1Department of Life Science, Institutes of 2Zoology and 3Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan 106; 4Faculty of Medical Technology, Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan 112; and 5Institute of Biochemistry, National Cheng Kung University, Tainan, Taiwan 701, Republic of China
Submitted 1 April 2004 ; accepted in final form 3 August 2004
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ABSTRACT |
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lysophosphatidic acid; sphingosine 1-phosphate; inflammation; intercellular adhesion molecule-1; nuclear factor-B; human umbilical cord vein endothelial cells
The cellular signals of LPA and S-1-P are transduced by two subfamilies of G protein-coupled receptors (GPCRs) encoded by endothelial differentiation genes (Edg Rs; see Refs. 2, 5, 21, 34, 45). Human Edg1 (S-1-P1), Edg3 (S-1-P3), Edg5 (S-1-P2), Edg6 (S-1-P4), and Edg8 (S-1-P5) transduce signals for S-1-P. Human Edg2 (LPA1), Edg4 (LPA2), and Edg7 (LPA3) transduce signals for LPA. Multiple signaling pathways are activated by Edg receptors, which have been characterized in heterologous expression systems, including ras-dependent activation of Erk 1/2, increases in intracellular Ca2+ concentration, and recruitment of rho GTPase and its downstream targets (2, 5, 21, 34, 45).
Endothelial cells form the inner lining of blood vessels and participate in important physiological processes, including materials exchange, coagulation, and wound healing. Several pathological phenotypes, including atherosclerosis, inflammation, and cancer, are associated with excessive activation or abnormalities of endothelial cells (15). Endothelial cells express at least three types of Edg receptors, including Edg1, Edg 2, and Edg3 (26). LPA and S-1-P regulate several endothelial functions, including proliferation, migration, and secretion of proteases (4, 26, 36, 37). It has also been suggested that these lipids might also play a role in the regulation of angiogenesis and blood vessel integrity (4, 28, 29, 31).
The mechanisms by which vascular endothelial cells capture circulating lymphocytes are well documented, and several endothelial cell receptors responsible for these interactions have been described. Among these molecules, intercellular adhesion molecule 1 (ICAM-1; CD54) is one of the most characterized adhesion molecules expressed on endothelial cells. ICAM-1 interacts with LFA-1 and Mac-1, members of the 2-integrin family, which are expressed on activated lymphocytes. Interactions among LFA-1, Mac-1, and ICAM-1 are responsible for the firm interaction between leukocytes and endothelial cells and therefore are important for subsequent processes.
ICAM-1 is constitutively expressed in the microvasculature but not in large arteries or veins. However, in atherosclerotic arteries, ICAM-1 expression is elevated in the endothelium covering atherosclerotic plaques (9, 48). Abnormal interactions between monocytes and endothelial cells have been suggested to be one of the early events in the generation of atherosclerotic plaque and also are necessary for wound healing (17, 40). Both pretreatment of human saphenous veins with anti-ICAM-1 antibodies and pretreatment of monocytes with anti-2-integrins significantly reduced monocyte adhesion to these vessels (7). Those observations suggest that abnormal ICAM-1 expression might be an important indicator of atherosclerosis.
Expression of ICAM-1 on endothelial cells is upregulated by inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-
, and also by plasma lipoprotein such as oxidized low-density lipoproteins (LDLs; see Refs. 11, 14, 24, 41). Because LPA and S-1-P stimulate the expression of these inflammatory cytokines from macrophages (27), and LPA is generated along with oxidized LDLs (13, 32, 42), we hypothesized that LPA and S-1-P may affect endothelial cell interactions with leukocytes through modulating the expression of ICAM-1. In this report, we present evidence that LPA and S-1-P enhance ICAM-1 expression in human umbilical cord vein endothelial cells (HUVECs) in a time- and concentration-dependent fashion. Furthermore, by using chemical inhibitors, we show that LPA and S-1-P enhance ICAM-1 expression through a Gi/o-, nuclear factor (NF)-
B- and possibly Rac-dependent and Rho-independent mechanism, which is consistent with the signaling pathways activated by LPLs binding to Edg receptors. In addition, the adhesion between U-937 human mononucleated cells and HUVECs is enhanced by LPL treatment. This enhancement is likely because of an increase in ICAM-1 expression in HUVECs, since the enhancement is prevented by pretreatment with functional blocking antibody against human ICAM-1. These results imply that the inflammatory effects of LPL are likely mediated through the enhancement of ICAM-1 expression.
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MATERIALS AND METHODS |
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Human ICAM-1 antibody (clone M19), FITC-conjugated mouse anti-human ICAM-1 monoclonal antibody (clone 6.5B5), and functional blocking anti-human ICAM-1 monoclonal antibody (clone 15.2) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Horseradish peroxidase-conjugated goat anti-mouse IgG was obtained from Boehringer Mannheim (Indianapolis, IN). FBS and M199 were purchased from Hyclone (Logan, UT). RPMI-1640 medium and trypsin were purchased from GIBCO-BRL (Grand Island, NY). Endothelial cell growth medium (EGM) was purchased from Cell Applications (San Diego, CA). Penicillin, streptomycin, and L-glutamine were purchased from Invitrogen (Carlsbad, CA).
Cell culture. HUVECs were isolated from fresh umbilical cords by treatment with 1% (vol/vol) collagenase in PBS at 37°C for 10 min. After elution with M199 containing 20% FCS, HUVECs were cultured on 0.04% gelatin-coated (Sigma) 10-cm plates in M199 supplemented with 100 U/ml penicillin, 100 mg/ml streptomycin, 2 mM L-glutamine (Invitrogen), 10% (vol/vol) FBS, and 25% (vol/vol) EGM, and cells underwent one passage weekly. Cells were subcultured after trypsinization [0.5% (vol/vol) trypsin solution, supplemented with 0.2% (vol/vol) EDTA] and used throughout passages 2 to 4. The human leukemic monoblast cell line, U-937 (CRL1593), was purchased from ATCC (American Type Culture Collection, Manassas, VA) and cultured in RPMI-1640 medium [supplemented with 0.2% (wt/vol) NaHCO3 and 0.03% (wt/vol) L-glutamine] containing 100 U/ml penicillin, 100 mg/ml streptomycin, and 10% (vol/vol) FBS. Unless otherwise indicated, all cultures were grown at 37°C in a humidified atmosphere containing 5% CO2 in 175-cm2 culture flasks. U-937 cell stocks were maintained by subculturing cells every 4th or 5th day in fresh medium at a seeding density of 0.5 x 105 cells/ml (subculturing was performed earlier if the cell density exceeded 1.5 x 105 cells/ml).
RT-PCR for ICAM-1. Total cellular RNA was extracted from HUVECs by the Tri-Zol reagent (GIBCO-BRL), and a Superscript kit (GIBCO-BRL) was used for the RT synthesis of cDNA. PCR amplification was performed with 35 cycles of 30 s at 94°C, 30 s at 62°C, and 2 min at 72°C. Oligonucleotides pairs were 5'-dGCAAGCTCCCAGTGAAATGCAAAC and 5'-dTGTCTACTGACCCCAACCCTTGATG for human ICAM-1. A 498-bp product was expected in the reaction. The primers used to amplify GAPDH were 5'-dACCACAGTTCATGCCATCAC and 5'-dTCCACCACCCTGTTGCTGTA. A 450-bp product was expected in the reaction. PCR products were resolved on 2% agarose gels, stained with ethidium bromide, and photographed.
Semiquantitative RT-PCR. To assess the levels of ICAM-1 mRNA in HUVECs, RT-PCR results were scanned using a PhosphoreImager and analyzed by ImageQuaNT software (Amersham Biosciences, Piscataway, NJ). Human GAPDH from the same sample in the RT-PCR was used as an internal control to correct the loading.
FACscan. Subconfluent cultures of HUVECs were serum starved with or without chemical inhibitors for 16 h and incubated with LPA or S-1-P for the indicated durations at 37°C. Suspensions of 106 HUVECs in a 50-µl volume of PBS with 0.1% fatty acid-free BSA received 20 µl FITC-conjugated human anti-ICAM-1 (clone 6.5B5) and were incubated for 30 min at 4°C. Antibody binding of HUVECs with and without stimulation was determined by CyFlow SL (Partec, Germany) and analyzed by WinMDI version 2.7 software.
Western blotting for ICAM-1.
Endothelial cells plated in six-well plates were treated with the indicated concentrations of LPA or S-1-P. Treated cells were then lysed with RIPA buffer (150 mM NaCl, 1.0% Nonidet P-40, 0.5% deoxycholate, 0.1% SDS, and 50 mM Tris, pH 8.0) containing protease inhibitor cocktail (Sigma) and 2 mM sodium vanadate. Equal amounts of cell lysates were separated by 410% SDS-PAGE and electrophoretically transferred to Immobilon membranes. The transferred membranes were blocked with blocking buffer (PBS + 0.1% Tween 20 with 1% BSA) at room temperature for 1 h. The membranes were immunoblotted with anti-human ICAM-1 monoclonal antibody for 2 h and then washed in washing buffer (0.1% Tween 20, without 1% BSA) one time for 15 min followed by two washes for 5 min. The membranes were blocked again in new blocking buffer for 1 h at room temperature and then immunoblotted with appropriate horseradish peroxidase-conjugated secondary antibodies for 1 h. Membranes were subsequently washed in washing buffer one time for 15 min followed by two washes for 5 min each. Proteins on each immunoblot were visualized with Renaissance Western blot chemiluminescence reagent (NEN Life Science, Boston, MA). Blots were stripped and reprobed with an antibody against human actin to demonstrate uniform loading of proteins.
Immunofluorescence staining. HUVECs were grown and treated on glass coverslips at 37°C. After being fixed in methanol (20°C) for 5 min and air-dried, 50 µl of mouse anti-human ICAM-1 monoclonal antibody (4.5 g/ml in 0.5% FBS-0.5% Tween 20-PBS) were applied as the primary antibody solution and incubated overnight at 4°C in a humidified chamber. After extensive rinsing with PBS, the coverslips were incubated with 50 µl of Cy3-conjugated goat anti-mouse IgG (DAKO, Carpinteria, CA) as the secondary antibody (1:20 in 0.5% FBS-0.5% Tween 20-PBS) for 2 h at 37°C. After three washes with PBS, cell nuclei were counterstained with 4',6'-diamidino-2-phenylindole (1:5,000 in 0.5% FBS-0.5% Tween 20-PBS) purchased from Sigma. Glass coverslips were subsequently washed three times with double-distilled water, mounted with Fluoromount G (Electron Microscopy Sciences, Washington, PA), and examined using a confocal microscope.
Confocal microscopy.
To examine the distribution of ICAM-1, immunostained cells were mounted with Immunomount G. Cells were observed using a laser-scanning confocal microscope (Leica model TCS SP2) with a Leica Mellis-Griot x63 numerical aperture oil immersion objective, with a pinhole of 1.5 and an electronic zoom of 1.5 or 2. Cy3 was excited using a 543-nm argon/krypton laser and detected with an 550- to 620-nm band-pass filter. Images were manipulated with a Leica TCS SP2 scanner.
Assay for U-937 adhesion to treated endothelium. HUVECs cultured in six-well plates were stimulated for 8 h with 5 µM LPA or S-1-P. After being gently washed three times with M199, U-937 monocytes (1 ml, 5 x 106 cells/ml) were added to the cultures and then incubated at 37°C for 1 h. In the inhibitory experiments, anti-human ICAM-1 functional blocking antibodies (10 µg/ml) or normal mouse IgG was added before the addition of U-937 monocytes. Cultures were then washed by placing 1 ml of M199 gently on the cultures three to five times until no visible suspension of U-937 cells was observed. After being washed, cell cultures were imaged by microscopy with a Kodak digital camera, and the number of monocytes per culture was counted.
Statistical analysis. Significant differences between treatment groups were tested using ANOVA followed by Duncan's new multiple range test (StatView; Abacus Concept, Berkeley, CA). Each experiment was repeated at least three times. A value of P < 0.05 was considered statistically significant.
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RESULTS |
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Toxin B blocked the enhancement effects of LPA and S-1-P on ICAM-1 expression. Rac has been shown to play important roles in regulating ICAM-1 expression in human endothelial cells (1). In addition, LPA has also been shown to be able to activate Rac in neuroblastoma cells (49). Therefore, we intended to determine whether Rac also participate in the enhancement effects of LPL on ICAM-1 expression on HUVEC. Toxin B, an inhibitor of the small GTPases Rho and Rac (16), was used in our assay. Pretreatment with 0.5 nM Toxin B for 2 h had no significant effect on the basal level of ICAM-1 protein expression in HUVECs, as detected by FACS. However, the stimulatory effects of 5 µM LPA or S-1-P on ICAM-1 expression in HUVECs were partially suppressed by Toxin B treatment (Fig. 9). Rho has no significant effect in the stimulatory property of LPA and S-1-P on ICAM-1 expression, suggesting that Rac might be involved in the enhancement effects of these LPLs on ICAM-1 expression on HUVEC.
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DISCUSSION |
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In our previous study, we showed that LPLs are wound-healing factors in the endothelium (26). Another report also suggested that LPA facilitates wound healing in in vivo systems (3). Because ICAM-1 is an important regulator of interactions between leukocytes and endothelial cells, this suggests that the facilitating effects of LPLs on wound healing might partially be mediated through enhancement of ICAM-1 expression. From DNA array analysis and also by results reported by others, we know that LPA also enhances the expression of endothelial-leukocyte adhesion molecule (ELAM) on endothelial cells (28, 29). ELAM is responsible for the initial rolling effect during interactions between leukocytes and endothelial cells. These results suggest that the effects of LPLs on leukocyte-endothelial cell interactions during wound healing occur at multiple levels. This is consistent with the fact that, when tissue encounters a mechanical wound, LPLs are released from activated platelets, which might act as one of the initiating signals for the subsequent wound-healing processes.
With confocal microscopy, we also observed that LPL-enhanced ICAM-1 expression formed significant capping on HUVECs. The aggregation of cell-surface molecules upon antibody cross-linking or association with other cell types has been described in several papers (20, 22). The capping effects are likely because of surface-expressed ICAM-1 associated with the intracellular cytoskeletal structure. However, the physiological roles of this capping by adhesion molecules is currently unclear.
Activation of Rac has been shown to play important roles in regulating ICAM-1 expression in human endothelial cells (1). In addition, binding of LPA to LPA1 also activates Rac (49). In this study, we showed that the enhancement effects of LPA and S-1-P on ICAM-1 expression in HUVECs could be partially blocked by Toxin B, an inhibitor of Rac. These results suggest that the effects of LPLs on ICAM-1 in HUVECs are at least partially mediated through Rac, which is consistent with the previous reports.
By DNA array analysis, we also observed that LPLs enhanced both IL-1 and TNF-
expression in macrophages (27). Both IL-1
and TNF-
are cytokines that regulate the blood vessel environment, specifically endothelial cell physiology. Expression of ICAM-1 on endothelial cells is also upregulated by these cytokines (11, 14). IL-1
and TNF-
also participate in a self-augmentation induction mechanism (10), which allows a positive-feedback mechanism to amplify the effects of these cytokines within a local milieu. Furthermore, TNF-
directly and potently stimulates sphingosine kinase activity in HUVECs, inducing the generation of S-1-P, which further enhances endothelial and macrophage functions (53). These results suggest that platelet-derived LPLs might facilitate wound-healing processes through complex cell-cell interactions in the local environment.
It has been reported that concentrations of LPA and S-1-P in serum can reach micromolar levels (19). Therefore, it is likely that, at the wounded area, local concentration of LPLs may easily reach micromolar concentrations. The high concentration of LPLs at these wounded areas might generate a gradient of ICAM-1 expression, which is expected to peak at the spot of platelet activation. This might result in maximized leukocyte-endothelial interaction at these hot spots, thereby facilitating the wound-healing process.
Hypercholesterolemia is a major risk factor for atherosclerosis. Delivery of cholesterol to HUVECs results in an increase in ICAM-1 levels (56). Upregulation of vascular cell adhesion molecule-1, ICAM-1, and E-selectin in endothelial cells by inflammatory cytokines such as vascular endothelial growth factor has also been implicated in facilitating the formation and progression of atherosclerotic plaque (6, 25). Abnormal expression of adhesion molecules on endothelial cells and the large amount of trans-endothelial macrophage accumulation are two of the early events in the process of atherosclerosis generation. As mentioned earlier, ICAM-1 plays a crucial role in leukocyte-endothelial cell interactions. Previous studies also indicated that ICAM-1 is an important molecule involved in atherosclerosis (51). These results strongly suggest that LPLs may play multiple roles in the process of atherosclerosis through regulating the expression of ICAM-1 and inflammatory cytokines.
Several groups have reported the effects of LPA and S-1-P on leukocyte interactions with the endothelium. In one study, S-1-P inhibited neutrophil-endothelial cell interactions and subsequent neutrophil invasion (23), whereas in another report (39), LPA enhanced HL-60 cell adherence to human aortic endothelial cells. Apparent diversity of the effects of LPA and S-1-P on leukocyte-endothelial cell interaction may be attributed to the use of different leukocytes and endothelial cell types. In our report, we clearly showed that both LPA and S-1-P are potent enhancers of U-937 cell adhesion to HUVECs, and this is likely because of the enhancement of ICAM-1 expression. Our results suggest that platelet-derived LPLs enhanced leukocyte-endothelial cell interactions, consistent with the fact that they might be important regulators of the wound-healing process.
In summary, our results clearly indicate that LPLs increase ICAM-1 mRNA and protein levels in a time- and concentration-dependent manner. This induction is inhibited by specific inhibitors for NF-B, Gi/o, and Rac. Furthermore, the enhancement effects of LPLs on ICAM-1 expression on HUVECs are responsible for augmentation of the adherence of U-937 cells to treated endothelium. Our results suggest that LPLs might be important physiological regulators of interactions between endothelial cells and mononuclear phagocytes. Therefore, these lipids might play an important role in the regulation of wound healing and possibly the generation of atherosclerosis.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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