Induction Of Adhesion Molecules Research Articles

Epigenetic Regulation of Tumor Necrosis Factor Alpha

Tumor necrosis factor alpha (TNF-alpha) is a potent cytokine which regulates inflammation via the induction of adhesion molecules and chemokine expression. Its expression is known to be regulated in a complex manner with transcription, message turnover, message splicing, translation, and protein cleavage from the cell surface all being independently regulated. This study examined both cell lines and primary cells to understand the developmental regulation of epigenetic changes at the TNF-alpha locus. We demonstrate that epigenetic modifications of the TNF-alpha locus occur both developmentally and in response to acute stimulation and, importantly, that they actively regulate expression. DNA demethylates early in development, beginning with the hematopoietic stem cell. The TNF-alpha locus migrates from heterochromatin to euchromatin in a progressive fashion, reaching euchromatin slightly later in differentiation. Finally, histone modifications characteristic of a transcriptionally competent gene occur with myeloid differentiation and progress with differentiation. Additional histone modifications characteristic of active gene expression are acquired with stimulation. In each case, manipulation of these epigenetic variables altered the ability of the cell to express TNF-alpha. These studies demonstrate the importance of epigenetic regulation in the control of TNF-alpha expression. These findings may have relevance for inflammatory disorders in which TNF-alpha is overproduced.

Adhesion of peripheral blood mononuclear cells and CD4+ T cells from patients with psoriasis to cultured endothelial cells via the interaction between lymphocyte function-associated antigen type 1 and intercellular adhesion molecule 1

The adhesion of CD4+ T cells to endothelial cells and their subsequent migration to skin tissue are essential to develop the psoriatic skin lesion. However, few studies have examined the role of adhesion molecules in the binding of T cells from patients with chronic plaque psoriasis to endothelial cells in vitro; thus, the adhesion molecules responsible for the development of skin lesions are still unclear. To identify the responsible adhesion molecules in the interaction between CD4+ T cells in patients with chronic plaque psoriasis and cytokine-stimulated endothelial cells. An in vitro adhesion assay between Calcein-labelled peripheral blood mononuclear cells (PBMC) and cytokine-stimulated human endothelial cultures, which exhibit a higher adhesion capacity to PBMC, was established, and the adhesion-inhibitory effects of a panel of antiadhesion molecule antibodies on the adhesion of PBMC from patients with psoriasis to endothelial cells were examined. Then, the inhibitory effects of selected antibodies acting on the interaction between CD4+ T cells from patients with psoriasis (purified by negative magnetic cell sorting) and cultured endothelial cells were examined. A significant increase (P < 0.01) in the adhesion of psoriatic PBMC to both endothelial cultures, human skin microvascular endothelial cells from adults (HMVEC-Ad) and human coronary arterial endothelial cells (HCAEC), compared with healthy PBMC, was demonstrated in our in vitro cell adhesion assay. Pretreatment of both endothelial cultures with tumour necrosis factor (TNF)-alpha (1000 U mL(-1)) induced the most frequent adhesion of PBMC from patients with psoriasis among the three inflammatory cytokines examined, i.e. TNF-alpha, interleukin-1beta and interferon-gamma [TNF-alpha-treated vs. nontreated: P < 0.001 (in both HMVEC-Ad and HCAEC)]. In both endothelial cultures treated with TNF-alpha, PBMC from patients with psoriasis exhibited significantly more frequent adhesion compared with those from healthy individuals (P < 0.001). The TNF-alpha-stimulated HMVEC-Ad, which exhibited the most frequent adhesion of PBMC, were selected for adhesion-inhibition experiments using monoclonal antibodies (mAbs) to adhesion molecules that are upregulated in psoriatic lesions, and the combination of antilymphocyte function-associated antigen type 1 (LFA-1) and anti-intercellular adhesion molecule 1 (ICAM-1) mAbs gave the greatest reduction of adhesion of PBMC from patients with psoriasis (approximately 69% reduction; P < 0.01). This combination of mAbs significantly reduced also the adhesion of CD4+ T cells from patients with psoriasis to TNF-alpha-stimulated HMVEC-Ad (approximately 62% reduction), compared with pretreatment with isotype control mAbs (P < 0.01). These findings indicate that the LFA-1/ICAM-1 interaction plays a major role in the adhesion of CD4+ T cells to endothelial cells and that TNF-alpha might play an important role for the induction of adhesion molecules on endothelial cells at psoriatic skin lesions.

The angiogenic factor thymidine phosphorylase up‐regulates the cell adhesion molecule P‐selectin in human vascular endothelial cells and is associated with P‐selectin expression in breast cancers

Thymidine phosphorylase (TP) is an angiogenic enzyme, catalysing the reversible phosphorylation of thymidine to thymine and 2-deoxyribose. TP is up-regulated in neoplasia, being associated with advanced tumour stage, microvessel density and prognosis in several tumour types. Although TP is a non-mitogenic migratory factor for endothelium, the mechanism by which TP mediates these effects is still unclear. We compared the gene expression profile of endothelial cells grown in vitro in the presence or absence of TP by cDNA microarray analysis. To determine the time-course of TP angiogenic induction, endothelial cells were stimulated with TP (10 ng/ml) for 5 and 18 h. Gene expression levels of Tie2, angiopoietin (Ang)1 and Ang2, measured by RNase protection assay (RPA), showed maximal alteration at 18 h. cDNA from human umbilical vein endothelial cells (HUVEC) grown for 18 h in the presence or absence of TP (10 ng/ml) was hybridized to a human cDNA cytokine array representing 375 angiogenic genes. Significantly altered expression occurred in 89 human angiogenic genes (72 genes were up-regulated and 17 down-regulated). Changes in five genes relevant to vascular remodelling biology (Tie2, nNos, P-selectin, ephrin-B1 and TP) were validated in triplicate experiments by real-time RT-PCR. But only P-selectin gene expression remained significant. Correlation between P-selectin and TP was assessed by immunohistochemistry on 161 human breast cancers, using human tissue microarray. Tumour cell TP correlated with tumour cell P-selectin but not with endothelial cell P-selectin. These data show that TP stimulates changes in mRNA expression maximally after 18 h culture in vitro. It confirms a role for TP in vascular remodelling involving several classes of genes, including the cell adhesion molecule, P-selectin. Although confirmation of the role of TP-mediated cell adhesion molecule (CAM) induction is required; however, this pathway may provide an attractive therapeutic target, since it is likely to affect several important tumour processes, including angiogenesis and metastasis.

The Host Inflammatory Response Promotes Liver Metastasis by Increasing Tumor Cell Arrest and Extravasation

Inflammation can play a regulatory role in cancer progression and metastasis. Previously, we have shown that metastatic tumor cells entering the liver trigger a proinflammatory response involving Kupffer cell-mediated release of tumor necrosis factor-alpha and the up-regulation of vascular endothelial cell adhesion receptors, such as E-selectin. Here, we analyzed spatio-temporal aspects of the ensuing tumor-endothelial cell interaction using human colorectal carcinoma CX-1 and murine carcinoma H-59 cells and a combination of immunohistochemistry, confocal microscopy, and three-dimensional reconstruction. E-selectin expression was evident mainly on sinusoidal vessels by 6 and 10 hours, respectively, following H-59 and CX-1 inoculation, and this corresponded to a stabilization of the number of tumor cells within the sinuses. Tumor cells arrested in E-selectin(+) vessels and appeared to flatten and traverse the vessel lining, away from sites of intense E-selectin staining. This process was evident by 8 (H-59) and 12 (CX-1) hours after inoculation, coincided with increased endothelial vascular cell adhesion molecule-1 expression, and involved tumor cell attachment in areas of intense vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 expression. Nonmetastatic (human) MIP-101 and (murine) M-27 cells induced a weaker response and could not be seen to extravasate. The results show that metastatic tumor cells can alter the hepatic microvasculature and use newly expressed endothelial cell receptors to arrest and extravasate.

Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption

A nonpsychoactive cannabinoid cannabidiol (CBD) has been shown to exert potent anti-inflammatory and antioxidant effects and has recently been reported to lower the incidence of diabetes in nonobese diabetic mice and to preserve the blood-retinal barrier in experimental diabetes. In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-kappaB activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs). HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-kappaB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs. Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment. Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis.

Glutathione regulation of redox-sensitive signals in tumor necrosis factor-α-induced vascular endothelial dysfunction

We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-α)-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte–endothelial monolayer binding. Since TNF-α induces various biological effects on vascular cells, TNF-α dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-α concentrations, we adopted the lower TNF-α (0.2 ng/ml) to rule out the possible involvement of other TNF-α-induced biological effects. Inhibition of glutathione synthesis by l-buthionine-( S, R)-sulfoximine (BSO) resulted in down-regulations of the TNF-α-induced adhesion molecule expression and monocyte–endothelial monolayer binding. BSO attenuated the TNF-α-induced nuclear factor-kappaB (NF-κB) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-α. Inhibition of ERK, JNK, or NF-κB attenuates TNF-α-induced ICAM-1 promoter activation and monocyte–endothelial monolayer binding. Our study indicates that TNF-α induces adhesion molecule expression and monocyte–endothelial monolayer binding mainly via activation of NF-κB in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-α. Although AP-1 activation by the lower TNF-α was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-α-induced adhesion molecule expression.

Severe malaria in Cameroonian children: correlation between plasma levels of three soluble inducible adhesion molecules and TNF-α

Plasma levels of three soluble inducible adhesion molecules, namely: intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and endothelial leucocyte adhesion molecule-1 (sELAM-1) or sE-selectin and the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-α) were measured in well-defined clinical groups of children with severe and uncomplicated malaria. The goal of the study was to investigate the role of these molecules in immunopathogenic processes associated with severe malaria in Cameroonian children. Results showed significantly increased plasma concentrations of sICAM-1, sVCAM-1 and sE-selectin in children with severe malaria compared to those with uncomplicated malaria and healthy children ( P < 0.001). TNF-α levels increased significantly in children with severe malaria, approximately 2-folds compared to those with uncomplicated malaria and about 3-folds compared to healthy children ( P < 0.001). More importantly, levels of TNF-α strongly correlated with those of the three adhesion molecules and were significantly associated with increased risk of death ( P = 0.03). In addition, children who died from severe malaria showed higher mean levels of all measured factors compared to those who recovered, with significant differences observed with sICAM-1 ( P < 0.001) and sE-selectin ( P = 0.002). Furthermore, children with severe malarial anemia relative to those without, showed significantly elevated levels of the three soluble molecules; and sICAM-1 was significantly associated with increased risk of severe anemia. Taken together, these results confirm the role of TNF-α and the three adhesion molecules in pathogenic processes associated with severe malaria in children, and suggest an association between sICAM-1 and severe malarial anemia.

Carbamylated Low-Density Lipoprotein Induces Monocyte Adhesion to Endothelial Cells Through Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1

Carbamylated low-density lipoprotein (LDL), the most abundant modified LDL isoform in human blood, has been recently implicated in causing the atherosclerosis-prone injuries to endothelial cells in vitro and atherosclerosis in humans. This study was aimed at testing the hypothesis that carbamylated LDL acts via inducing monocyte adhesion to endothelial cells and determining the adhesion molecules responsible for the recruitment of monocytes. Exposure of human coronary artery endothelial cells with carbamylated LDL but not native LDL caused U937 monocyte adhesion and the induction of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 adhesion molecules as measured by cell enzyme-linked immunosorbent assay. Silencing of intercellular adhesion molecule-1 by siRNA or its inhibition using neutralizing antibody resulted in decreased monocyte adhesion to the endothelial cells. Similar silencing or neutralizing of vascular cell adhesion molecule-1 alone did not have an effect but was shown to contribute to intercellular adhesion molecule-1 when tested simultaneously. Taken together, these data provide evidence that intercellular adhesion molecule-1 in cooperation with vascular cell adhesion molecule-1 are essential for monocyte adhesion by carbamylated low-density lipoprotein-activated human vascular endothelial cells in vitro.

Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.

Resveratrol blunts tumor necrosis factor-α-induced monocyte adhesion and transmigration

The leukocyte recruitment and transmigration across the endothelial barrier into the vessel wall are crucial steps in atherosclerosis. Leukocyte trafficking on the endothelium is elicited by induction of endothelial adhesion molecules, and its transmigration is mediated by degradation of basement membrane proteins through enzymatic activity of matrix metalloproteinases (MMP). The current study investigated whether resveratrol, a polyphenol present in grapes and red wine, was capable of inhibiting leukocyte adhesion to tumor necrosis factor (TNF)-α-activated endothelium. It was found that resveratrol inhibited the TNF-α-activated endothelial expression of vascular cell adhesion molecule-1 in a dose-dependent manner. In addition, resveratrol hampered THP-1 monocyte adhesion to activated endothelial cells. This study further examined whether resveratrol interfered with transendothelial migration of leukocytes. The MMP-2 gelatinolytic activity of endothelial cells was enhanced by TNF-α, which was attenuated by an addition of ≥25 µM resveratrol. In addition, 25 µM resveratrol mitigated the MMP-9 activity of THP-1 cells, followed by a marked inhibition of transendothelial migration. These results demonstrated that resveratrol suppressed monocyte adhesion and migration induced by TNF-α through modulating expression of adhesion molecules and gelatinolytic activity of MMP. These findings suggest that dietary resveratrol may be therapeutic agent for inhibiting leukocyte recruitment into the subendothelium during inflammatory atherosclerosis.

Vasculoprotective Effects of Anti-Tumor Necrosis Factor-α Treatment in Aging

Vascular aging is associated with dysregulation of tumor necrosis factor (TNF)-alpha expression. TNF-alpha is a master regulator of vascular proatherogenic phenotypic changes, and it has been linked to endothelial dysfunction and apoptosis. To test the hypothesis that anti-TNF-alpha treatment exerts vasculoprotective effects in aging, aged (29 months old) F344 rats were treated with etanercept (1 mg/kg/week for 4 weeks), which binds and inactivates TNF-alpha. In aged carotid arteries, relaxations to acetylcholine were decreased, and endothelial O2* production was increased (as shown by dihydroethidine fluorescence measurements). Etanercept treatment significantly improved responses to acetylcholine and decreased vascular NAD(P)H oxidase activity and expression. In aged carotid and coronary arteries, there were increases in DNA fragmentation rate and caspase 3/7 activity (indicating an increased rate of apoptotic cell death), which were attenuated by etanercept treatment. In aged vessels, there was an up-regulation of inflammatory markers, including inducible nitric-oxide synthase and intercellular adhesion molecule-1, which was decreased by etanercept treatment. In carotid arteries of young animals, recombinant TNF-alpha elicited endothelial dysfunction, oxidative stress, and increased apoptosis and proinflammatory gene expression, mimicking many of the symptoms of vascular aging. Thus, we propose that anti-TNF-alpha treatment exerts anti-aging vasculoprotective effects.

CXCR4, a Key Modulator of Vascular Progenitor Cells

A growing body of evidence suggests that circulating progenitors participate in vascular healing and remodeling under physiological and pathological conditions (Figure).1–3 It is believed that the majority of vascular progenitor cells originate from the bone marrow. Stem cells within the bone marrow usually exist in a quiescent state. Specific signals stimulate the stem cells to differentiate and move to systemic circulation (Mobilization). Progenitors are recruited and stay at the site of vascular repair or neovascularization (Homing), where they differentiate into endothelial-like cells or smooth muscle–like cells (Differentiation) and proliferate (Proliferation). The molecular processes leading to their mobilization from the bone marrow and homing to the sites of vascular remodeling or neovascularization are not fully understood.4,5 In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology , two articles6,7 provide new insights into the essential role of CXCR4, the receptor for stromal cell–derived factor-1 (SDF-1) for the mobilization and the recruitment of bone marrow (BM)-derived cells. CXCR4 is notably expressed on hematopoietic stem cells and has previously been shown to play a key role in their homing and mobilization.8 Activation of this G protein–coupled 7-transmembrane receptor induces adhesion molecules on the hematopoietic progenitor/stem cell surface thereby enhancing their homing capacities9 and regulating their proliferation.10 Contribution of bone marrow–derived cells to neointima formation and angiogenesis. On severe vascular injury, bone marrow–derived cells are …

Vascular C-Reactive Protein in the Pathogenesis of Coronary Artery Disease:Role of Vascular Inflammation and Oxidative Stress

Atherosclerosis is considered to be a chronic inflammatory disease. Vascular inflammation occurs in response to injury induced by various stimuli, such as oxidative stress, shear stress, infection, and so on. This concept is supported by the recent clinical findings that C-reactive protein (CRP) is an independent risk factor for coronary heart disease. CRP, which was originally identified as a protein that could precipitate the C-polysaccharide of pneumococcal cell walls, has been widely used as a clinical marker of the state of inflammation, since its production by hepatocytes increases during the acute phase of the inflammatory response. Recent investigations have provided two new concepts for the research field of CRP, namely, its extra-hepatic production and its potent biological activities such as the induction of adhesion molecules and chemokines. Recently, we demonstrated that smooth muscle cells and macrophages in coronary arteries expressed CRP protein and mRNA, as evaluated using coronary specimens of coronary artery disease (CAD) patients obtained by atherectomy. The expression of vascular CRP was closely associated with NAD(P)H oxidase, an important enzymatic origin of reactive oxygen species (ROS) in vessel walls. Furthermore, CRP directly up-regulated NAD(P)H oxidase p22(phox) and enhanced ROS generation in cultured coronary artery smooth muscle cells. Thus, vascular CRP is likely to be a direct participant in vascular inflammation and lesion formation via its potent biological effects. Since lysophosphatidylcholine, a major atherogenic lipid of oxidized LDL, was reported to activate vascular NAD(P)H oxidase, we speculate that there is a vicious circle consisting of vascular NAD(P)H oxidase, ROS and oxidized LDL. Since phagocytic NAD(P)H oxidase is at the first line of the host defense system, it is important to selectively suppress vascular NAD(P)H oxidase in the localized inflammatory lesions in therapeutic strategies for CAD. In this review, we will discuss the roles of vascular CRP and NAD(P)H oxidase in the pathogenesis of CAD from the viewpoint of oxidative stress.

A Novel Role for Thrombin in Hematopoietic Stem/Progenitor Cell Homing.

Thrombin, an important serine protease, not only plays a pivotal role in platelet aggregation and coagulation, but also through activation of its receptor, seven transmembrane, G-protein-coupled receptor PAR-1, elicits numerous cellular responses in platelets and endothelial cells such as induction of adhesion molecules, production of chemokines, activation of matrix metalloproteinase (MMP)-2, cytoskeletal reorganization and migration. Thrombin is also one of the inflammatory molecules elevated during G-CSF mobilization of hematopoietic stem/progenitor cells (HSPC) and their collection by leukapheresis. We recently reported that components of leukapheresis products including thrombin enhance in vitro chemotaxis of CD34+ cells towards an SDF-1 gradient and in vivo homing to bone marrow (BM) niches in a murine model (Blood 2005; 105:40). In this study we investigated whether thrombin enhances the homing-related responses of human HSPC (CD34+ cells) through MMPs, especially membrane-type (MT)1-MMP which is known to be localized on the leading edge of migrating cells and both activates latent proMMPs (MMP-2, -9) and itself has strong pericellular proteolytic activity. We found that stimulation of CD34+ cells with thrombin upregulates mRNA for MT1-MMP and MMP-9 as well as MT1-MMP protein expression (Western blot, flow cytometry) and proMMP-2 and proMMP-9 secretion (zymography). Thrombin was also found to (i) prime trans-Matrigel chemoinvasion of CD34+ cells towards a low SDF-1 gradient (20 ng/mL), which was inhibited by epigallocatechin-3-gallate, a potent inhibitor of MT1-MMP, and (ii) activate MMP-2 in of co-cultures of CD34+ cells with stromal cells (BM fibroblasts and HUVEC) which secrete proMMP-2. We also found that SDF-1 upregulates mRNA and protein expression of MT1-MMP. Moreover, using confocal microscopy we demonstrate for the first time that in CD34+ cells, PAR-1, like CXCR4, is localized in the GM1 fraction of lipid rafts and stimulation of these cells with thrombin as well as SDF-1 increases incorporation of MT1-MMP into membrane lipid rafts. Furthermore, disruption of lipid raft formation by the cholesterol-depleting agent methyl-b-cyclodextrin inhibits MT1-MMP incorporation into membrane lipid rafts and also trans-Matrigel chemoinvasion of CD34+ cells towards SDF-1. Thus we conclude that thrombin, through PAR-1 signalling and the SDF-1-CXCR4 axis, upregulates the incorporation of MT1-MMP into membrane lipid rafts and the interaction of these axes enhances the homing-related responses of HSPC towards SDF-1.

The paradox of pro-inflammatory cytokines in cancer

Cytokines such as IL-1 and TNF are primarily pro-inflammatory. The inflammation induced by these cytokines is reflected in the type of genes they induce. In the pathogenesis of carcinogenesis as well as tumor growth and spread, cytokines such as IL-1 and TNF induce chemokines that attract neutrophils. Neutrophils are key players in the production of reactive oxygen species and carcinogenesis. Another aspect of pro-inflammatory cytokines is the induction of adhesion molecules and metalloproteinases, both of which provide mechanisms for tumor invasion. Blocking cytokines, however, will reduce tumor growth and spread if administered at sufficient concentrations and will require parenteral therapy. However, blocking cytokines will not kill tumor cells nor prevent carcinogenesis. Blocking cytokines is best as an adjunct therapy together with tumorocidal drugs.

Induction of adhesion molecules upon the interaction between eosinophils and bronchial epithelial cells: Involvement of p38 MAPK and NF-κB

Eosinophils are principal effector cells of inflammation in allergic asthma, characterized by their infiltration and accumulation at inflammatory sites mediated by chemokine eotaxin, and interaction with adhesion molecules expressed on bronchial epithelial cells. In this study, tumor necrosis factor (TNF)-α and/or the interaction of eosinophils and bronchial epithelial BEAS-2B cells were found to up-regulate the cell surface expression of adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 on BEAS-2B cells, and ICAM-1 and leukocyte function-associated antigen-1 (LFA-1) on eosinophils. Interaction of eosinophils and BEAS-2B cells could induce the release of granulocyte macrophage colony-stimulating factor (GM-CSF) and activate both p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activities in BEAS-2B cells but only NF-κB activity in eosinophils. Both proteasome inhibitor MG-132 and selective p38 MAPK inhibitor SB 203580 could significantly decrease the expression of ICAM-1 on BEAS-2B cells and CD18 on eosinophils upon co-culture with or without TNF-α treatment. However, the expression of VCAM-1 on BEAS-2B cells was only up-regulated by TNF-α-induced NF-κB activity. The interaction of eosinophils and bronchial epithelial cells therefore plays an important role in the up-regulation of adhesion molecules on eosinophils and epithelial cells via differential intracellular signalling pathways during allergic inflammation.

Induction of ICAM-1 and VCAM-1 adhesion molecules in endothelial cells by TNF receptor 1 through the NF-kB1 pathway

Induction of ICAM-1 and VCAM-1 adhesion molecules in endothelial cells by TNF receptor 1 through the NF-kB1 pathway

Vasculoprotective effects of angiotensin receptor blockers: beyond the renin–angiotensin–aldosterone system?

Vasculoprotective effects of angiotensin receptor blockers: beyond the renin–angiotensin–aldosterone system?

Postprandial hyperglycemia alters inflammatory and hemostatic parameters

Glucose or glucose derived products are increased in blood during the postprandial phase and are, to a certain extent, related to meal composition. Glucose and glucose derived products such as advanced glycation end products (AGEs) can be formed in the intracellular compartment but can also be absorbed as AGEs or AGE precursors present in food. Glucose, glucose metabolites and AGEs alter endothelial cell functions, induce adhesion molecule overexpression (ICAM-1, VCAM), cytokine release (IL-6, MCP-1) and tissue factor production. Tumor necrosis factor alpha systemic level is increased during the postprandial phase as are augmented C reactive protein and fibrinogen level. Hyperglycemia induced an increase in plasminogen activator inhibitor, and shortened fibrinogen half life. Hyperglycemia and AGEs provoked an oxidant stress. The formation of reactive oxygen intermediates perturbates NO (Nitric oxide) formation and are deleterious for cell functions. All the modifications observed in the postprandial phase are not too deleterious but their iterative characteristics may lead to vascular dysfunction.

Gefitinib-induced platelet-derived microparticle and ICAM-1 in Japanese patients with non-small cell lung cancer

17056 Background: We recently discovered that platelet activation is observed in patients receiving gefitinib. Nomura et al. reported that activated platelets generated platelet-derived microparticle (PDMP) and this PDMP could induce adhesion molecules and an interaction between white blood cells and endothelial cells. Theaim of the present study was to identify the clinical significance between PDMP and intercellular adhesion molecule-1 (ICAM-1) in lung cancer patients receiving gefitinib. Methods: Patients with a diagnosis of non-small cell lung cancer were entered into this study. Blood samples were withdrawn before and one week and two weeks after the administration of gefitinib. PDMP and ICAM-1 were measured using an enzyme-linked immunosorbent assay kit. A total of 25 patients was recruited in the study. The characteristics of the study subjects were: age: 42–78 years (median: 68 years); gender: male vs. female = 14 vs. 11; tumor histology: adenocarcinoma vs. squamous cell carcinoma = 17 vs. 8. Nine patients were responders and the other 16 patients were non-responders. Results: The plasma concentration of PDMP significantly increased after receiving gefitinib (before vs. one week vs. two weeks = 14.1±12.0 U vs. 17.9±16.9 U (p&lt;0.05) vs. 14.6±12.0 U n = 25). The plasma concentration of ICAM-1 significantly increased after receiving gefitinib (before vs. one week vs. two weeks = 296.2±85.1 ng/ml vs. 319.4±78.9 ng/ml vs. 344.8±74.0 ng/ml (p&lt;0.05) n = 16). Conclusions: Platelets were activated by gefitinib therapy, and the effect of gefitinib is related to a reaction of not only blocked EGFR but also platelet activation and in part endothelial cells and leukocytes through activated platelets. The mechanisms underlying some adverse events in gefitinib-treated patients are poorly understood. Our results suggest that one of the mechanisms causing gefitinib-related adverse effects depends on platelet activation. No significant financial relationships to disclose.