology 91:450.[Medline]
. Biochem. Biophys. Res. Commun. 189:601.[Medline]
B in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. Mol. Cell. Biol. 16:4231.[Abstract]
c chain. J. Clin. Invest. 98:604.[Medline]
-dependent angiogenesis. Mol. Cell. Biol. 17:4015.[Abstract]
and IL-1. Int. J. Cancer. 85:182.[Medline]
, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc. Natl. Acad. Sci. USA 84:5277. is mediated by 4 integrins. Angiogenesis. 2:265.[Medline]
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