Upregulation Of Intercellular Adhesion Molecule-1 Expression Research Articles

Accumulation of γδT cells in the decidua is promoted by RANKL which upregulates ICAM-1 via NF-κB.

The mechanism underlying the accumulation of γδT cells in the decidua, which helps maintain maternal-fetal immunotolerance in early pregnancy, is unknown. This study reveals that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. Decidual γδT (dγδT) cells help maintain maternal-fetal immunotolerance in early pregnancy. However, the mechanism underlying the accumulation of γδT cells in the decidua is unknown. Previous work showed that RANKL upregulated intercellular adhesion molecule 1 (ICAM-1) in decidual stromal cells (DSCs), and Rankl knockout mice had limited dγδT cell populations. In this study, we measured the expression levels of RANKL/RANK and ICAM-1 in DSCs, in addition to the integrins of ICAM-1 on dγδT cells, and the number of dγδT cells from patients with recurrent spontaneous abortion (RSA) and normal pregnant women in the first trimester. RSA patients showed significantly decreased RANKL/RANK and ICAM-1/CD11a signaling in decidua, and a decreased percentage of dγδT cells, which was positively correlated with DSC-derived RANKL and ICAM-1. Next, an in vitro adhesion experiment showed that the enhanced attraction of human DSCs to dγδT cells after RANKL overexpression was almost completely aborted by anti-ICAM-1. Furthermore, Rankl knockout mice showed a significant reduction in NF-κB activity compared with wild-type controls. Finally, we applied a selective NF-κB inhibitor named PDTC to validate the role of NF-κB in RANKL-mediated ICAM-1 upregulation. Taken together, our data show that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. A reduction in RANKL/ICAM-1 signaling in DSCs may result in insufficient accumulation of γδT cells in decidua and, in turn, RSA.

Up-Regulated Expression of ICAM1, MT1A, PTGS2, LCE3D, PPARD, and GM-CSF2 Following Solar Skincare Protection and Repair Strategies in a 3-Dimensional Reconstructed Human Skin Model.

Clinical, optical and histological research confirms that solar skin damage continues to pose a threat to human skin health globally despite widespread sunscreen usage and sun awareness campaigns. Despite this, very few studies examine the critical changes in gene expression and DNA repair activity following recommended topical solar protection and repair strategies to ameliorate the harmful effects of ultraviolet, visible light and near-infrared radiation. To investigate alterations in gene expression following topical solar protection and solar repair strategies. Using epidermal keratinocytes and dermal fibroblasts derived from a 3-dimensional reconstructed human skin model, gene expression was assessed via the Genemarkers Standard Skin Panel using 112 genes deploying two analytical techniques: DNA microarray and quantitative real-time PCR exploration. Tissues were inoculated with products then collected after 24 hours following application of solar protection formulations and 16 hours following solar repair formulations (The Essential Six, RATIONALE, Victoria, Australia). A DNA microarray revealed 67 genes that were significantly up-regulated or down-regulated following the treatment. The quantitative real-time PCR revealed that, in comparison to the control, the genes encoding Intercellular Adhesion Molecule 1 (ICAM1), Metallothionein 1A (MT1A), Prostaglandin-Endoperoxide Synthase 1 (PTGS2), Late Cornified Envelope 3D (LCE3D), Peroxisome Proliferator Activated Receptor (PPARD), and Granulocyte/Macrophage Colony Stimulating Factor 2 (GM-CSF2) have been up-regulated following usage of the solar protection regime, 1.87, 861.16, 4.34, 1.91, 1.06, and 3.6, respectively. ICAM1, MT1A, PTGS2, LCE3D, PPARD, and GM-CSF2 were up-regulated following use of the solar repair regime, 3.78, 2.98, 14.89, 5.09, 2.42, and 13.51, respectively. This study demonstrates that a specific solar protection and repair regime upregulated genes involved in photoprotection and repair mechanisms in a 3-dimensional (3D) reconstructed human-like skin model.

Long non-coding RNA MALAT1 exacerbates acute respiratory distress syndrome by upregulating ICAM-1 expression via microRNA-150-5p downregulation.

Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury in which severe inflammatory responses induce cell apoptosis, necrosis, and fibrosis. This study investigated the role of lung adenocarcinoma transcript 1 (MALAT1) in ARDS and the underlying mechanism involved. The expression of MALAT1, microRNA-150-5p (miR-150-5p), and intercellular adhesion molecule-1 (ICAM-1) was determined in ARDS patients and lipopolysaccharide (LPS)-treated human pulmonary microvascular endothelial cells (HPMECs). Next, the interactions among MALAT1, miR-150-5p, and ICAM-1 were explored. Gain- or loss-of-function experiments in HPMECs were employed to determine cell apoptosis and inflammation. Furthermore, a mouse xenograft model of ARDS was established in order to verify the function of MALAT1 in vivo. MALAT1 and ICAM-1 were upregulated, while miR-150-5p was downregulated in both ARDS patients and LPS-treated HPMECs. MALAT1 upregulated ICAM-1 expression by competitively binding to miR-150-5p. MALAT1 silencing or miR-150-5p overexpression was shown to suppress HPMEC apoptosis, decrease the expressions of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and E-selectin in HPMECs, as well as alleviated lung injury in nude mice. These findings demonstrated that MALAT1 silencing can potentially suppress HPMEC apoptosis and alleviate lung injury in ARDS via miR-150-5p-targeted ICAM-1, suggestive of a novel therapeutic target for ARDS.

Effect of irradiation-induced intercellular adhesion molecule-1 expression on natural killer cell-mediated cytotoxicity toward human cancer cells

Background aimsIrradiation enhances the adhesion between natural killer (NK) cells and target cells by up-regulating intercellular adhesion molecule-1 (ICAM-1) on target cells. Therefore, we investigated the effect of irradiation-induced ICAM-1 expression on human cancer cells on NK cell–mediated cytotoxicity. MethodsExpression levels of ICAM-1 on the target cell surface before and after irradiation of six human cancer cell lines (HL60, SKBR-3, T47D, HCT-116, U937 and U251) were analyzed by flow cytometry. Ex vivo expansion of NK cells from human peripheral blood mononuclear cells was performed by co-culture with irradiated K562 cells. The related adhesion molecule lymphocyte function–associated antigen 1 (LFA-1) on NK cells was analyzed by flow cytometry. An enzyme-linked immunosorbent assay was used to detect interferon-γ (IFN-γ), and WST-8 assays were performed to check NK cell cytotoxicity. Finally, blocking assays were performed using monoclonal antibodies against ICAM-1 or LFA-1. ResultsLFA-1 expression increased on NK cells after expansion (P < 0.001). The expression of ICAM-1 was significantly upregulated by irradiation after 24 h in various cell lines, including HL60 (P < 0.001), SKBR-3 (P < 0.001), T47D (P < 0.001) and U937 (P < 0.001), although the level of expression depended on the cell line. ICAM-1 expression was extremely low before and after irradiation in U251 cells. NK cell–mediated cytotoxicity increased after irradiation of HL60 (P < 0.001), SKBR-3 (P < 0.001), T47D (P = 0.003), and U937 (P = 0.004) cells, in which ICAM-1 expression was significantly increased after irradiation. IFN-γ production by NK cells in response to HL60 (P < 0.001) and T47D (P = 0.011) cells significantly increased after irradiation. NK cell–mediated cytotoxicity against irradiated SKBR-3 (P < 0.001) and irradiated T47D cells (P = 0.035) significantly decreased after blocking of ICAM-1. Blocking of LFA-1 on NK cells resulted in reduced cytotoxicity against irradiated HL60 (P < 0.001) and irradiated SKBR-3 (P < 0.001). ConclusionsIrradiation upregulates ICAM-1 expression on the surface of human cancer cells and enhances activated NK cell–mediated cytotoxicity. Therefore, irradiation combined with NK cell therapy may improve the antitumor effects of NK cells.

Tumor Necrosis Factor-Alpha Up-Regulates ICAM-1 Expression and Release in Intestinal Myofibroblasts by Redox-Dependent and -Independent Mechanisms.

Intercellular adhesion molecule-1 (ICAM-1) is distributed and expressed on cell surface and is present in circulation as soluble form (sICAM-1). Tumor necrosis factor-alpha (TNFα) and radical oxygen species (ROS) up-regulate the expression of ICAM-1. This study demonstrates for the first time in 18 Co cells, a myofibroblast cell line derived from human colonic mucosa, an up-regulation of ICAM-1 expression and sICAM-1 release induced by oxidative stress and TNFα stimulation. The intracellular redox state was modulated by L-buthionine-S,R-sulfoximine (BSO) or N-acetylcysteine (NAC), inhibitor and precursor respectively of GSH synthesis. ROS production increases in cells treated with BSO or TNFα, and this has been related to an up-regulation of ICAM-1 expression and sICAM-1 release. The involvement of metalloproteinases in ICAM-1 release has been demonstrated. Moreover, also expression and activation of A disintegrin and metalloproteinase 17, a membrane-bound enzyme known as TNFα-converting enzyme (TACE), have been related to ROS levels. This suggests the possible involvement of TACE in the cleavage of ICAM-1 on cell surface in condition of oxidative stress. NAC down-regulates the expression and release of ICAM-1 as well as the expression and activation of TACE. However, in TNFα stimulated cells NAC treatment reduces only in part ICAM-1 expression and sICAM-1 release. Given this TNFα may also act on these events by a redox-independent mechanism.

Amphiregulin enhances intercellular adhesion molecule-1 expression and promotes tumor metastasis in human osteosarcoma.

Osteosarcoma is a common, high malignant, and metastatic bone cancer. Amphiregulin (AREG) has been associated with cancer cellular activities. However, the effect of AREG on metastasis activity in human osteosarcoma cells has yet to be determined. We determined that AREG increases the expression of intercellular adhesion molecule-1 (ICAM-1) through PI3K/Akt signaling pathway via its interaction with the epidermal growth factor receptor, thus resulting in the enhanced cell migration of osteosarcoma. Furthermore, AREG stimulation increased the association of NF-κB to ICAM-1 promoter which then up-regulated ICAM-1 expression. Finally, we observed that shRNA silencing of AREG decreased osteosarcoma metastasis in vivo. Our findings revealed a relationship between osteosarcoma metastatic potential and AREG expression and the modulating effect of AREG on ICAM-1 expression.

CD99 ligation induces intercellular cell adhesion molecule-1 expression and secretion in human gingival fibroblasts

ObjectiveTo examine CD99 expression and its functional role in ICAM-1 induction in human gingival fibroblasts (HGFs) and human gingival epithelial cells (HGECs) by activating cells with anti-CD99 monoclonal antibody, MT99/3. BackgroundEngagement of CD99 with agonistic antibodies has been shown to regulate immune responses, cell adhesion and migration, and cell death in several studies. Particularly, this engagement results in transendothelial migration of leukocytes mediated by intercellular adhesion molecule-1 (ICAM-1) induction in endothelial cells. MethodsTotal mRNA and protein were isolated from HGFs and HGECs for analyses of CD99 and ICAM-1 expression. Surface expression of CD99 and ICAM-1 was analysed by flow cytometry, and the detection of soluble ICAM-1 was assayed by immunoprecipitation and ELISA. ResultsCD99 surface expression was constitutive on HGFs to a greater extent than that on HGECs. CD99 ligation with MT99/3 induced ICAM-1 mRNA expression in HGFs, but not in HGECs. Interestingly, CD99 ligation led to an increased level of soluble ICAM-1 detected in culture supernatant, whereas interleukin-1β (IL-1β) treatment induced expression of membrane-bound ICAM-1. Furthermore, ICAM-1 induction by CD99 engagement was demonstrated to involve the activation of the p50 subunit of nuclear factor-kappaB (NF-κB), extracellular signal-regulated kinase, and p46 c-Jun N-terminal kinase that differed from that by IL-1β treatment. ConclusionOur study has shown the involvement of CD99 ligation in the up-regulation of ICAM-1 expression and its secretion in gingival fibroblasts, which may be essential for better understanding of the pathogenesis of periodontal disease.

NF‐κ B‐dependent upregulation of ICAM‐1 by HPV16‐E6/E7 facilitates NK cell/target cell interaction

NK cell recognition of tumor cells is mediated by a delicate balance of signals received by MHC class I-binding inhibitory NK cell receptors and activating NK cell receptors, which mainly bind to virus-, stress- or tumor-induced ligands. In addition, adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) and its receptors, the lymphocyte function-associated antigen-1 (LFA-1) and Mac-1, are crucial for immune synapse formation and NK cell-mediated killing. In this study, we show that expression of the adhesion molecule ICAM-1 was rapidly induced by E6 and -E7 oncoproteins of HPV16, -18, -5 and -8, but not of HPV38 and -6 in primary human keratinocytes after retroviral transduction. ICAM-1 was upregulated in E6E7-expressing keratinocytes both at mRNA and protein levels. The observed ICAM-1 upregulation in HPV16-E6E7-expressing keratinocytes was partially dependent on activation of the NF-κB pathway. Importantly, the upregulated ICAM-1 expression in HPV16-E6E7-expressing keratinocytes led to enhanced conjugate formation with NK cells. We previously showed that HPV16-positive cervical carcinomas frequently express low levels of inhibitory NK cell ligands and high levels of activating NK cell ligands. Moreover, levels of the adhesion molecule ICAM-1 are enhanced by HPV16-E6/E7. Therefore, strategies that aim at harnessing NK cells might be beneficial for the treatment of cervical carcinoma.

Lipopolysaccharide-evoked activation of p38 and JNK leads to an increase in ICAM-1 expression in Schwann cells of sciatic nerves

Lipopolysaccharide is a major constituent of the outer membrane of Gram-negative bacteria. It activates monocytes and macrophages to produce cytokines such as tumor necrosis factor-alpha and interleukins IL-1beta and IL-6. These cytokines appear to be responsible for the neurotoxicity observed in peripheral nervous system inflammatory disease. It has been reported that, in the central nervous system, the expression level of intercellular adhesion molecule-1 (ICAM-1) was dramatically upregulated in response to LPS, as well as many inflammatory cytokines. ICAM-1 contributes to multiple processes seen in central nervous system inflammatory disease, for example migration of leukocytes to inflammatory sites, and adhesion of polymorphonuclear cells and monocytes to central nervous system cells. In the present study, we found that lipopolysacharide evoked ICAM-1 mRNA and protein expression early at 1 h post-injection, and the most significant increase was seen at 4 h. Immunofluorescence double-labeling suggested that most of the ICAM-1-positive staining was located in Schwann cells. Using Schwann cell cultures, we demonstrated that ICAM-1 expression in Schwann cells is regulated by mitogen-activated protein kinases, especially the p38 and stress-activated protein kinase/c-Jun N-terminal kinase pathways. Thus, it is thought that upregulation of ICAM-1 expression in Schwann cells may be important for host defenses after peripheral nervous system injury, and reducing the biosynthesis of ICAM-1 and other cytokines by blocking the cell signal pathway might provide a new strategy against inflammatory and immune reaction after peripheral nerve injury.

Regulation of endothelial adhesion molecules by ligands binding to the scavenger receptor.

Monocyte adherence to the endothelium, their penetration to the subendothelial space and excessive lipid accumulation (foam cell formation) are the initial events in atherogenesis. Scavenger receptors have been reported to play an important role in foam cell formation, since modified low density lipoproteins can be taken up via scavenger receptors in a non-down-regulated fashion. In this study we demonstrate that stimulation of scavenger receptors in endothelial cells induces the expression of endothelial adhesion molecules. Polyinosinic acid (poly I), a known scavenger receptor ligand, significantly induced the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells when compared with polycytidylic acid (poly C), a structurally related compound to poly I, which does not bind to the scavenger receptor. The effect of scavenger receptor ligands on the endothelial cell line EA hy. 926 was also tested. Poly I up-regulated ICAM-1 expression also on EA hy. 926 cells, while it had no effect on IL-1 beta or tumour necrosis factor-alpha (TNF-alpha) production on the same cell line. Poly I-induced ICAM-1 expression on EA hy. 926 cells could be inhibited by H7, a protein kinase C inhibitor, while HA 1004, a preferential protein kinase A inhibitor, had no effect on ICAM-1 expression. The role of protein kinase C in scavenger receptor-mediated adhesion molecule upregulation was confirmed by the ability of poly I to directly activate protein kinase C, when measured with 3H-phorbol dibutyrate binding to EA hy. 926 cells, while poly C again was ineffective.

Increased expression of intercellular adhesion molecule-1 (ICAM-1) in a murine model of pulmonary eosinophilia and high IgE level.

T lymphocytes and eosinophils are probably involved in the pathogenesis of allergic bronchopulmonary aspergillosis (ABPA), a disease characterized by pulmonary eosinophilia and high serum and lavage IgE levels. We recently developed a murine model of ABPA. To investigate the mechanisms of T lymphocyte and eosinophil recruitment to the lung in this disease, we examined the expression of ICAM-1 in the lung tissue of mouse challenged with Aspergillus fumigatus (Af) antigen. C57B1/6 mice were intranasally exposed to Af (Af group) or saline (control group) three times a week for 1, 2 or 3 weeks. On days 4, 7, 14 and 21, mice were killed and lung tissue was fixed in acetone and embedded in glycol methacrylate. Serial 2-microns sections were stained with chromotrope 2R and MoAbs against ICAM-1, CD11a/CD18 (LFA-1) and CD3. Af-challenged mice presented significant increases in eosinophil, T lymphocyte and LFA-1-positive cell count and up-regulated expression of ICAM-1 in the lung tissue at all the time points examined. ICAM-1 expression intensity correlated with the number of T lymphocytes (r = 0.59, P < 0.01), LFA-1-positive cells (r = 0.68, P < 0.001), but not of eosinophils (r = -0.24, P > 0.05). These findings suggest that up-regulation of ICAM-1 expression is involved in the inflammatory process of this murine model of ABPA, and that this up-regulation may be more relevant to the the T lymphocyte accumulation in the lung.

Cisplatin up‐regulates ICAM‐1 expression in endothelial cell via a NF‐κB dependent pathway

The anticancer drug cis-diammindichloroplatin (cisplatin) can cause severe side-effects, but to date, the mechanisms of action of these dangerous side-effects have not been completely elucidated. Since cellular adhesion molecules (CAMs), by mediating the recruitment of circulating leukocytes to the blood vessel wall and their subsequent migration into the subendothelial spaces, play a crucial role in several pathophysiologic processes, we sought potential proof for CAMs in the pathophysiology of cisplatin-induced vascular damage. In vitro, human umbilical vein endothelial cells (HUVECs) were subjected to various concentrations of cisplatin, considerable up-regulation of intercellular adhesion molecule-1 (ICAM-1) but not P-selectin, E-selectin, and vascular cell adhesion molecule 1 at both messenger mRNA and protein expression levels were observed. Electrophoretic mobility shift assays and Western blotting analysis revealed that cisplatin up-regulates ICAM-1 expression in HUVECs via an NF-kappaB-dependent pathway. Further intravital microscopy study demonstrated that significantly higher (P < 0.01) numbers of rolling and sticking leukocytes on the wall of postcapillary venules in male Golden Syrian hamster's cheek pouch bearing a human cervical carcinoma were observed, while inhibition of ICAM-1 by using specific anti-ICAM-1 antibody can attenuate cisplatin-stimulated leukocyte/endothelium interactions. These data suggest that ICAM-1 involves in the pathophisiologic process of cisplatin-induced vascular toxicity and may be exploited for therapeutic advantage.

TNF-α-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells

Up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the lung airway epithelium is associated with the epithelium-leukocyte interaction, critical for the pathogenesis of various lung airway inflammatory diseases such as asthma. However, little is known about how ICAM-1 is up-regulated in human airway epithelial cells. In this study, we show that tumor TNF-alpha induces monocyte adhesion to A549 human lung airway epithelium and also up-regulation of ICAM-1 expression. These effects were significantly diminished by pre-treatment with diphenyliodonium (DPI), an inhibitor of NADPH oxidase-like flavoenzyme. In addition, the level of reactive oxygen species (ROS) was increased in response to TNF-alpha in A549 cells, suggesting a potential role of ROS in the TNF-alpha-induced signaling to ICAM-1 expression and monocyte adhesion to airway epithelium. Further, we found out that expression of RacN17, a dominant negative mutant of Rac1, suppressed TNF-alpha-induced ROS generation, ICAM-1 expression, and monocyte adhesion to airway epithelium. These findings suggest that Rac1 lies upstream of ROS generation in the TNF-alpha-induced signaling to ICAM-1 expression in airway epithelium. Finally, pretreatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, reduced TNF-alpha-induced ICAM-1 expression and both DPI and RacN17 significantly diminished NF-kappaB activation in response to TNF-alpha. Together, we propose that Rac1-ROS-linked cascade mediate TNF-alpha-induced ICAM-1 up-regulation in the airway epithelium via NF-kappaB-dependent manner.

Transforming growth factor-beta 1 (TGF-beta1)-mediated inhibition of glial cell proliferation and down-regulation of intercellular adhesion molecule-1 (ICAM-1) are interrupted by interferon-gamma (IFN-gamma).

We utilized a model of myelin basic protein (MBP) activation in vivo and MBP-stimulated cultures in vitro to study the influence of TGF-beta1 on glial cell proliferation and ICAM-1/leucocyte function-associated antigen-1 (LFA-1) expression, and to observe the antagonistic effects of TGF-beta1 and IFN-gamma. TGF-beta1 inhibited MBP-stimulated and MBP-activated glial cell proliferation, especially in MBP-stimulated separated microglia and astrocytes, and down-regulated the expression of ICAM-1 on MBP-stimulated glial cells and separated microglia. ICAM-1 expression on MBP-activated glial cells was intensely suppressed, whereas its expression on MBP-stimulated astrocytes was not influenced. TGF-beta1 had no effect on LFA-1 expression. In contrast, IFN-gamma up-regulated ICAM-1 expression, but inhibited proliferative response on MBP-stimulated glial cells when cultured without TGF-beta1. Examination of TGF-beta1 and IFN-gamma interactions revealed that TGF-beta1-mediated inhibition of proliferation and down-regulation of ICAM-1 on glial cells were prevented by IFN-gamma. The suppressive effect was re-established with high doses of TGF-beta1 in cultures, indicating that biological effects of TGF-beta1 vary depending on nitric oxide (NO) production, its concentration in the microenvironment and regulation of the cytokine network.

Role of ROS and MAPK in TPA‐induced ICAM‐1 expression in the myeloid ML‐1 cell line

Intercellular adhesion molecule 1 (ICAM-1) has been implicated in playing a key role in the mechanism of inflammatory process initiated in response to environmental agents, and during normal hematopoietic cell differentiation. Though induction of ICAM-1 by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in myeloid cells has been reported, the molecular mechanism by which TPA upregulates ICAM-1 expression remains unclear. In the present study, we investigated the signaling mechanism associated with TPA-induced ICAM-1 expression in ML-1 cells. Herein, our microarray, flow cytometry, and Western blot analysis indicated that ICAM-1 was constitutively expressed at a low level in ML-1 cells, but its expression was further upregulated at both the mRNA and protein levels in response to TPA. ICAM-1 expression in response to TPA was inhibited by pretreatment with GF109203X [a specific inhibitor of protein kinase C (PKC)], or with PD98059 and U0126 (specific inhibitors of MEK), suggesting the importance of PKC, and Erk1/2 signaling cascades in this response. Interestingly, ICAM-1 expression in response to TPA-induced PKC activation was linked to the generation of reactive oxygen species (ROS), as pretreatment with NAC (an ROS scavenger) blocked both ErK1/2 activation and ICAM-1 expression induced by TPA. In addition, TPA-induced ICAM-1 expression was blocked by inhibition of nuclear factor-kappaB (NF-kappaB) activation following pretreatment with BAY11-7085 (a specific inhibitor of NF-kappaB activation). TPA-induced NF-kappaB activation was shown by increased degradation of IkB (NF-kappaB specific inhibitory protein). Together, these observations demonstrated that TPA, a potent activator of PKC, induces ICAM-1 expression via a ROS- and ERK1/2-dependent signaling mechanism in ML-1 cells.

Cytokines differentially regulate ICAM-1 and VCAM-1 expression on human gingival fibroblasts

The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) on human gingival fibroblasts (HGF) may be important for migration and retention of inflammatory cells in periodontally diseased tissue. This study aimed to assess which cytokines regulate ICAM-1 and VCAM-1 expression on HGF. Tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma enhanced both ICAM-1 and VCAM-1 expression on HGF. Interleukin (IL)-1beta mainly up-regulated ICAM-1 expression. On the other hand, IL-4 and IL-13 enhanced only VCAM-1 expression on HGF. IL-10 did not modulate both ICAM-1 and VCAM-1 expression. Transforming growth factor (TGF)-beta1 enhanced ICAM-1 expression. However, TGF-beta1 inhibited the VCAM-1 expression induced by TNF-alpha or IL-4. Both ICAM-1 and VCAM-1 expression by HGF was inhibited by nuclear factor-kappaB (NF-kappaB) activation inhibitor (MG-132). Mitogen-activated protein kinases (MAPK) inhibitors did not influence ICAM-1 expression induced by TNF-alpha. Interestingly, VCAM-1 expression was enhanced by MEK inhibitor (PD98059) and c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125). These results mean that the balance of cytokines in periodontally diseased tissue may be essential for control of ICAM-1 and VCAM-1 expression on HGF, and the balance of ICAM-1 and VCAM-1 expression might be important for regulation of leucocytes infiltration and retention in periodontally diseased tissue.

Role of Anti-Endothelial Cell Antibody in the Development of Coronary Arterial Lesions in Kawasaki Disease

Background and Objectives：Anti-endothelial cell antibodies (AECA) are found in the sera of many patients with Kawasaki disease (KD). In this study, the pathogenic role of AECA in the development of coronary arterial lesions of KD was investigated. Subjects and Methods：Serum IgM-AECA concentrations were measured in 22 KD patients. Cultured human coronary artery endothelial cells (HCAEC) were incubated with either acute or convalescent phase sera, and their expressions of intercellular adhesion molecule-1 (ICAM-1) assessed. IgM fractions of the sera were purified, and their ability to induce ICAM-1 mRNA and protein expressions evaluated. To address the signal transduction pathways involved in IgM-AECA-induced ICAM-1 expression, the blocking effect of four protein kinase inhibitors, PD98059, SB203580, dimethylaminopurine (DMAP) and parthenolide were measured. Results：IgM-AECA was present in 14 out of 22 (64%) acute KD sera. ICAM-1 expression of HCAEC incubated with acute KD sera (117.1±46.7) and AECA-positive acute KD sera (143.3±37.5) were significantly higher than those of the convalescent KD sera (88.9±14.4, p<0.05) or AECA-negative acute KD sera (71.2±11.8, p<0.05), respectively. IgM-AECA from KD patients significantly induced ICAM-1 protein and mRNA expression. The upregulation of ICAM-1 expression was significantly inhibited by SB203580, DMAP and parthenolide, but not by PD98059. Conclusion：IgM-AECA was detected in the sera of about 2/3 of acute KD patients, which activated endothelial cells by upregulation of ICAM-1 expression, possibly via p38, JNK MAPK and NF-κB signal transduction pathways. Thus, IgM-AECA may play a pathogenic role in the development of coronary arterial lesions in KD patients. (Korean Circulation J 2006;36:723-731)

Upregulation of ICAM-1 Expression in the Conjunctiva of Patients with Chronic Graft-Versus-Host Disease

To correlate conjunctival intercellular adhesion molecule 1 (ICAM-1) expression with cytologic and clinical findings of chronic graft-versus-host disease (GVHD). Seven patients with chronic GVHD-related keratoconjunctivitis and five age-matched normal controls were recruited for the study. Clinical examination included medical history, visual acuity, evaluation of ocular signs and symptoms (scored from 0 to 3), corneal fluorescein staining (scored from 0 to 5 on the basis of the number of corneal sectors involved), Schirmer test type I, and break-up time (BUT). Impression cytology samples were collected from the nasal and inferior bulbar conjunctiva of patients and controls. Goblet cells were counted in three randomly selected fields and averaged. Immunofluorescent staining for ICAM-1 was carried out and the percentage of cells expressing the marker was evaluated. All patients showed signs and symptoms of keratoconjunctivitis sicca. Schirmer test type I and BUT were reduced (4.8+/-6.7 mm/5 min and 3.9+/-2.7 seconds, respectively). Goblet cells were significantly reduced in GVHD eyes with respect to normal eyes (65+/-30.5 and 192+/-16.9 cells/field respectively; p<0.001). Goblet cell number was directly related to Schirmer test values (p<0.01, rho=0.817) and inversely related to total sign score (p<0.01, rho=-0.939). ICAM-1 expression was increased in GVHD eyes with respect to normal controls, in which no staining was observed. ICAM-1 expression showed an inverse relation to goblet cell number (p<0.01, rho=-0.852) and Schirmer test values (p<0.01, rho=-0.926), and was directly correlated to total sign score (p<0.01, rho=0.982). Conjunctival ICAM-1 expression is increased in GVHD patients. The severity of the disease is associated with tear parameters, goblet cell decrease, and inflammatory markers, such as ICAM-1.

Rebamipide Reduces Indomethacin-Induced Gastric Injury in Mice via Down-Regulation of ICAM-1 Expression

Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric mucosal injury occurs through subsequent events following free radical production derived from activated neutrophils. In this study, we hypothesized that rebamipide, a novel anti-ulcer agent, exerts a protective effect on NSAID-induced gastric injury through its antioxidant properties. The protective effect of rebamipide in a mouse model of indomethacin-induced gastric injury and mechanisms for this effect were investigated. Pre-treatment with rebamipide significantly inhibited indomethacin-induced gastric mucosal injury in mice. Gastric thiobarbituric acid reactive substances (TBARS) levels and myeloperoxidase (MPO) activity substantially increased 3 hr after indomethacin administration. These increases were significantly inhibited by pre-treatment with rebamipide. Furthermore, rebamipide pre-treatment notably decreased intercellular adhesion molecule-1 (ICAM-1) expression that was up-regulated in gastric tissue treated with indomethacin. Therefore, rebamipide may reduce indomethacin-induced gastric mucosal injuries through its antioxidant effect, which inhibits the neutrophil activation step following up-regulation of ICAM-1 expression on endothelial cells.

The relationship between the protective effect of amifostine and decreased intercellular adhesion molecule 1 expression

Purpose The objective of our study was to characterize the relationship between the protective effect of amifostine and decreased intercellular adhesion molecule 1 (ICAM-1) expression in early-phase, radiation-induced otitis media and to illustrate the possible mechanism of early-phase radiation-induced otitis media. Materials and methods A comparison study of middle ear tissue was performed by the expression of ICAM-1 and the electron microscope from total 38 guinea pigs. Group A, consisting of 2 pigs, was used as control, and these pigs were not irradiated. Groups B, C, D, and E, consisting of 9 pigs each, were irradiated. Sterile saline was administered intraperitoneally to the pigs in groups B and D before irradiation, and amifostine was administered intraperitoneally as an aqueous solution 30 minutes before irradiation to the pigs in groups C and E. The pigs in groups B and C were killed on the second day after irradiation, and the pigs in groups D and E were killed 30 days after irradiation. Results Intercellular adhesion molecule 1 was strongly expressed in the middle ear mucosa of the irradiated pigs after a 45-Gy dose of radiation was administered. Enhanced ICAM-1 expression was accompanied by pathomorphologic changes in the middle ear tissue. Scanning electron microscopy demonstrated the changes. Intercellular adhesion molecule 1 expression in the mucosa of the groups killed on the second day was stronger than that in the mucosa of the groups killed 30 days after irradiation. Amifostine protected the middle ear from radiation injury, and we found that the expression of ICAM-1 in the middle ear mucosa was down-regulated. However, slight expression of ICAM-1 remained 30 days after irradiation. Conclusions Irradiation increased the expression of ICAM-1 in the middle ear mucosa. Amifostine protected the middle ear from early irradiation injury. There was a relationship between oxygen free radicals derived from irradiation and up-regulation of ICAM-1 expression. Continuous ICAM-1 expression might be related to stenosis of the eustachian tube.