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vß3 Integrin1
*
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy;
Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy;
Department of Pathology and Laboratory Medicine, Tulane Cancer Center, Tulane University Medical Center, New Orleans, LA 70112;
§
Advanced BioScience Laboratories, Kensington, MD 20895;
¶
Department of Medicine, Division of Clinical Immunology and Allergy, Los Angeles, CA 90024; and
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Gesellschaft für Strahlung und Umweltforschung-National Research Center for Environment and Health, Institute for Molecular Virology, Neuherberg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, and IFN-
, synergizes with Tat
to promote in nude mice the development of angioproliferative KS-like
lesions that are not observed with each factor alone. Inflammatory
cytokines induce the tissue expression of both basic fibroblast growth
factor (bFGF) and vascular endothelial growth factor (VEGF), two
angiogenic molecules highly produced in primary KS lesions. However,
bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial
cells to migrate, to adhere, and to grow in response to Tat in vitro.
Tat angiogenic effects correlate with the expression of the
vß3 integrin that is induced by bFGF and
binds the arginine-glycine-aspartic acid (RGD) region of Tat. In
contrast, no correlation is observed with the expression of
vß5, which is promoted by VEGF and binds
Tat basic region. Finally, KS lesion formation induced by bFGF and Tat
in nude mice is blocked by antagonists of RGD-binding integrins.
Because vß3 is an RGD-binding integrin
that is highly expressed in primary KS lesions, where it colocalizes
with extracellular Tat on vessels and spindle cells, these results
suggest that vß3 competitors may represent
a new strategy for the treatment of AIDS-KS. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In particular, picomolar concentrations of extracellular Tat promote
the locomotion, adhesion, and growth of spindle cells of endothelial
cell (EC) origin derived from KS lesions (KS cells) (5, 6, 12, 13) and of normal EC, considered to be the precursors of KS
cells (14). However, to become responsive to these effects
of Tat, EC require a preactivation with inflammatory cytokines (IC)
(12, 13, 15). Among them, IL-1ß, TNF-, and IFN-
play a major role in inducing EC responsiveness to the in vitro effects
of Tat (15, 16, 17, 18). These IC are the same increased in
lesions and blood of AIDS-KS patients and patients at risk of KS
(17, 18, 19, 20, 21, 22, 23, 24).
The requirement of other factors for Tat effects is observed also in vivo. In fact, Tat promotes the development of angioproliferative KS-like lesions in mice only when injected with suboptimal (nonlesion forming) amounts of basic fibroblast growth factor (bFGF) (8), an angiogenic molecule highly expressed by KS cells both in vitro and in primary lesions (8, 25, 26, 27).
Although angiogenesis is triggered by soluble angiogenic factors, it is
modulated by integrin receptors that mediate the adhesive interactions
between EC and the extracellular matrix (ECM) (28).
Interestingly, Tat basic sequence present in the product of
tat I exon binds the
vß5 integrin
(29), whereas the arginine-glycine-aspartic acid (RGD)
region present at the carboxyl-terminal of Tat binds the
vß3 integrin, and by
this interaction mediates the adhesion of EC and KS cells to Tat
(12).
In this study, we show that the in vivo KS-promoting effect of Tat is
triggered by IC expressed in KS lesions and that it requires both the
presence of bFGF, but not of vascular endothelial growth factor (VEGF),
and the binding of the RGD region of Tat to RDG-binding integrin
receptors such as
vß3.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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rHIV-1 Tat protein (from the IIIB isolate) was obtained and
handled as previously described to avoid protein oxidation
(5, 6, 7, 8). Human rbFGF, VEGF, mouse rIL-1ß, TNF-, and
IFN- were purchased from Boehringer Mannheim (Mannheim, Germany) or
Promega (Madison, WI). Gelatin (from bovine skin) and BSA (fraction V)
were from Sigma (St. Louis, MO). Human collagen IV and matrigel, a
reconstituted basement membrane derived from a tumor cell line
(30), were obtained from Collaborative Research (Bedford,
MA). The glycine-arginine-glycine-aspartic acid-serine (GRGDS) peptide
(31) and the mutated glycine-arginine-glycine-glutamic
acid-serine (GRGES) peptide were from Research Genetics (Huntsville,
AL). Rabbit polyclonal anti-bFGF, anti-VEGF,
anti-ß5, and
anti-ß3 Abs used for immunohistochemistry
on mice tissues were from Santa Cruz Biotechnology (Santa Cruz,
CA).
Animal experiments and immunostainings
Proteins were injected s.c. into the lower back (right side) of BALB/c nu/nu athymic mice. The negative control (PBS-0.1% BSA, protein suspension buffer) was injected into the left side. Proteins or buffer (in 200 µl of final volume) were mixed with 200 µl of Matrigel before inoculation. Matrigel is not essential to observe lesion formation, but it increases the efficiency of the assay (8). Mice were sacrificed 6 days later. At this time, the sites of injection were evaluated for the presence of macroscopic angioproliferative lesions. Tissue samples were taken from all sites, fixed in Formalin, and analyzed microscopically after hematoxylin-eosin staining, as previously described (8).
For the immunohistochemical stainings, frozen tissue sections from the sites of inoculation were stained with the primary Abs by the peroxidase-antiperoxidase method, as reported elsewhere (8). The slides were counterstained with Mayer’s hematoxylin solution (Sigma) before evaluation. Animal care was in accordance with institutional and international guidelines.
Cell cultures and cell adhesion, migration, and growth experiments
HUVEC, passages 4–8, were obtained, characterized, and cultured, as described (5, 15).
Cell adhesion assays were performed with HUVEC seeded onto Tat-coated plates and incubated for 1 h at 37°C in a 5% CO2 atmosphere. After incubation, adherent cells were fixed with 3% paraformaldehyde, stained with Giemsa, and quantitated by light microscopy, as previously described (32), by counting 5 high power fields/well.
Migration assays were conducted at 37°C in 5% CO2 for 5 h in the Boyden chambers separated in two compartments by polycarbonate filters (12 µm pore; Nucleoprobe, Cabin John, MD) coated with type IV collagen (13). HUVEC were placed in the upper compartment of the Boyden chambers, whereas Tat or its resuspension buffer (PBS-0.1% BSA), which was employed as the negative control, was placed in the lower compartment. Migrated cells were fixed in ethanol, double stained by toluidine-blue and by hematoxylin-eosin, and quantitated by light microscopy by counting 5 fields/filter, as described previously (13).
Cell growth assays were performed with HUVEC seeded onto gelatin-coated plates and grown in the presence or absence of Tat in medium containing 10% FBS. Media and Tat were replaced after 2 days, and cells were counted after 4 days by trypan blue dye exclusion (in triplicate), as previously described (5, 15).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exposure to a combination of the same IC increased in KS patients induces EC to become responsive to the cell adhesion, growth, migration, and invasion effects of Tat (12, 13, 15, 16, 17, 18). Experiments were therefore performed to evaluate the in vivo effect of these IC.
As shown in Table I
, injection of Tat
alone had no effects on lesion formation, as previously reported
(8). Similarly, recombinant IL-1ß, TNF-, or IFN-
was not capable of inducing angioproliferative lesions in mice when
injected either alone or by combining two of them together at 0.1 or
0.5 µg each. Again, the injection of mice with IL-1ß, TNF-, and
IFN- combined together at 0.1 µg each had no effects, even in the
presence of Tat. In contrast, the combination of these cytokines at 0.5
µg each promoted the development of angioproliferative KS-like
lesions in 8% of the inoculated mice, which increased to 50% of the
inoculated mice in the presence of Tat (Table I). Thus, IL-1ß,
TNF-, and IFN- are all required to observe the synergy with Tat
in inducing macroscopic vascular lesions and histological changes
closely resembling early KS in humans. However, the least amount of IC
required to exert this angiogenic synergy with Tat is 0.5 µg of each
cytokine.
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Combined IL-1ß, TNF-, and IFN- induce production and
release of bFGF and VEGF in cultured EC and/or KS cells
(33, 34, 35). These angiogenic factors are highly expressed in
KS lesions and mediate autocrine and paracrine KS and EC growth effects
and angiogenesis (8, 25, 26, 27, 33, 34, 35, 36). Therefore,
immunohistochemical analyses of the mice tissues inoculated with IC
were performed to evaluate the expression of these angiogenic factors.
Injection of combined IC at concentrations exerting angiogenic synergy
with Tat induced high levels of expression of both bFGF and VEGF (Fig. 1). In contrast, lower IC concentrations,
not sufficient to synergize with Tat in promoting angiogenesis (Table I
), were not capable of inducing a significant bFGF and/or VEGF
expression (data not shown). These findings strongly suggested that IC
may synergize with Tat in vivo by promoting bFGF and VEGF
expression.
|
). Thus, although IC induce
expression of both bFGF and VEGF, Tat synergizes with bFGF, but not
with VEGF to promote KS-like lesion formation in mice.
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As mentioned above, EC require a preactivation with combined IC to become responsive to the in vitro effects of Tat (12, 13, 15, 16, 17, 18). Because IC induce both bFGF and VEGF expression, but bFGF and not VEGF cooperates with Tat in inducing angiogenic lesions in mice, experiments were addressed to verify whether bFGF or VEGF were capable of inducing EC to become responsive to the in vitro angiogenic effects of Tat, as found previously with IC.
The culture of HUVEC with bFGF induced these cells to adhere onto
immobilized Tat, whereas exposure to VEGF had no effects (Fig. 2). Similarly, HUVEC cultured with bFGF,
but not after culture with VEGF, migrated and proliferated in response
to soluble Tat (Fig. 2). Thus, bFGF, but not VEGF, synergizes with Tat
in vivo because only bFGF induces EC responsiveness to the adhesion,
migration, and growth effects of Tat.
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bFGF and VEGF activate different angiogenic pathways that require
different integrins. Specifically, bFGF promotes angiogenesis by
inducing vß3
expression, whereas VEGF induces
vß5 expression
(37). These integrins modulate angiogenesis by affecting
EC invasion, migration, adhesion, and growth (28). As
mentioned above, Tat basic sequence binds
vß5 (29),
whereas the RGD region of Tat binds
vß3
(12).
Because only IC or bFGF, but not VEGF, synergized with Tat to promote lesions in mice and to induce EC growth, migration, and adhesion to Tat, immunohistochemical stainings were performed to analyze the type of integrins expressed in mice upon injection of bFGF, VEGF, or IC.
As shown in Table III and in Fig. 3, tissues from mice injected with bFGF
showed a prevalent ß3 expression, whereas
injection of VEGF induced mostly ß5 expression.
Specifically, bFGF injection induced a 14-fold increase of
ß3 expression over basal levels and only a
2.4-fold increase of ß5 expression. In
contrast, VEGF induced 0- and 7-fold increase of
ß3 and ß5 expression,
respectively. Consistent with the induction of both bFGF and VEGF (Fig. 1), the injection of combined IL-1ß, TNF-, and IFN- promoted
the expression of both ß3 and
ß5, although the former was more expressed than
the latter. In particular, following IC injection,
ß3 expression was increased up to 18-fold over
basal levels, whereas ß5 was augmented up to
8-fold (Table III). Thus, ß3 expression induced
by IC or bFGF correlated with the angiogenic synergy by Tat (Tables I,
II, and III). In contrast, the expression of
ß5, induced by VEGF, did not correlate with
lesion formation. This suggested that the binding of Tat RGD region to
vß3 is required for
the synergistic effect of combined bFGF and Tat.
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To evaluate whether the in vivo angiogenic effect of combined Tat
and bFGF requires the engagement of RGD-binding integrins, in vivo
experiments were performed with integrin antagonists. As shown in Fig. 4, competitors of RGD-binding integrins
such as RGD peptides (31, 38) blocked the development of
KS-like lesions induced by the injection of combined Tat and bFGF in
mice. To the contrary, the mutated RGE control peptide had no effects
(Fig. 4). Histologic examination of the lesions indicated that RGD
peptides, but not RGE peptides, blocked angiogenesis, spindle cell
growth, and hemorrhagies (see legend to Fig. 4), the typical features
of KS lesions (8, 14). Thus, the engagement of RGD-binding
integrins by Tat is required to observe the synergistic angiogenic
KS-promoting effect of bFGF and Tat.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
and IFN- (12, 13, 15, 16, 17, 18). These IC are increased in
tissues and blood of AIDS-KS patients or in patients at risk of KS
(17, 18, 19, 20, 21, 22, 23, 24).
The results shown herein indicate that these same IC also trigger the
angiogenic effects of Tat in vivo. In fact, injection of combined
IL-1ß, TNF-, IFN-, and Tat promotes in nude mice the
development of angioproliferative KS-like lesions in which both bFGF
and VEGF are highly expressed (Table I and Fig. 1). This is consistent
with IC capability of promoting bFGF and VEGF production in vitro by EC
and KS cells (33, 34, 35). In addition, it resembles primary
human KS lesions, in which both angiogenic molecules are highly
expressed (27, 36) and cooperate to mediate angiogenesis,
edema, and tumor growth through autocrine (bFGF) and paracrine (bFGF
and VEGF) effects (11, 25, 26, 27, 33, 34, 35, 36). However, IL-1ß,
TNF-, and IFN- are not capable of inducing angioproliferative
lesions in mice when each cytokine is inoculated alone or when two of
them are combined. The synergism among these three cytokines is likely
to occur because IFN- up-regulates TNF receptor expression
(39); TNF and IL-1, in turn, increase IFN- receptor
levels (40); and TNF mimics the effects of IL-1 on EC
(41). Nevertheless, to exert angiogenic synergy with Tat,
however, IL-1ß, TNF-, and IFN- have to be injected at
concentrations sufficient to induce a significant level of bFGF and/or
VEGF expression (Table I and Fig. 1). These findings confirmed that Tat
is not directly angiogenic, but it enhances the effect of true
angiogenic factors (8). In fact, our recent work indicates
that Tat releases sequestered, extracellular-bound bFGF into a soluble
form by competing for its heparin binding sites (42). As a
consequence, Tat enhances the mitogenic effect of bFGF on EC
(42). On the contrary, Tat does not synergize with VEGF in
promoting EC growth (42). Consistent with these in vitro
findings, in this study we have shown that Tat exerts in vivo
synergistic angiogenic effects with bFGF, but not with VEGF (Table II).
In agreement with these in vivo findings, the exposure of EC to bFGF
induces their adhesion onto immobilized Tat as well as their migration
and growth in response to soluble Tat. On the contrary, cell exposure
to VEGF has no effects (Fig. 2). These results indicate that bFGF is
specifically required for Tat angiogenic effect.
Previous work demonstrated that bFGF and VEGF promote angiogenesis by
inducing distinct integrin pathways: VEGF promotes the expression of
vß5 (37),
an integrin that binds Tat basic sequence (29), whereas
bFGF induces the expression of the
vß3 integrin
(37), which binds Tat RGD region (12).
The vß3 receptor,
which binds the RGD region of ECM molecules such as vitronectin
(43), is highly expressed by KS cells both in vitro and in
primary human KS lesions (8, 12). In addition,
vß3 expression is
induced in normal EC by the same IC that induce EC responsiveness to
Tat (12, 18).
Immunohistochemical analyses of the mice tissues indicated that,
differently from VEGF-induced ß5 expression,
the expression of ß3, which is induced by IC or
bFGF, correlates with Tat angiogenic effects (Tables I, II, and III,
and Fig. 3). These results suggested that the selective angiogenic
effect of Tat could be due to the specific interaction of its RGD
sequence with the vß3
integrin, whose expression is triggered by bFGF or IC, but not by VEGF.
This is also supported by in vitro results indicating that Abs directed
against vß3, but not
anti-vß5 Abs block
Tat-induced migration and invasion of EC and KS cells
(42).
Additional experiments confirmed that the in vivo angiogenic effect of
Tat requires the engagement of RGD-binding integrins. In fact, the
injection of RGD peptides, which are known inhibitors of specific
integrin function (31, 38), but not of mutated control RGE
peptides, inhibits the development of angioproliferative lesions
induced in nude mice by combined Tat and bFGF (Fig. 4).
The involvement of the RGD region in the in vivo angiogenic effect of
Tat is consistent with previous in vitro studies showing that, as for
the RGD region of ECM molecules (44, 45, 46, 47), the binding of
Tat-RGD region to vß3
provides EC with the adhesion signal they require to proliferate in
response to mitogens (8, 12, 42), promotes cellular
migration, and activates the expression of collagenase IV (8, 13, 42, 48), a protease that plays a key role in angiogenesis and
tumor progression (45, 47). Moreover, Tat was found
capable of inducing the expression of p125 focal adhesion kinase (p125
FAK) that is activated by integrin triggering (49, 50 and
data not shown). This effect is specifically mediated by the RGD region
of Tat, because mutations of this Tat region, but not of other Tat
sequences, strongly decrease Tat-induced p125 FAK tyrosine
phosphorylation (50).
Although Tat was reported to stimulate angiogenesis by the binding of its basic sequence to the VEGF receptor Flk-1/KDR (51), this is unlikely to occur in our experimental system or in primary KS lesions. In fact, Tat has no effect on resting EC (5, 6, 12, 13, 15, 16, 17, 18) and it does not promote angiogenesis when it is inoculated alone in mice (8, 17). Furthermore, in primary KS lesions the amount of VEGF is much higher than that of Tat (8, 35, 36), making unlikely a competition of the VEGF receptor by Tat as opposed to its natural ligand. Finally, KS is found in several epidemiologic forms that are not associated with HIV-1 infection, but is more frequent and aggressive in AIDS (10, 11), indicating a role for Tat as a progression and not as an initiating factor.
IC and bFGF are highly expressed in AIDS-KS lesions (8, 16, 24, 27), in which extracellular Tat costains with
vß3 on both EC and KS
cells (8). This suggests that the mechanisms of Tat action
described in this study are operative in vivo and that integrin
competitors may be considered as a potential therapeutic strategy for
AIDS-KS.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Barbara Ensoli, Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. E-mail address:
3 Abbreviations used in this paper: KS, Kaposi’s sarcoma; bFGF, basic fibroblast growth factor; EC, endothelial cells; ECM, extracellular matrix; GRGDS, glycine-arginine-glycine-aspartic acid-serine; GRGES, glycine-arginine-glycine-glutamic acid-serine; IC, inflammatory cytokines; RGD, arginine-glycine-aspartic acid; RGE, arginine-glycine-glutamic acid; VEGF, vascular endothelial growth factor.
Received for publication February 18, 1999. Accepted for publication May 26, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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produced by CD8+ T cells infiltrating Kaposi’s sarcoma induces spindle cells with angiogenic phenotype and synergy with HIV-1 Tat. Blood 91:956. induces endothelial cells to proliferate and to invade the extracellular matrix in response to HIV-1 Tat. J. Immunol. 162:1165. and IL-1 in patients with AIDS: enhanced level of TNF is related to higher cytotoxic activity. Clin. Exp. Immunol. 78:329.[Medline]
and interleukin 6-like activities in AIDS-related Kaposi’s sarcoma: an immunohistological study. APMIS 97:533.[Medline]
and decreased IL-2 gene expression are associated with HIV-1 infection. J. Immunol. 152:5031.
-interferon production in peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes from Kaposi’s sarcoma patients correlation with the presence of human herpesvirus 8 in PBMC and lesional macrophages. Blood 91:968.vß5 integrin to the basic domain of the HIV-1 Tat protein and vitronectin. J. Cell Biol. 121:461.
integrins. Science 270:1500. induces cell surface expression of both types of tumor necrosis factor receptors. FEBS Lett. 312:87.[Medline]
each up-regulate both the expression of IFN- and enhance IFN--induced HLA-DR expression on human monocytes and on a human monocytic cell line. J. Immunol. 150:1205.[Abstract]
5ß1 and
vß3 integrins and by
mobilizing sequestered basic fibroblast growth factor. Blood. In
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vß3 and 5ß1 integrins during human melanoma cell invasion. Cancer Res. 53:3411.vß3 for angiogenesis. Science 264:569.vß3. Cell 85:683.[Medline]
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