* Department of Surgery,
College of Agriculture, and
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536; and
Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa 52242
Received March 13, 2003; accepted May 6, 2003
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ABSTRACT |
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Key Words: PCB; endothelial cells; inflammation; metastasis; atherosclerosis; vascular disease.
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INTRODUCTION |
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A growing body of evidence indicates that the direct adhesive interaction between tumor cells and endothelial cells is the critical step in the formation of blood-borne metastasis. It requires the binding of tumor cells to specific adhesion molecules on the surface of endothelial cells. Chemokines, such as monocyte chemoattractant protein-1 (MCP-1) (Youngs et al., 1997) and several adhesion molecules, including E-selectin (Krause and Turner, 1999
) and intercellular adhesion molecule-1 (ICAM-1) (Johnson, 1999
), may mediate this process. It was shown that the upregulation of endothelial cell adhesion molecules increased the adhesion of tumor cells to the endothelium. This process may initiate the migration of tumor cells through the endothelium into underlying tissues and protect them against destruction by cells of the immune system (Maemura and Dickson, 1994
). Expression of chemokines and adhesion molecules is regulated by alterations of the cellular oxidative status through the activation of redox-responsive transcription factors, such as nuclear factor-
B (NF-
B) or activator protein-1 (AP-1) (Collins and Cybulsky, 2001
). Thus, increased oxidative stress can modulate the gene expression profile in the vascular endothelium, favoring the induction of inflammatory mediators and thus the stimulation of metastatic processes.
The vascular endothelium forms an interface between the blood and the underlying layers of the vessel walls, and thus it is exposed to a variety of pathophysiological stimuli, such as environmental toxicants, including polychlorinated biphenyls (PCBs). Indeed, endothelial cells may be targets for the bioactivation and toxicity of these compounds (Annas et al., 1998). However, only sparse information is available about the effects of PCBs on endothelial cell metabolism. We show that the exposure of endothelial cells to selected PCBs, and especially to PCB 77, can result in the induction of cellular oxidative stress, decrease in cellular antioxidants, and activation of NF-
B (Hennig et al., 2002
; Toborek et al., 1995
). In addition, selected PCBs elevated the permeability across endothelial monolayers (Toborek et al., 1995
). Based on the consensus that cancer metastasis can exploit the mechanisms of endothelial cell activation and the inflammatory responses, we hypothesize that PCB-induced endothelial cell toxicity can result in the development of metastatic processes.
The vascular endothelium plays a critical role not only in cancer metastasis but also in atherogenesis. Endothelial cell dysfunction and the upregulation of inflammatory mediators is one of the main early events in atherogenesis. In fact, recent evidence indicates that atherosclerosis is a chronic inflammatory disease. Our data on PCB-induced toxicity in endothelial cells suggest a possible involvement of this group of compounds in the development of atherosclerosis (Hennig et al., 2002; Toborek et al., 1995
). Indeed, several epidemiological studies indicated a strong link between PCB exposure and increased development of heart disease and/or elevated mortality due to atherosclerosis (Gustavsson and Hogstedt, 1997
; Hay and Tarrel, 1997
). These research findings are supported further by the reports on PCB-induced vascular changes in other species. For example, exposure to PCBs produced vascular lesions in the placental labyrinthine zones of viable fetuses in minks, induced the degeneration of endothelial cells, and induced the formation of thrombi and hemorrhages. The presence of extracellular fluid between the interstitial layer of maternal vessels and the syncytiotrophoblast also indicated compromised endothelial integrity (Backlin et al., 1998
).
Because of the potential involvement of PCBs in the induction of oxidative stress and proinflammatory responses, that is, the processes that play important roles in both cancer metastasis and atherogenesis, the aim of this paper is to determine the proinflammatory reactions of PCB 104 in the vascular endothelium. PCB 104 is a typical example of a nonplanar PCB congener with multiple ortho-chlorine-substituents. In this paper we provide strong evidence that PCB 104 can induce oxidative stress and the expression of inflammatory mediators in human vascular endothelial cells.
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MATERIALS AND METHODS |
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The human monocytic leukemia cell line THP-1 was used to study cell adherence. THP-1 cells were purchased from the American Type Culture Collection (Manassas, VA) and cultured in suspension in RPMI 1640 medium supplemented with 10% FBS, 25 mM of glucose, 10 mM of HEPES, 1.0 mM of sodium pyruvate, 50 µM of 2-mercaptoethanol, 100 U/ml of penicillin, and 100 U/ml of streptomycin.
Serum concentration of PCBs can reach approximately 3 µM in people exposed to these toxicants (Jensen, 1989; Wassermann et al., 1979
); however, local levels of PCBs in extracellular space are not known. Therefore, in the present study, the HUVEC were treated with a range of PCB 104 concentrations, such as 1, 10, or 20 µM (AccuStandard, New Haven, CT). A similar experimental design was used in our previously published study (Lee et al., 2003
). A stock solution of PCB 104 was prepared in DMSO, and the same amounts of dimethylsulfoxide (DMSO) as in PCB-treated cells were added to control cultures. The basic composition of the experimental medium was the same as that of growth medium, except for the serum concentration, which was lowered to 10%. In selected experiments, tumor necrosis factor-
(TNF-
; R&D Systems, Minneapolis, MN) at the concentration of 20 ng/ml was used as a positive control.
Measurement of reactive oxygen species (ROS).
The generation of ROS was measured using 2',7'-dichlorofluorescein (DCF) and rhodamine 123 fluorescence methods. To determine DCF fluorescence, the cells were loaded with 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA), which freely enters the cells. In the cytoplasm, the ester groups were hydrolyzed by cellular esterases to form dichlorodihydrofluorescein (H2DCF). H2DCF was then oxidized by intracellular ROS to highly fluorescent DCF. To measure rhodamine 123 fluorescence, the cells were loaded with dihydrorhodamine 123, which is oxidized by ROS to rhodamine 123 (Negre-Salvayre et al., 2002).
Fluorescence of DCF and rhodamine 123 was assessed as described in Toborek et al. (2002) with modifications. Briefly, confluent HUVEC cultures, grown on 24-well cell culture plates, were rinsed three times with Hanks balanced salt solution (HBSS) and incubated with 20 µM of H2DCF-DA or 5 µM of dihydrorhodamine 123 in HBSS for 30 min at 37°C. Then the cells were rinsed twice with HBSS and incubated with PCB 104 for 30 min in a cell culture incubator. At the end of incubation, the cultures were rinsed twice with HBSS, and 0.5 ml of HBSS was added into each well. The relative fluorescence intensity of the cells was assessed using a fluorescence plate reader. The excitation and emission wavelengths to determine DCF fluorescence were 485 and 530 nm, respectively; and for 123 rhodamine fluorescence they were 488 and 510 nm, respectively.
Reverse transcription and polymerase chain reaction (RT-PCR).
RT-PCR was performed as described in Toborek et al. (2002). Briefly, total RNA was extracted by TRI reagent (Sigma, St. Louis, MO) according to the manufacturers guidelines. Reverse transcription was performed at 42°C for 60 min and followed by incubation at 95°C for 5 min. The reaction mixture (20 µl of total volume) consisted of 1 µg of isolated total RNA, 5 mM of MgCl2, 10 mM of TrisHCl, pH 9.0, 50 mM of KCl, 0.1% Triton X-100, 1 mM of dNTP, 1 unit/µl of recombinant RNasin ribonuclease inhibitor, 15 U/µg of avian myeloblastosis virus (AMV) reverse transcriptase, and 0.5 µg of oligo(dT)15 primer. For the determination of target genes, specific amplification profiles were used (Table 1
). The PCR mixture consisted of a Taq PCR Master Mix (Qiagen, Valencia, CA), 2 µl of the reverse transcription product, and 20 pmol of primer pairs in a total volume of 50 µl. The PCR products were separated by 2% agarose (Invitrogen, Carlsbad, CA) gel electrophoresis, stained with SYBR Gold (Molecular Probes, Eugene, OR) solution for 1 h, and visualized by phosphoimage analysis (FLA-2000, Fuji, Stamford, CN).
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Enzyme-linked immunosorbent assay (ELISA).
MCP-1 concentrations in the cell culture supernatants were determined using the Quantikine® Human MCP-1 Immunoassay kit (R&D Systems, Minneapolis, MN). Briefly, the HUVEC were cultured to confluence in 6-well plates and treated for 18 h with different doses of PCB 104. At the end of the treatment period, 100-µl aliquots of cell culture media were transferred to antiMCP-1 antibody-coated wells and incubated for 2 h. Then peroxidase-conjugated secondary polyclonal antibody was added into each well. Following a wash to remove any unbound antibody-enzyme reagents, a substrate solution was added into each well and a reaction was allowed to develop for 20 min. Next, color development was stopped and absorbance was measured at 450 nm using a microplate reader (Molecular Devices, Sunnyvale, CA).
Immunofluorescence analysis (IFA).
The HUVEC were grown to confluence on two-chamber culture slides (Falcon; Becton Dickinson Labware, Franklin Lakes, NJ) and incubated with 20 µM of PCB 104 or 20 ng/ml of TNF- for 18 h. The cells were then washed with PBS and fixed with 2% paraformaldehyde in PBS for 20 min. After three consecutive washes to remove paraformaldehyde, the cells were permeabilized for 10 min with 0.1% Triton X-100 in PBS. Unspecific binding was blocked by incubation with 0.1% bovine serum albumin in PBS for 30 min. The cells were then stained for 1 h at room temperature with an anti-human E-selectin (CD62E, 5 µg/ml) or anti-human ICAM-1 (CD54, 1 µg/ml) mouse monoclonal antibody (R&D Systems, Minneapolis, MN), followed by a 1-h incubation with a fluorescein isothiocyanate (FITC)-conjugated anti-mouse secondary antibody (2 µg/ml; Santa Cruz Biotechnology, Santa Cruz, CA). The slides were then washed three times with PBS, mounted using a Gel/MountTM aqueous mounting medium (Biomeda, Foster City, CA), and evaluated using a Nikon Eclipse E600 fluorescence microscope (Nikon Instruments Inc., Melville, NY) at a magnification of x400.
Cell adhesion assay.
The adhesion of THP-1 cells to the HUVEC was assessed according to the method of Braut-Boucher et al. (1995) with modifications. Briefly, the HUVEC were grown to confluence on gelatin-coated 24-well plates. The HUVEC were treated with different doses of PCB 104 for 7 h at 37°C and, prior to the adhesion assay, washed three times with HBSS containing 1% BSA (HBSS/BSA).
THP-1 (a human monocytic leukemia cell line) cells were activated with lipopolysaccharide (2 µg/ml, 10-min incubation), washed three times with HBSS/BSA, and suspended in the amount of 1.0 x 106 cells/ml HBSS/BSA. The activated THP-1 cells were labeled with 5 µg/ml of calcein-AM (Calbiochem, La Jolla, CA) by 30-min incubation at 37°C, followed by three washings with HBSS/BSA. Activated and labeled THP-1 cells were then incubated with PCB 104treated HUVEC for 30 min at 37°C. Nonadherent cells were removed by careful three-time washings with HBSS. The adherence of calcein-labeled THP-1 cells was quantified by fluorescence measurements of endothelial monolayers using an excitation of 490 nm and an emission of 517 nm.
Statistical analysis.
Routine statistical analysis of data was completed using Sigma Stat 2.0 (SPSS Inc., Chicago, IL). A one-way ANOVA was used to compare the responses among the treatments. The treatment means were compared using Bonferronis least significant procedure. A statistical probability of P < 0.05 was considered significant.
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RESULTS |
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To establish whether PCB 104 induced an increase in MCP-1 mRNA levels that can be translated into elevated protein expression, a sandwich ELISA was employed to determine MCP-1 protein production in cultures treated with increasing doses of PCB 104 for 18 h. Because MCP-1 is secreted from the cells, the determinations were performed in cell culture media. The results of these experiments are shown in Figure 2C. Compared to the control or 1-µM PCB 104, exposure to 10- and 20-µM PCB 104 significantly increased the MCP-1 protein levels.
PCB 104 Upregulates E-Selectin and ICAM-1 Expression in Endothelial Cells
Among adhesion molecules, E-selectin and ICAM-1 play an important role in mediating the adhesion of both tumor cells and leukocytes to the vascular endothelium. Therefore, the effects of PCB 104 on the expression of these adhesion molecules were assessed in the present study. The effects of PCB 104 on E-selectin and ICAM-1 expression are shown in Figures 3 and 4
, respectively. PCB 104 at concentration of 1 µM did not affect the expression of adhesion molecules. However, a statistically significant increase in both E-selectin (Fig. 3A
) and ICAM-1 (Fig. 4A
) mRNA levels was observed in cells treated with PCB 104 at concentrations of 10 or 20 µM when compared to controls as well as cultures exposed to 1 µM PCB 104. In addition, the level of E-selectin mRNA expression was significantly higher in cells treated with 20 µM PCB 104 as compared to that in cultures incubated with 10-µM PCB 104.
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To determine whether increased levels of E-selectin and ICAM-1 mRNA were associated with elevated protein levels, expression of these adhesion molecules on the surface of endothelial cells was determined by immunocytochemistry. Consistent with gene expression studies, treatment with 20-µM PCB 104 for 18 h markedly upregulated the protein expression of both E-selectin and ICAM-1 (middle panels on Figs. 3C and 4C
, respectively). Treatments with TNF-
at a concentration of 20 ng/ml were used as positive controls in these experiments (right panels on Figs. 3C
and 4C
).
Exposure to PCB 104 Upregulates Cell Adhesion to Endothelial Cell Monolayers
The adherence of THP-1 cells (a human acute monocytic leukemia cell line) to PCB 104treated HUVEC was assessed to determine whether the induction of inflammatory mediators observed in PCB 104treated endothelial cells can stimulate cell adhesion. Because of their cancer and leukocyte linkage, THP-1 cells are ideally suited for the experiments related to cancer metastasis and atherogenesis. Consistent with the data on MCP-1 and adhesion molecules, PCB 104 markedly and in a concentration-dependent manner stimulated the adherence of THP-1 cells to endothelial monolayers (Fig. 5). The maximum effect on cell adhesion was observed in the HUVEC treated with 20-µM PCB 104.
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DISCUSSION |
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PCB 104 is an example of a group of highly ortho-chlorine-substituted, non-coplanar PCB congeners. Such PCBs are not typical AhR or constitutive androstane receptor (CAR) agonists. The biological effects of these PCBs include neurotoxicity, estrogenicity, and insulin release, as well as altered regulation of intracellular calcium and signal transduction mechanisms (Fischer et al., 1998; Kodavanti and Tilson, 2000
). In addition, it was demonstrated that PCB 104 can induce cellular apoptosis through the caspase-mediated mechanism (Lee et al., 2003
; Shin et al., 2000
). In this paper we provide consistent evidence that PCB 104 also can markedly stimulate the production of proinflammatory responses in endothelial cells.
It is generally accepted that the induction of inflammatory responses is mediated by alterations of the redox status of the cells. Therefore, to address this possibility, the oxidative status of endothelial cells treated with PCB 104 was measured by DCF and rhodamine 123 fluorescence. These probes can detect a broad spectrum of ROS and oxidizing reactions. However, it should be pointed out that neither of these probes detects superoxide anion radicals. DCF fluorescence is localized in the cytosol; in contrast, rhodamine 123 fluorescence is sequestered in the mitochondria (Negre-Salvayre et al., 2002). We indicated that treatment of endothelial cells with increasing doses of PCB 104 markedly elevated the oxidative stress in cultured endothelial cells.
The results of the present study further demonstrated that exposure of human endothelial cells to PCB 104 can markedly induce the expression of inflammatory mediators, such as MCP-1, E-selectin, and ICAM-1, both at mRNA and protein levels. The effects on mRNA levels were very early events, with the maximum increase observed already after a 1- or 2-h treatment. Although this early elevation gradually decreased in cultures exposed to PCB 104 for a longer period of time, it was sufficient to induce protein levels of inflammatory mediators that were measured after an 18-h exposure.
MCP-1 is a member of the CC chemokine family, and it stimulates the chemotaxis and transmigration of monocytes, lymphocytes, and granulocytes (Mukaida et al., 1998). An increased production of MCP-1 is associated with a variety of processes, including cancer metastasis (Amann et al., 1998
; Hefler et al., 1999
; Youngs et al., 1997
) and early stages of atherosclerosis (Boring et al., 1998
). At least two distinct mechanisms may be involved in the prometastatic effects of MCP-1. First, MCP-1 can exert direct chemotactic effects on tumor cells, as was shown using MCF-7 cells, a cell line obtained from human breast carcinoma (Youngs et al., 1997
). This chemotactic influence of MCP-1 on tumor cells is mediated by a receptor-stimulated signaling pathway. Thus, it appears that MCP-1 can directly attract tumor cells and induce tumor cell migration across the vascular endothelium with the subsequent generation of tumor metastasis. A second mechanism by which MCP-1 may stimulate the development of cancer metastasis may be related to its chemotactic effects toward leukocytes (Mukaida et al., 1998
). Activated leukocytes can migrate across the endothelium and degrade extracellular matrix proteins, which separate the endothelium from the underlying layers of the vascular wall. Such a process can markedly facilitate the invasion of tumor cells, a process associated with the development of metastasis. The role of MCP-1 in tumor metastasis has been supported by the observations that the levels of this chemokine were elevated in the serum of ovarian cancer patients (Hefler et al., 1999
) and in the urine of patients with bladder cancer (Amann et al., 1998
). In addition, the urinary MCP-1 levels were strongly correlated with tumor stage, grade, and distant metastasis (Amann et al., 1998
).
Evidence indicates that MCP-1 also can play an important role in atherogenesis. To support its role in the initiation and development of atherosclerosis, it was shown that MCP-1 deficiency significantly reduced atherosclerosis in low-density lipoprotein (LDL) receptor-deficient mice fed a high cholesterol diet (Gu et al., 1998). In a similar study, the selective absence of CCR2, the receptor for MCP-1, markedly decreased atherosclerotic lesion formation in apolipoprotein (apo) E-deficient mice (Boring et al., 1998
).
PCB 104-induced overexpression of adhesion molecules may also play a role in vascular pathologies associated with cancer metastasis and/or atherosclerosis. For example, convincing experimental data have been generated on the involvement of E-selectin in breast and colon cancer metastasis (Krause and Turner, 1999). Several glycoprotein ligands also have been identified on the surface of colon cancer cells, which serve as specific receptors for E-selectin (Tomlinson et al., 2000
). In addition, circulating levels of this adhesion molecule were identified as useful clinical markers of tumor progression and metastasis (Alexiou et al., 2001
). Recent experimental evidence also indicated that the inhibition of E-selectinmediated cancer cell adhesion may be an efficient strategy to inhibit cancer metastasis (Khatib et al., 2002
).
In addition to its role in cancer metastasis, overexpression of E-selectin is associated with the development of atherosclerosis. During atherogenesis, the migration of leukocytes through the vascular endothelium initially involves relatively transient adherence of leukocytes to endothelial cells, which results in leukocytes "rolling" over the endothelium (McIntyre et al., 1997). This process is followed by firm leukocyte adhesion and transmigration across the vascular endothelium. Leukocyte rolling is mediated by the overexpression of adhesion molecules of the selectin family, such as E-selectin. The importance of the adhesion molecules of the selectin family in the development of atherosclerosis has been confirmed in studies that demonstrated the presence of both E- and P-selectin on the surface of endothelial cells overlying atherosclerotic plaques (Wood et al., 1993
).
ICAM-1 is an adhesion molecule of the immunoglobulin superfamily critically involved in both cancer metastasis and atherogenesis. To support the role of ICAM-1 in cancer metastasis, it was demonstrated that serum levels of soluble ICAM-1 (sICAM-1) were elevated in patients with non-smallcell lung cancer and correlated with the tissue expression of ICAM-1 and tumor stage (Grothey et al., 1998). In addition, metastatic lung cancer was associated with higher sICAM-1 as compared to localized tumors (Grothey et al., 1998
), and the highest levels of sICAM-1 were observed in patients with liver metastasis (Sprenger et al., 1997
). ICAM-1 expression also correlated with progression of malignant melanoma (Hakansson et al., 1999
) and renal cell carcinoma (Tanabe et al., 1997
). The role of ICAM-1 in tumor cell metastasis was confirmed by the observation that antisense ICAM-1 oligonucleotides decreased the metastasis of malignant melanoma by approximately 50% (Miele et al., 1994
).
In the development of atherosclerosis, ICAM-1 stimulates firm adhesion of leukocytes to the vascular endothelium. ICAM-1 is expressed at low levels on the surface of nonstimulated endothelial cells. In addition, stimuli such as TNF-, IL-1, interferon-
(Dustin et al., 1986
), or shear stress (Nakashima et al., 1998
) can markedly induce the expression of this adhesion molecule. The stimulatory involvement of hemodynamic stress in the upregulation of ICAM-1 may play an important role in the development of atherosclerosis in hypertension. ICAM-1 is markedly expressed in the early stages of atherosclerosis, and it stimulates the adhesion of monocytes and T lymphocytes. The significance of this adhesion molecule in atherosclerosis was confirmed in clinical studies, which determined elevated levels of sICAM-1 in asymptomatic patients who are prone to develop cardiovascular disease (Ridker et al., 1998
).
In summary, the present study indicates that PCB 104, that is, a highly ortho-chlorinesubstituted, non-coplanar PCB congener, can induce profound vascular effects, as demonstrated by the increase in cellular oxidation and upregulation of MCP-1, E-selectin, and ICAM-1. These effects were both time- and concentration-dependent. In addition, the upregulation of these inflammatory mediators was associated with the increased adhesion of THP-1 cells to vascular endothelial cells. Such PCB 104induced vascular pathology can participate in the development of cancer metastasis and/or atherosclerosis.
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ACKNOWLEDGMENTS |
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NOTES |
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