Prostaglandin E2/EP1 Signaling Pathway Enhances Intercellular Adhesion Molecule 1 (ICAM-1) Expression and Cell Motility in Oral Cancer Cells

Oral squamous cell carcinoma has a striking tendency to migrate and metastasize. Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis. However, the effects of COX-2 on human oral cancer cells are largely unknown. We found that overexpression of COX-2 or exogenous PGE₂ increased migration and intercellular adhesion molecule 1 (ICAM)-1 expression in human oral cancer cells. Using pharmacological inhibitors, activators, and genetic inhibition of EP receptors, we discovered that the EP1 receptor, but not other PGE receptors, is involved in PGE₂-mediated cell migration and ICAM-1 expression. PGE₂-mediated migration and ICAM-1 up-regulation were attenuated by inhibitors of protein kinase C (PKC)δ, and c-Src. Activation of the PKCδ, c-Src, and AP-1 signaling pathway occurred after PGE₂ treatment. PGE₂-induced expression of ICAM-1 and migration activity were inhibited by a specific inhibitor, siRNA, and mutants of PKCδ, c-Src, and AP-1. In addition, migration-prone sublines demonstrated that cells with increased migration ability had higher expression of COX-2 and ICAM-1. Taken together, these results indicate that the PGE₂ and EP1 interaction enhanced migration of oral cancer cells through an increase in ICAM-1 production.     

Elevated Concentrations of Circulating Intercellular Adhesion Molecule 1 (ICAM-1) and of Vascular Cell Adhesion Molecule 1 (VCAM-1) in HIV-1 Infection

The aim of this study was to determine whether elevated levels of circulating forms of the soluble adhesion molecules, Intercellular Adhesion Molecule-1 (cICAM-1), Vascular Cell Adhesion Molecule-1 (cVCAM-1) and E-Selectin (cE-Selectin) are observed in the sera of HIV-1 infected individuals as compared to healthy HIV seronegative adults and whether these elevated levels can be correlated with disease progression. Significantly elevated levels of cICAM-1—ranging from 184 to 1116 ng/ml with a mean of 617 ng/ml—and cVCAM-1—ranging from 653 to 3456 ng/ml with a mean of 1500 ng/ml—were observed in the sera of 29 HIV-1 infected individuals as compared to controls-ranging from 152 to 354 ng/ml with a mean of 248 ng/ml for cICAM-1 and from 328 to 792 ng/ml with a mean of 560 ng/ml for cVCAM-1 (P < 0.001). The serum concentrations of cE-Selectin of the HIV-1 infected individuals did not differ from those of the healthy controls. The elevated levels of cICAM-1, cVCAM-1 did not correlate with the CD4 count or the serum concentration of C-reactive protein. However, a significant correlation was observed between the serum concentrations of cVCAM-1 and those of neopterin. Since cICAM-1 as well as cV-CAM-1 can interfere with adhesion events leading to immunological functions, it can be suggested that the high amounts of these circulating forms of adhesion molecules, when present in the sera of HIV-1 positive individuals, can further disturb the immune system of these patients. In addition, the present study also suggests that the seric concentrations of cVCAM-1 can be used as pronostic indicators.     

野生型p53基因对内皮细胞细胞间粘附分子-1表达的影响

细胞间粘附分子－１（ＩＣＡＭ－１）是介导白细胞与内皮细胞粘附的重要粘附分子．为研究野生型ｐ５３基因对内皮细胞ＩＣＡＭ－１表达的影响,分别采用流式细胞术和ＲＴ－ＰＣＲ／ＨＰＬＣ方法测定ＩＣＡＭ－１蛋白及ｍＲＮＡ水平．静息状态的内皮细胞表面结构性地表达有少量的ＩＣＡＭ－１,在肿瘤坏死因子α（ＴＮＦα,１０～１０００Ｕ／ｍｌ）诱导下,其表达呈剂量依赖性增加．将ｐ５３基因导入内皮细胞,则显著抑制ＴＮＦα诱导的内皮细胞表面ＩＣＡＭ－１的表达．ｐ５３基因的导入对静息状态内皮细胞表面结构性表达的ＩＣＡＭ－１影响较小．ｐ５３基因主要通过降低ＩＣＡＭ－１的ｍＲＮＡ水平而抑制内皮细胞表面ＩＣＡＭ－１的表达,但对蛋白的抑制程度小于对ｍＲＮＡ的抑制程度．提示：ｐ５３基因对内皮细胞ＩＣＡＭ－１表达的影响除转录水平控制外,还存在转录后水平的调控     

Endothelial Cell Adhesion Molecule Expression and Lymphocyte Adhesion to Endothelial Cells: Effect of Nitric Oxide

Interactions between circulating leukocytes and vascular endothelial cells are of fundamental importance in controlling normal recirculation and migration of cells into sites of inflammation. Nitric oxide (NO), which is synthesized by vascular endothelial cells, has been reported to decrease the binding of platelets, monocytes, macrophages, and neutrophils to endothelial cells. Using NO donors and inhibitors of the enzyme NO synthase, we found no evidence that physiologically relevant levels of NO alter adhesion of purified lymphocytes to an endothelial cell line derived from human umbilical vein endothelial cells (SGHEC-7). In addition, NO donors did not alter the cell surface expression of VCAM-1, ICAM-1, or E-selectin on SGHEC-7 cells.     

细胞间粘附分子1的研究进展

细胞间粘附分子1(ICAM-1),又名CD54,是一种重要的细胞表面粘附分子,属免疫球蛋白超家族．它可与鼻病毒以及整合素家族成员结合,参与炎症,普通感冒,变态反应及移植排斥反应．文章就其细胞分布、表达调节、结构功能、基因工程以及临床应用进行了综述．     

GroEL1, from Chlamydia pneumoniae, Induces Vascular Adhesion Molecule 1 Expression by p37(AUF1) in Endothelial Cells and Hypercholesterolemic Rabbit

The expression of vascular adhesion molecule-1 (VCAM-1) by endothelial cells may play a major role in atherogenesis. The actual mechanisms of chlamydia pneumoniae (C. pneumoniae) relate to atherogenesis are unclear. We investigate the influence of VCAM-1 expression in the GroEL1 from C. pneumoniae-administered human coronary artery endothelial cells (HCAECs) and hypercholesterolemic rabbits. In this study, we constructed the recombinant GroEL1 from C. pneumoniae. The HCAECs/THP-1 adhesion assay, tube formation assay, western blotting, enzyme-linked immunosorbent assay, actinomycin D chase experiment, luciferase reporter assay, and immunohistochemical stainings were performed. The results show that GroEL1 increased both VCAM-1expression and THP-1 cell adhesives, and impaired tube-formation capacity in the HCAECs. GroEL1 significantly increased the VCAM-1 mRNA stability and cytosolic AU-binding factor 1 (AUF1) level. Overexpression of the p37(AUF1) significantly increased VCAM-1 gene expression in GroEL1-induced bovine aortic endothelial cells (BAECs). GroEL1 prolonged the stability of VCAM-1 mRNA by increasing both p37(AUF1) and the regulation of the 5' untranslated region (UTR) of the VCAM-1 mRNA in BAECs. In hypercholesterolemic rabbits, GroEL1 administration enhanced fatty-streak and macrophage infiltration in atherosclerotic lesions, which may be mediated by elevated VCAM-1 expression. In conclusion, GroEL1 induces VCAM-1 expression by p37(AUF1) in endothelial cells and enhances atherogenesis in hypercholesterolemic rabbits.     

Soluble E-Selectin Enhances Intercellular Adhesion Molecule-1 (ICAM-1) Expression in Human Tumor Cell Lines

E-selectin mediates neovascularization via its soluble form, while its membrane-bound form initiates binding of tumor cells to vascular endothelium. Therefore, it was studied whether soluble E-selectin regulates further adhesion molecules on tumor cells. In tumor cells but not in related nonmalignant cells, intercellular adhesion molecule (ICAM)-1 expression was strikingly increased from 5 to 68% positive cells byin vitroinoculation of a recombinant E-selectin–IgG1 within 24 h, as analyzed by flow cytometry. The absence of changes in the expression of vascular cell adhesion molecule, integrin ligands (CD11a, CD18, integrin α4), and sialyl-Lewis X indicates a specific effect of soluble E-selectin on ICAM-1. A cell adhesion assay revealed that the enhanced adhesion of T-cells to tumor cells mediated by soluble E-selectin-induced ICAM-1 expression was at a maximum after a 12-h incubation period. Therefore, ICAM-1 regulation on tumor cells might be a mechanism of immune escape.     

Endothelial Cell-Selective Adhesion Molecule Expression in Hematopoietic Stem/Progenitor Cells Is Essential for Erythropoiesis Recovery after Bone Marrow Injury

Numerous red blood cells are generated every second from proliferative progenitor cells under a homeostatic state. Increased erythropoietic activity is required after myelo-suppression as a result of chemo-radio therapies. Our previous study revealed that the endothelial cell-selective adhesion molecule (ESAM), an authentic hematopoietic stem cell marker, plays essential roles in stress-induced hematopoiesis. To determine the physiological importance of ESAM in erythroid recovery, ESAM-knockout (KO) mice were treated with the anti-cancer drug, 5-fluorouracil (5-FU). ESAM-KO mice experienced severe and prolonged anemia after 5-FU treatment compared to wild-type (WT) mice. Eight days after the 5-FU injection, compared to WT mice, ESAM-KO mice showed reduced numbers of erythroid progenitors in bone marrow (BM) and spleen, and reticulocytes in peripheral blood. Megakaryocyte-erythrocyte progenitors (MEPs) from the BM of 5-FU-treated ESAM-KO mice showed reduced burst forming unit-erythrocyte (BFU-E) capacities than those from WT mice. BM transplantation revealed that hematopoietic stem/progenitor cells from ESAM-KO donors were more sensitive to 5-FU treatment than that from WT donors in the WT host mice. However, hematopoietic cells from WT donors transplanted into ESAM-KO host mice could normally reconstitute the erythroid lineage after a BM injury. These results suggested that ESAM expression in hematopoietic cells, but not environmental cells, is critical for hematopoietic recovery. We also found that 5-FU treatment induces the up-regulation of ESAM in primitive erythroid progenitors and macrophages that do not express ESAM under homeostatic conditions. The phenotypic change seen in macrophages might be functionally involved in the interaction between erythroid progenitors and their niche components during stress-induced acute erythropoiesis. Microarray analyses of primitive erythroid progenitors from 5-FU-treated WT and ESAM-KO mice revealed that various signaling pathways, including the GATA1 system, were impaired in ESAM-KO mice. Thus, our data demonstrate that ESAM expression in hematopoietic progenitors is essential for erythroid recovery after a BM injury.     

Interleukin-1α Released from Epithelial Cells after Adenovirus Type 37 Infection Activates Intercellular Adhesion Molecule 1 Expression on Human Vascular Endothelial Cells

A key event in virus-induced inflammation (leukocyte extravasation through the endothelium) is the local activation of endothelial cells, as indicated by the expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin. In order to identify triggers of inflammation in adenovirus infection, we inoculated respiratory and ocular epithelial cells with adenovirus type 37 (Ad37), a human pathogen associated with keratoconjunctivitis as well as urogenital and respiratory infections. Fluids from virus-infected epithelial cells activated ICAM-1 (and to a lesser extent, VCAM-1) expression on cultured human umbilical vein endothelial cells. Blocking studies with anticytokine antibodies implicated interleukin-1alpha (IL-1alpha) as the epithelial cell-derived factor which activated endothelial cell ICAM-1 expression. The results thus identify epithelial cell-derived IL-1alpha as a potentially important activator of endothelial cells in Ad37-induced inflammation.     

Role of ICAM-3 in Intercellular Adhesion and Activation of T Lymphocytes

The immune system requires a fine regulation of intercellular communication for its normal function. There are several regulated molecular pathways involved in leukocyte cell interactions (Springer, 1990; Hynes, 1992). Among them, the interaction of the leukocyte integrin LFA-1 (CDlla/CD18) with its ligands provides multiple accessory adhesion signals of capital importance during different functions of the immune response, such as antigen presentation (Harding and Unanue, 1991), T-B lymphocyte interaction (Moy and Brian, 1992), cellular cytotoxicity (Makgoba et al., 1988; Altmann et al., 1989; Davignon et al, 1981; Akella and Hall, 1992), allogenic and autologous mixed lymphocyte reactions (Bagnasco et al., 1990) and recirculation and homing of lymphocytes through tissue endothelium (Hamann et al., 1988; Pals et al, 1988).     

Role of ICAM-3 in Intercellular Adhesion and Activation of T Lymphocytes

The immune system requires a fine regulation of intercellular communication for its normal function. There are several regulated molecular pathways involved in leukocyte cell interactions (Springer, 1990; Hynes, 1992). Among them, the interaction of the leukocyte integrin LFA-1 (CDlla/CD18) with its ligands provides multiple accessory adhesion signals of capital importance during different functions of the immune response, such as antigen presentation (Harding and Unanue, 1991), T-B lymphocyte interaction (Moy and Brian, 1992), cellular cytotoxicity (Makgoba et al., 1988; Altmann et al., 1989; Davignon et al, 1981; Akella and Hall, 1992), allogenic and autologous mixed lymphocyte reactions (Bagnasco et al., 1990) and recirculation and homing of lymphocytes through tissue endothelium (Hamann et al., 1988; Pals et al, 1988).     

RelA/p65翻译后修饰对NF-κB转录激活的影响

RelA/p65是NF-κB的一个亚单位,其翻译后修饰能够精细地调控NF-κB的转录激活,并在炎症反应及炎症反应相关疾病的发生和发展过程中发挥重要的作用. RelA的翻译后修饰主要包括磷酸化、乙酰化、甲基化以及泛素化等.这些翻译后修饰不仅能在生理和病理的条件下有效地调控NF-κB的转录激活,彼此之间还存在着复杂的相互作用,一种翻译后修饰可以使另一种修饰增强或是抑制,从而综合而完善地调控NF κB的转录活性.本文就近年来RelA的翻译后修饰及这些修饰之间的相互作用对NF-κB信号通路影响的最新研究进展进行综述.     

Novel Cytokine-independent Induction of Endothelial Adhesion Molecules Regulated by Platelet/Endothelial Cell Adhesion Molecule (CD31)

Tumor necrosis factor–α, interleukin-1, and endotoxin stimulate the expression of vascular endothelial cell (EC) adhesion molecules. Here we describe a novel pathway of adhesion molecule induction that is independent of exogenous factors, but which is dependent on integrin signaling and cell–cell interactions. Cells plated onto gelatin, fibronectin, collagen or fibrinogen, or anti-integrin antibodies, expressed increased amounts of E-selectin, vascular cell adhesion molecule–1, and intercellular adhesion molecule–1. In contrast, ECs failed to express E-selectin when plated on poly-l-lysine or when plated on fibrinogen in the presence of attachment-inhibiting, cyclic Arg-Gly-Asp peptides. The duration and magnitude of adhesion molecule expression was dependent on EC density. Induction of E-selectin on ECs plated at confluent density was transient and returned to basal levels by 15 h after plating when only 7 ± 2% (n = 5) of cells were positive. In contrast, cells plated at low density displayed a 17-fold greater expression of E-selectin than did high density ECs with 57 ± 4% (n = 5) positive for E-selectin expression 15 h after plating, and significant expression still evident 72 h after plating. The confluency-dependent inhibition of expression of E-selectin was at least partly mediated through the cell junctional protein, platelet/endothelial cell adhesion molecule–1 (PECAM-1). Antibodies against PECAM-1, but not against VE-cadherin, increased E-selectin expression on confluent ECs. Co– culture of subconfluent ECs with PECAM-1– coated beads or with L cells transfected with full-length PECAM-1 or with a cytoplasmic truncation PECAM-1 mutant, inhibited E-selectin expression. In contrast, untransfected L cells or L cells transfected with an adhesion-defective domain 2 deletion PECAM-1 mutant failed to regulate E-selectin expression. In an in vitro model of wounding the wound front displayed an increase in the number of E-selectin–expressing cells, and also an increase in the intensity of expression of E-selectin positive cells compared to the nonwounded monolayer. Thus we propose that the EC junction, and in particular, the junctional molecule PECAM-1, is a powerful regulator of endothelial adhesiveness.The endothelial lining of the vascular system normally displays a nonactivated, nonadhesive phenotype. Stimulation with agents such as tumor necrosis factor-α (TNF-α)¹, interleukin-1 (IL-1), or lipopolysaccharide (LPS) are known to induce the expression of proteins on the endothelial surface that mediate coagulation (Bevilacqua et al., 1986), leukocyte adhesion (Bevilacqua et al., 1985; Gamble et al., 1985; Pober et al., 1986b ; Doherty et al., 1989), and leukocyte transendothelial migration (Furie et al., 1989; Moser et al., 1989). The endothelial antigens that are important for the adhesion of leukocytes are members of the selectin family, E- and P-selectin, and the immunoglobulin gene superfamily, vascular cell adhesion molecule–1 (VCAM-1) and intercellular adhesion molecule–1 (ICAM-1) (Carlos and Harlan, 1994; Litwin et al., 1995).The induction of E-selectin expression on endothelial cells (ECs) in vitro after cytokine stimulation is transient and independent of the continued presence of the stimulant (Pober et al., 1986a ). Previous studies have shown that E-selectin mRNA and protein levels peak between 2 and 4 h, respectively, after treatment with an agonist, returning to near basal levels by 24 h (Bevilacqua et al., 1989; Read et al., 1994). VCAM-1 (Osborn et al., 1989) and ICAM-1 (Pober et al., 1986b ) are maximal 6 and 12 h, respectively, after stimulation.In contrast to the transiency of E-selectin and VCAM expression demonstrated by the in vitro data, these antigens have been detected on venular endothelium in chronic inflammatory lesions, such as the synovium in rheumatoid arthritis (Koch et al., 1991), and the skin in psoriasis (Petzelbauer et al., 1994). E-selectin expression is also detected on angiogenic vessels in human hemangiomas, a noninflammatory angiogenic disease (Kraling et al., 1996). Moreover, the architecture and anatomic localization of capillary loops influence the pattern of endothelial expression of E-selectin and VCAM-1, independently of the availability of cytokines (Petzelbauer et al., 1994). Thus it is likely that alternate control mechanisms exist to allow prolonged, locality-based expression of adhesion molecules on the endothelium. At least one of these alternate mechanisms may be flow, since increased shear stress has been shown to selectively modulate adhesion molecule expression, upregulating ICAM-1 but not E-selectin or VCAM-1 (Nagel et al., 1994).Since sites of inflammation are often associated with morphological changes including cell retraction of the endothelium (Schumacher, 1973), we hypothesized that cell contacts may be important in the regulation of endothelial phenotype. We describe here the central role of the junctional protein, platelet/endothelial cell adhesion molecule–1 (PECAM-1), through the formation of cell–cell interactions, in the maintenance of the functional integrity of the endothelial monolayer. Furthermore, we demonstrate a novel pathway for the induction of adhesion molecules on endothelial cells that is independent of exogenous addition of cytokines, but is related to integrin- and cell shape–associated signaling events.     

Binding of LFA-1 (CD11a) to Intercellular Adhesion Molecule 3 (ICAM-3; CD50) and ICAM-2 (CD102) Triggers Transmigration of Human Immunodeficiency Virus Type 1-Infected Monocytes through Mucosal Epithelial Cells

Transmigration of human immunodeficiency virus (HIV)-infected mononuclear cells through the genital mucosa is one of the possible mechanisms of sexual transmission of HIV. Here, we investigated the transmigration of cell-associated R5-tropic HIV type 1 (HIV-1) through a tight monolayer of human epithelial cells in vitro. We show that this process is dependent on an initial interaction between alphaLbeta2 integrin CD11a/CD18 on infected monocytic cells and intercellular adhesion molecule 2 (ICAM-2; CD102) and ICAM-3 (CD50) on the apical membrane of epithelial cells. The CD50 and CD102 ligands were overexpressed on epithelial cells when the cells were activated by proinflammatory cytokines in the cellular microenvironment. An accumulation of proviral DNA was found in the transmigrated cells, clearly reflecting the preferential transepithelial migration of HIV-1-infected cells under proinflammatory conditions. Our observations provide new insights supporting the hypothesis that HIV-infected mononuclear cells contained in genital secretions from infected individuals may cross the epithelial genital mucosa of an exposed receptive sexual partner, particularly under inflammatory conditions of damaged genital tissue. Understanding the fundamental aspects of the initial HIV entry process during sexual transmission remains a critical step for preventing human infection and developing further vaccinal strategies and virucidal agents.     

Effect of Proteasome Inhibitor on Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intercellular Adhesion Molecule-1 (ICAM-1) Expressions in Rat Model of Atherosclerosis

Background:The effect of proteasome inhibitors on atherosclerosis is known to vary depending on the atherosclerosis stage. Previous studies have shown that the highest proteasome expression in atherosclerotic lesions is at the progression stage. Adhesion molecules play a role in the progression stage of atherosclerosis, but no studies have analyzed the effect of proteasome inhibitors on the expression of adhesion molecules at this stage.Methods:This experimental study aimed to analyze the effect of a proteasome inhibitor, namely bortezomib, on the vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule1 (ICAM-1) expressions in blood vessels of rat model of atherosclerosis at the progression stage. This study used 18 male Wistar rats divided into three groups, i.e. group I that is the control group given standard feed, group II induced by atherosclerosis, and group III induced by atherosclerosis and given bortezomib. Atherosclerosis induction was performed using vitamin D3 (700,000 IU/kg) orally by gastric intubation on the 1st day and atherogenic feed given for four days. Bortezomib 50 µg/kgBW/day was administered intra-peritoneally. The expression of VCAM-1 and ICAM-1 molecules was measured using immunohistochemistry and analyzed quantitatively using Adobe Photoshop software.Results:The statistical test showed differences in VCAM-1 expression between atherosclerosis + Bortezomib group and atherosclerosis group, but there were no differences in the expression of ICAM-1 and atherosclerotic lesions between the groups.Conclusion:Administration of bortezomib 50μg/kg for four days in progressive atherosclerosis model rats can inhibit VCAM-1 expression, although it does not affect ICAM-1 expression and cannot inhibit atherosclerotic lesion formation.Key Words: Atherosclerosis, Bortezomib, Proteasome, VCAM-1, ICAM-1     

The Role of Reactive Oxygen Intermediates in the Regulation of Cytokine-Induced ICAM-1 Surface Expression on Endothelial Cells

ICAM-1 upregulation by endothelial cells plays a pivotal role in many disease processes, but signalling mechanisms leading to increased expression are poorly understood. In the current study we investigated the regulatory capacity of reactive oxygen intermediates (ROIs) in ICAM-1 activation by stimulating endothelial cells with the pro-inflammatory cytokines IL-1β, TNFα, IFNγ, IL-2, and IL-4 prior to antioxidant treatment. ICAM-1 was expressed constitutively and upregulated on ECV304 by IL1-β, IL2, and IFNγ and on SKHEP-1 by IFNγ, IL1-β, and TNFα. Phenanthroline (PHE) and disulfiram (DIS) showed the greatest ability to inhibit cytokine-stimulated ICAM-1 expression and in a dose-dependent manner. The α,α-diphenyl-β-picrylhydrazyl (DPPH) conversion assay showed that PHE and DIS had zero ability to scavenge free radicals and thus no known antioxidant activity. However, both are known metal chelators and our findings therefore suggest a unique role for metal ions in the control of cytokine-induced ICAM-1 expression on endothelial cells.