Intercellular Adhesion Molecule-1 Function Research Articles

Systematic pan-cancer analysis insights into ICAM1 as an immunological and prognostic biomarker.

Intercellular adhesion molecule 1 (ICAM1) is a cell surface adhesion glycoprotein in the immunoglobulin supergene family. It is associated with several epithelial tumorigenesis processes, as well as with inflammation. However, the function of ICAM1 in the prognosis of tumor immunity is still unclear. This study aimed to examine the immune function of ICAM1 in 33 tumor types and to investigate the prognostic value of tumors. Using datasets from the Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Cancer Cell Lines Encyclopedia (CCLE), Human Protein Atlas (HPA), and cBioPortal, we investigated the role of ICAM1 in tumors. We explored the potential correlation between ICAM1 expression and tumor prognosis, gene mutations, microsatellite instability, and tumor immune cell levels in various cancers. We observed that ICAM1 is highly expressed in multiple malignant tumors. Furthermore, ICAM1 is negatively or positively associated with different malignant tumor prognoses. The expression levels of ICAM1 were correlated with the tumor mutation burden (TMB) in 11 tumors and with MSI in eight tumors. ICAM1 is a gene associated with immune infiltrating cells, such as M1 macrophages and CD8+ T cells in gastric and colon cancer. Meanwhile, the expression of ICAM1 is associated with several immune-related functions and immune-regulation-related signaling pathways, such as the chemokine signaling pathway. Our study shows that ICAM1 can be used as a prognostic biomarker in many cancer types because of its function in tumorigenesis and malignant tumor immunity.

Dextran sulfate prevents excess aggregation of human pluripotent stem cells in 3D culture by inhibiting ICAM1 expression coupled with down-regulating E-cadherin through activating the Wnt signaling pathway

BackgroundHuman pluripotent stem cells (hPSCs) have great potential in applications for regenerative medicine and drug development. However, 3D suspension culture systems for clinical-grade hPSC large-scale production have been a major challenge. Accumulating evidence has demonstrated that the addition of dextran sulfate (DS) could prevent excessive adhesion of hPSCs from forming larger aggregates in 3D suspension culture. However, the signaling and molecular mechanisms underlying this phenomenon remain elusive.MethodsBy using a cell aggregate culture assay and separating big and small aggregates in suspension culture systems, the potential mechanism and downstream target genes of DS were investigated by mRNA sequence analysis, qRT-PCR validation, colony formation assay, and interference assay.ResultsSince cellular adhesion molecules (CAMs) play important roles in hPSC adhesion and aggregation, we assumed that DS might prevent excess adhesion through affecting the expression of CAMs in hPSCs. As expected, after DS treatment, we found that the expression of CAMs was significantly down-regulated, especially E-cadherin (E-cad) and intercellular adhesion molecule 1 (ICAM1), two highly expressed CAMs in hPSCs. The role of E-cad in the adhesion of hPSCs has been widely investigated, but the function of ICAM1 in hPSCs is hardly understood. In the present study, we demonstrated that ICAM1 exhibited the capacity to promote the adhesion in hPSCs, and this adhesion was suppressed by the treatment with DS. Furthermore, transcriptomic analysis of RNA-seq revealed that DS treatment up-regulated genes related to Wnt signaling resulting in the activation of Wnt signaling in which SLUG, TWIST, and MMP3/7 were highly expressed, and further inhibited the expression of E-cad.ConclusionOur results demonstrated that DS played an important role in controlling the size of hPSC aggregates in 3D suspension culture by inhibiting the expression of ICAM1 coupled with the down-regulation of E-cad through the activation of the Wnt signaling pathway. These results represent a significant step toward developing the expansion of hPSCs under 3D suspension condition in large-scale cultures.

The Effects of Fibrinogen's Interactions with Its Neuronal Receptors, Intercellular Adhesion Molecule-1 and Cellular Prion Protein.

Neuroinflammatory diseases, such as Alzheimer’s disease (AD) and traumatic brain injury (TBI), are associated with the extravascular deposition of the fibrinogen (Fg) derivative fibrin and are accompanied with memory impairment. We found that during the hyperfibrinogenemia that typically occurs during AD and TBI, extravasated Fg was associated with amyloid beta and astrocytic cellular prion protein (PrPC). These effects coincided with short-term memory (STM) reduction and neurodegeneration. However, the mechanisms of a direct Fg–neuron interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain neurons were treated with Fg in the presence or absence of function-blockers of its receptors, PrPC or intercellular adhesion molecule-1 (ICAM-1). Associations of Fg with neuronal PrPC and ICAM-1 were characterized. The expression of proinflammatory marker interleukin 6 (IL-6) and the generation of reactive oxygen species (ROS), mitochondrial superoxide, and nitrite in neurons were assessed. Fg-induced neuronal death was also evaluated. A strong association of Fg with neuronal PrPC and ICAM-1, accompanied with overexpression of IL-6 and enhanced generation of ROS, mitochondrial superoxide, and nitrite as well as the resulting neuronal death, was found. These effects were reduced by blocking the function of neuronal PrPC and ICAM-1, suggesting that the direct interaction of Fg with its neuronal receptors can induce overexpression of IL-6 and increase the generation of ROS, nitrite, and mitochondrial superoxide, ultimately leading to neuronal death. These effects can be a mechanism of neurodegeneration and the resultant memory reduction seen during TBI and AD.

Fibrinogen Interaction with Astrocyte ICAM-1 and PrPC Results in the Generation of ROS and Neuronal Death

Many neuroinflammatory diseases, like traumatic brain injury (TBI), are associated with an elevated level of fibrinogen and short-term memory (STM) impairment. We found that during TBI, extravasated fibrinogen deposited in vasculo-astrocyte interfaces, which was associated with neurodegeneration and STM reduction. The mechanisms of this fibrinogen-astrocyte interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain astrocytes were treated with fibrinogen in the presence or absence of function-blocking antibody or peptide against its astrocyte receptors intercellular adhesion molecule-1 (ICAM-1) or cellular prion protein (PrPC), respectively. Fibrinogen interactions with astrocytic ICAM-1 and PrPC were characterized. The expression of pro-inflammatory markers, generations of reactive oxygen species (ROS) and nitric oxide (NO) in astrocytes, and neuronal death caused by astrocyte-conditioned medium were assessed. Data showed a strong association between fibrinogen and astrocytic ICAM-1 or PrPC, overexpression of pro-inflammatory cytokines and overproduction of ROS and NO, resulting in neuronal apoptosis and death. These effects were reduced by blocking the function of astrocytic ICAM-1 and PrPC, suggesting that fibrinogen association with its astrocytic receptors induce the release of pro-inflammatory cytokines, resulting in oxidative stress, and ultimately neuronal death. This can be a mechanism of neurodegeneration and the resultant STM reduction seen during TBI.

Biological function of intercellular adhesion molecule-1 gene in coronary heart disease and its mediated primary regulatory network: a literature based secondary analysis

To explore the biological function of intercellular adhesion molecule-1 (ICAM-1) gene in coronary heart disease (CHD) and to establish a primary regulatory network mediated by ICAM-1 gene. The databases were searched from January 1st 2006 to December 31st 2018, including Wanfang, CNKI, VIP, Google scholar and PubMed databases for published researches on clinical study of CHD gene ICAM-1. The experimental group was CHD patients, and the control group was healthy people. Meta-analysis was employed to analyze the relationship between ICAM-1 gene and CHD. Gene Ontology (GO) and KEGG Pathway database were employed to conduct function annotation and pathway analysis. A total of 8 papers were enrolled into this analysis, Meta-analysis showed that the level of ICAM-1 in the experimental group was significantly higher than that in the control group [mean difference (MD) = 15.29, 95% confidence interval (95%CI) = 10.95-19.62, P < 0.000 01], surface ICAM-1 was significantly related with CHD. The GO analysis results showed that ICAM-1 molecular function mainly involved virus receptor activity, receptor activity, transmembrane signal receptor activity, protein binding, etc.; cell components mainly involve plasma membrane integral components, immune synapses, plasma membrane, etc.; biological processes mainly involve the positive regulation of cell adhesion, leukocyte adhesion, leukocyte migration and leukocyte adhesion, etc. A primary CHD regulatory network mediated by ICAM-1 gene was established based on KEGG Pathway database, and ICAM-1 was mainly expressed in endothelial cells, and further regulated the occurrence and development of CHD by promoting the proliferation of leukocytes. ICAM-1 may regulate the occurrence and development of CHD by regulating the related biological processes of leukocytes. The successful establishment of the ICAM-1 mediated CHD regulatory network can lay a theoretical foundation for further exploring the specific regulatory role of ICAM-1 and other related genes in CHD occurrence.

Hyperfibrinogenemia-mediated astrocyte activation

Fibrinogen (Fg)-containing plaques are associated with memory loss during various inflammatory neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, stroke, and traumatic brain injury. However, mechanisms of its action in neurovascular unit are not clear. As Fg is a high molecular weight blood protein and cannot translocate far from the vessel after extravasation, we hypothesized that it may interact with astrocytes first causing their activation. Cultured mouse cortical astrocytes were treated with Fg in the presence or absence of function-blocking anti-mouse intercellular adhesion molecule 1 (ICAM-1) antibody, or with medium alone (control). Expressions of ICAM-1 and tyrosine receptor kinase B (TrkB) as markers of astrocyte activation, and phosphorylation of TrkB (pTrkB) were assessed. Fg dose-dependently increased activation of astrocytes defined by their shape change, retraction of processes, and enhanced expressions of ICAM-1 and TrkB, and increased pTrkB. Blocking of ICAM-1 function ameliorated these Fg effects. Data suggest that Fg interacts with astrocytes causing overexpression of ICAM-1 and TrkB, and TrkB phosphorylation, and thus, astrocyte activation. Since TrkB is known to be involved in neurodegeneration, interaction of Fg with astrocytes and the resultant activation of TrkB can be a possible mechanism involved in memory reduction, which were observed in previous studies and were associated with formation of complexes of Fg deposited in extravascular space with proteins such as Amyloid beta or prion, the proteins involved in development of dementia.

Immunological Properties of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells.

SummaryAge-related macular degeneration is caused by dysfunction and loss of retinal pigment epithelium (RPE) cells, and their transplantation may rescue visual functions and delay disease progression. Human embryonic stem cells (hESCs) may be an unlimited source of RPE cells for allotransplantation. We analyzed the immunomodulatory properties of hESC-derived RPE (hESC-RPE) cells, and showed that they inhibited T cell responses. Co-culture experiments showed that RPE cells inhibited interfon-γ secretion and proliferation of activated T cells. Furthermore, hESC-RPE cells enhanced T cell apoptosis and secretion of the anti-inflammatory cytokine interleukin-10 (IL-10). In addition, RPE cells altered the expression of T cell activation markers, CD69 and CD25. RPE cells transplanted into RCS rats without immunosuppression survived, provided retinal rescue, and enhanced IL-10 blood levels. Our data suggest that hESC-RPE cells have immunosuppressive properties. Further studies will determine if these properties are sufficient to alleviate the need for immunosuppression therapy after their clinical allotransplantation.

Endothelial CD2AP Binds the Receptor ICAM-1 To Control Mechanosignaling, Leukocyte Adhesion, and the Route of Leukocyte Diapedesis In Vitro.

Inflammation is driven by excessive transmigration (diapedesis) of leukocytes from the blood to the tissue across the endothelial cell monolayer that lines blood vessels. Leukocyte adhesion, crawling, and transmigration are regulated by clustering of the endothelial mechanosensitive receptor intercellular adhesion molecule-1 (ICAM-1). Whereas several proteins are known to promote ICAM-1 function, the molecular mechanisms that limit ICAM-1-mediated adhesion to prevent excessive leukocyte transmigration remain unknown. We identify the endothelial actin-binding protein CD2-associated protein (CD2AP) as a novel interaction partner of ICAM-1. Loss of CD2AP stimulates the dynamics of ICAM-1 clustering, which facilitates the formation of ICAM-1 complexes on the endothelial cell surface. Consequently, neutrophil adhesion is increased, but crawling is decreased. In turn, this promotes the neutrophil preference for the transcellular over the paracellular transmigration route. Mechanistically, CD2AP is required for mechanosensitive ICAM-1 downstream signaling toward activation of the PI3K, and recruitment of F-actin and of the actin-branching protein cortactin. Moreover, CD2AP is necessary for ICAM-1-induced Rac1 recruitment and activation. Mechanical force applied on ICAM-1 impairs CD2AP binding to ICAM-1, suggesting that a tension-induced negative feedback loop promotes ICAM-1-mediated neutrophil crawling and paracellular transmigration. To our knowledge, these data show for the first time that the mechanoreceptor ICAM-1 is negatively regulated by an actin-binding adaptor protein, i.e., CD2AP, to allow a balanced and spatiotemporal control of its adhesive function. CD2AP is important in kidney dysfunction that is accompanied by inflammation. Our findings provide a mechanistic basis for the role of CD2AP in inflamed vessels, identifying this adaptor protein as a potential therapeutic target.

Acid Sphingomyelinase-Derived Ceramide Regulates ICAM-1 Function during T Cell Transmigration across Brain Endothelial Cells.

Multiple sclerosis (MS) is a chronic demyelinating disorder of the CNS characterized by immune cell infiltration across the brain vasculature into the brain, a process not yet fully understood. We previously demonstrated that the sphingolipid metabolism is altered in MS lesions. In particular, acid sphingomyelinase (ASM), a critical enzyme in the production of the bioactive lipid ceramide, is involved in the pathogenesis of MS; however, its role in the brain vasculature remains unknown. Transmigration of T lymphocytes is highly dependent on adhesion molecules in the vasculature such as intercellular adhesion molecule-1 (ICAM-1). In this article, we hypothesize that ASM controls T cell migration by regulating ICAM-1 function. To study the role of endothelial ASM in transmigration, we generated brain endothelial cells lacking ASM activity using a lentiviral shRNA approach. Interestingly, although ICAM-1 expression was increased in cells lacking ASM activity, we measured a significant decrease in T lymphocyte adhesion and consequently transmigration both in static and under flow conditions. As an underlying mechanism, we revealed that upon lack of endothelial ASM activity, the phosphorylation of ezrin was perturbed as well as the interaction between filamin and ICAM-1 upon ICAM-1 clustering. Functionally this resulted in reduced microvilli formation and impaired transendothelial migration of T cells. In conclusion, in this article, we show that ASM coordinates ICAM-1 function in brain endothelial cells by regulating its interaction with filamin and phosphorylation of ezrin. The understanding of these underlying mechanisms of T lymphocyte transmigration is of great value to develop new strategies against MS lesion formation.

Intercellular Adhesion Molecule-1 Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells and Impairs Bio-Scaffold-Mediated Bone RegenerationIn Vivo

Mesenchymal stem cell (MSC) loaded bio-scaffold transplantation is a promising therapeutic approach for bone regeneration and repair. However, growing evidence shows that pro-inflammatory mediators from injured tissues suppress osteogenic differentiation and impair bone formation. To improve MSC-based bone regeneration, it is important to understand the mechanism of inflammation mediated osteogenic suppression. In the present study, we found that synovial fluid from rheumatoid arthritis patients and pro-inflammatory cytokines including interleukin-1α, interleukin-1β, and tumor necrosis factor α, stimulated intercellular adhesion molecule-1(ICAM-1) expression and impaired osteogenic differentiation of MSCs. Interestingly, overexpression of ICAM-1 in MSCs using a genetic approach also inhibited osteogenesis. In contrast, ICAM-1 knockdown significantly reversed the osteogenic suppression. In addition, after transplanting a traceable MSC-poly(lactic-co-glycolic acid) construct in rat calvarial defects, we found that ICAM-1 suppressed MSC osteogenic differentiation and matrix mineralization in vivo. Mechanistically, we found that ICAM-1 enhances MSC proliferation but causes stem cell marker loss. Furthermore, overexpression of ICAM-1 stably activated the MAPK and NF-κB pathways but suppressed the PI3K/AKT pathway in MSCs. More importantly, specific inhibition of the ERK/MAPK and NF-κB pathways or activation of the PI3K/AKT pathway partially rescued osteogenic differentiation, while inhibition of the p38/MAPK and PI3K/AKT pathway caused more serious osteogenic suppression. In summary, our findings reveal a novel function of ICAM-1 in osteogenesis and suggest a new molecular target to improve bone regeneration and repair in inflammatory microenvironments.

Effects of continuous sedation with propofol on peripheral blood mononuclear cell and intercellular adhesion molecule in beagles with combined burn-blast injuries

To observe the effects of continuous sedation with propofol on peripheral blood mononuclear cell (PBMC) and intercellular adhesion molecule 1 (ICAM-1) in beagles with combined burn-blast injuries. A total of 32 male beagles were randomly divided into 4 groups of normal control (NC), combined injury control (CC), propofol 1 (P1) and propofol 2 (P2) (n = 8 each). Except for NC group, the other 3 groups were subject to severe combined burn-blast injury. And sodium lactate Ringer's solution was infused after trauma according to the Parkland formula, including NC group. At the same time, P1 and P2 groups received continuous intravenous infusions of 2 mg×kg(-1)×h(-1), 5 mg×kg(-1)×h(-1) doses of propofol respectively for 72 hours. The serum concentrations of ICAM-1 and lymphocyte function associated antigen-1 (LFA-1) were measured by enzyme-linked immunosorbent assay (ELISA) at 6, 24, 48, 72 h post-injury. Flow cytometry was used to detect the major histocompatibility complex (MHC) antigen expression on CD14(+) monocytes, CD4(+)/CD8(+) T lymphocyte rate and PBMC apoptosis rate. The level of ICAM-1 in CC group ((10.5 ± 1.1), (10.8 ± 1.3), (12.3 ± 1.4) ng/ml) was significantly higher than that in NC group ((7.4 ± 1.4), (7.4 ± 1.1), (7.4 ± 1.6) ng/ml) at 12, 24, 48 h post-injury (all P < 0.05). The level of ICAM-1 in P1 group was significantly lower than that in CC group ((10.7 ± 1.3) vs (12.3 ± 1.4) ng/ml) while the level of ICAM-1 in P2 group was significantly lower than that in P1 group at 72 h post-injury ((8.8 ± 1.4) vs (10.7 ± 1.3) ng/ml) (both P < 0.05). The level of LFA-1 in CC group ((7.3 ± 1.3), (8.4 ± 1.3), (9.6 ± 1.7) ng/ml) was significantly higher than that in NC group ((5.1 ± 1.2), (5.4 ± 1.3), (5.8 ± 1.2) ng/ml) at 24, 48, 72 h post-injury (all P < 0.05). MHC antigen expression on the CD14(+) monocytes of P2 group was obviously higher than that of CC and P1 groups ((46 ± 13)% vs (26 ± 15)% and (32 ± 12)%, both P < 0.05). The CD4/CD8 rate in P1 and P2 was significantly higher than that in CC group (1.71 ± 0.26, 1.82 ± 0.31 and 1.81 ± 0.24, 1.96 ± 0.24 vs 1.41 ± 0.34, 1.34 ± 0.26) at 48, 72 h post-injury (all P < 0.05). At 72 h post injury, the PBMC apoptosis rate in CC and P1 group was obviously higher than that of the NC group ((2.57 ± 0.21)% and (1.64 ± 0.10)% vs (0.81 ± 0.11)%) (both P < 0.01); the apoptosis rate in P2 group was significantly lower than that in P1 group ((1.09 ± 0.15)% vs (1.64 ± 0.10)%) (P < 0.01). Propofol may improve the immune function after combined burn-blast injuries through suppressing an excessive release of ICAM-1 and PBMC apoptosis in a concentration-dependent manner.

Role of ICAM-1 polymorphisms (G241R, K469E) in mediating its single-molecule binding ability: Atomic force microscopy measurements on living cells

Atherosclerosis (As) is characterized by chronic inflammation and is a major cause of human mortality. ICAM-1-mediated adhesion of leukocytes in vessel walls plays an important role in the pathogenesis of atherosclerosis. Two single nucleotide polymorphisms (SNPs) of human intercellular adhesion molecule-1 (ICAM-1), G241R and K469E, are associated with a number of inflammatory diseases. SNP induced changes in ICAM-1 function rely not only on the expression level but also on the single-molecule binding ability which may be affected by single molecule conformation variations such as protein splicing and folding. Previous studies have shown associations between G241R/K469E polymorphisms and ICAM-1 gene expression. Nevertheless, few studies have been done that focus on the single-molecule forces of the above SNPs and their ligands.In the current study, we evaluated both single molecule binding ability and expression level of 4 ICAM-1 mutations – GK (G241/K469), GE (G241/E469), RK (R241/K469) and RE (R241/E469). No difference in adhesion ability was observed via cell adhesion assay or atomic force microscopy (AFM) measurement when comparing the GK, GE, RK, or RE genotypes of ICAM-1 to each other. On the other hand, flow cytometry suggested that there was significantly higher expression of GE genotype of ICAM-1 on transfected CHO cells. Thus, we concluded that genetic susceptibility to diseases related to ICAM-1 polymorphisms, G241R or K469E, might be due to the different expressions of ICAM-1 variants rather than to the single-molecule binding ability of ICAM-1.

Actin-binding proteins differentially regulate endothelial cell stiffness, ICAM-1 function and neutrophil transmigration.

Chronic vascular inflammation is driven by interactions between activated leukocytes and the endothelium. Leukocyte β2-integrins bind to endothelial intercellular adhesion molecule 1 (ICAM-1), which allows leukocyte spreading, crawling and transendothelial migration. Leukocytes scan the vascular endothelium for permissive sites to transmigrate, which suggests that there is apical membrane heterogeneity within the endothelium. However, the molecular basis for this heterogeneity is unknown. Leukocyte adhesion induces ICAM-1 clustering, which promotes its association to the actin-binding proteins filamin B, α-actinin-4 and cortactin. We show that these endothelial proteins differentially control adhesion, spreading and transmigration of neutrophils. Loss of filamin B, α-actinin-4 and cortactin revealed adaptor-specific effects on a nuclear-to-peripheral gradient of endothelial cell stiffness. By contrast, increasing endothelial cell stiffness stimulates ICAM-1 function. We identify endothelial α-actinin-4 as a key regulator of endothelial cell stiffness and of ICAM-1-mediated neutrophil transmigration. Finally, we found that the endothelial lining of human and murine atherosclerotic plaques shows elevated levels of α-actinin-4. These results identify endothelial cell stiffness as an important regulator of endothelial surface heterogeneity and of ICAM-1 function, which in turn controls the adhesion and transmigration of neutrophils.

Silibinin inhibits ICAM-1 expression via regulation of N-linked and O-linked glycosylation in ARPE-19 cells.

To evaluate the effects of silibinin on intercellular adhesion molecule-1 (ICAM-1) expression, we used ARPE-19 cells as a model in which tumor necrosis factor (TNF-α) and interferon (IFN-γ) enhanced ICAM-1 expression. This upregulation was inhibited by silibinin. In an adherence assay using ARPE-19 and THP-1 cells, silibinin inhibited the cell adhesion function of ICAM-1. The inhibitory effects of silibinin on ICAM-1 expression were mediated via the blockage of nuclear translocation of p65 proteins in TNF-α and phosphorylation of STAT1 in IFN-γ-stimulated cells. In addition, silibinin altered the degree of N-linked glycosylation posttranslationally in ARPE-19 cells by significantly enhancing MGAT3 gene expression. Silibinin can increase the O-GlcNAc levels of glycoproteins in ARPE-19 cells. In a reporter gene assay, PUGNAc, which can also increase O-GlcNAc levels, inhibited NF-κB reporter activity in TNF-α-induced ARPE-19 cells and this process was augmented by silibinin treatment. Overexpression of OGT gene was associated with reduced TNF-α-induced ICAM-1 levels, which is consistent with that induced by silibinin treatment. Taken together, silibinin inhibits ICAM-1 expression and its function through altered O-linked glycosylation in NF-κB and STAT1 signaling pathways and decreases the N-linked glycosylation of ICAM-1 transmembrane protein in proinflammatory cytokine-stimulated ARPE-19 cells.

Glucosamine Modulates TNF-α–Induced ICAM-1 Expression and Function Through O-Linked and N-Linked Glycosylation in Human Retinal Pigment Epithelial Cells

The purpose of this article was to investigate the effects of glucosamine (GlcN) on the TNF-α-induced expression of intercellular adhesion molecule 1 (ICAM-1) and the function of ICAM-1 in ARPE-19 cells in vitro. We quantified protein levels of TNF-α-induced ICAM-1 in ARPE-19 cells with Western blotting. The effects of GlcN on O-linked glycosylation, and therefore on ICAM-1 expression, were compared after the addition of alloxan, an inhibitor of O-linked N-acetylglucosamine transferase (OGT), or O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), an inhibitor of N-acetylglucosaminidase (O-GlcNAcase [OGA]), or after OGT gene overexpression. The effect of GlcN on the N-linked glycosylation of ICAM-1 was evaluated by the change in its molecular mass on Western blotting. The effect of O-linked glycosylation on the nuclear factor κB (NF-κB) signaling pathway was examined using an NF-κB reporter gene assay. The effect of GlcN on ICAM-1 adhesion activity was examined using an ICAM-1 adhesion assay. GlcN, PUGNAc, and OGT overexpression inhibited TNF-α-induced ICAM-1 expression and NF-κB activity in ARPE-19 cells. Alloxan increased ICAM-1 expression and NF-κB activity in TNF-α-induced ARPE-19 cells. GlcN and tunicamycin reduced the molecular mass of TNF-α-induced ICAM-1 in ARPE-19 cells. The proteasome inhibitor MG-132 suppressed the GlcN-induced reduction in the molecular mass of TNF-α-induced ICAM-1. GlcN also attenuated the adhesion activity of TNF-α-induced ICAM-1. GlcN inhibits ICAM-1 expression and functions by modulating the O-linked glycosylation of factors involved in NF-κB signaling and by reducing the N-linked glycosylation of TNF-α-induced ICAM-1 in ARPE-19 cells. These effects may contribute to the GlcN-mediated anti-inflammatory effects in the eye.

ICAM-1 K469E polymorphism is a genetic determinant for the clinical risk factors of T2D subjects with retinopathy in Indians: a population-based case–control study

ObjectiveElevated levels of intercellular adhesion molecule-1 (ICAM-1) are demonstrated in diabetes complications. The current study aims to understand association of K469E (rs5498) in ICAM-1 gene, in type 2 diabetic (T2D)...

Intercellular adhesion molecule‐1 (ICAM‐1) in ulcerative colitis: presence, visualization, and significance

The intensive research of recent years has suggested that the cause of ulcerative colitis (UC) involves a genetic predisposition to an uncontrolled or unbalanced immune response to luminal or epithelial antigens or against other external factors. Intercellular adhesion molecule-1 (ICAM-1) is pivotal for the influx of neutrophil granulocytes into colonic mucosa, and gene analyses have found polymorphisms in the gene encoding ICAM-1, indicating that changes in ICAM-1 function may be involved in the pathogenesis of UC. Clinical trials of the ICAM-1 antisense oligonucleotide Alicaforsen, which inhibits the synthesis of ICAM-1, have shown positive results in the treatment of patients with left-sided (distal) UC. In addition to emphasizing the central role of ICAM-1 in active stages of UC, the results provide hope for the development and introduction of a more specific and efficient treatment for UC than those currently available. This review discusses the results from studies on the expression of ICAM-1 in colonic tissue from patients with UC.

Tumor-derived intercellular adhesion molecule-1 mediates tumor-associated leukocyte infiltration in orthotopic pancreatic xenografts

Tumor infiltration of immune cells (polymorphonuclear cells [PMNs] and macrophages) was initially thought to be an attempt by the host organism to combat malignancy. It appears, however, that certain subsets of chronically activated immune cells likely promote tumor growth, facilitate tumor cell survival and aid in metastasis. The association between tumor cells and tumor-associated PMNs has been demonstrated in several types of cancer, but the presence of tumor-associated PMNs in pancreatic cancer has not been well studied in vivo. Intercellular adhesion molecule-1 (ICAM-1) functions in cell-cell and cell-extracellular matrix adhesion and has a physiological role in PMN tight adhesion of leukocytes via interaction with the ligands LFA-1 and Mac-1. Increased ICAM-1 expression correlates with poor prognosis in pancreatic cancer. Therefore, the aim of this study was to investigate the function of ICAM-1 and tumor-associated PMNs in pancreatic cancer progression using ICAM-1-null (ICAM-1(-/-)) mice. We hypothesize that ICAM-1 null mice have decreased pancreatic cancer progression. Surprisingly, there is no significant difference in pancreatic cancer progression in wild-type versus ICAM-1 null mice. Interestingly, we found that tumor-derived ICAM-1 co-localizes with host PMNs at the leading edge of the tumor in ICAM-1 null mice. These results suggest that tumor-derived ICAM-1 is a sufficient ligand for tumor-associated PMNs and may play a role in subsequent tumor growth and metastasis.

Intercellular adhesion molecule-1 (ICAM-1) in ulcerative colitis: Presence, visualization, and significance

The intensive research of recent years has suggested that the cause of ulcerative colitis (UC) involves a genetic predisposition to an uncontrolled or unbalanced immune response to luminal or epithelial antigens or against other external factors. Intercellular adhesion molecule-1 (ICAM-1) is pivotal for the influx of neutrophil granulocytes into colonic mucosa, and gene analyses have found polymorphisms in the gene encoding ICAM-1, indicating that changes in ICAM-1 function may be involved in the pathogenesis of UC. Clinical trials of the ICAM-1 antisense oligonucleotide Alicaforsen, which inhibits the synthesis of ICAM-1, have shown positive results in the treatment of patients with left-sided (distal) UC. In addition to emphasizing the central role of ICAM-1 in active stages of UC, the results provide hope for the development and introduction of a more specific and efficient treatment for UC than those currently available. This review discusses the results from studies on the expression of ICAM-1 in colonic tissue from patients with UC.

Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation

AbstractTetraspanins associate with several transmembrane proteins forming microdomains involved in intercellular adhesion and migration. Here, we show that endothelial tetraspanins relocalize to the contact site with transmigrating leukocytes and associate laterally with both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Alteration of endothelial tetraspanin microdomains by CD9–large extracellular loop (LEL)–glutathione S–transferase (GST) peptides or CD9/CD151 siRNA oligonucleotides interfered with ICAM-1 and VCAM-1 function, preventing lymphocyte transendothelial migration and increasing lymphocyte detachment under shear flow. Heterotypic intercellular adhesion mediated by VCAM-1 or ICAM-1 was augmented when expressed exogenously in the appropriate tetraspanin environment. Therefore, tetraspanin microdomains have a crucial role in the proper adhesive function of ICAM-1 and VCAM-1 during leukocyte adhesion and transendothelial migration.