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Biomedical subjects

A Ariel

Publications and source records attributed to A Ariel.

12 recordsLinked to original sources
PubMed2001

Cell surface-expressed moesin-like receptor regulates T cell interactions with tissue components and binds an adhesion-modulating IL-2 peptide generated by elastase.

The adhesion of leukocytes to the extracellular matrix (ECM) depends on their responses to variations in the chemotactic signals in their milieu, as well as on the functioning of cytoskeletal and context-specific receptors. Ezrin, radixin, and moesin constitute a family of proteins that link the plasma membrane to the actin cytoskeleton. The surface expression of moesin on T cells and its role in cell adhesion has not been fully elucidated. Recently, we found that IL-2 peptides generated by elastase modified the adhesion of activated T cells to ECM ligands. Here, we further examined the adhesion regulatory effects of EFLNRWIT, one of the IL-2 peptides, as well as the existence and putative function of its receptor on T cells. We found that when presented to T cells in the absence of another activator, the EFLNRWIT peptide induced cell adhesion to vessel wall and ECM components. Binding of a radiolabeled peptide to T cells, precipitation with the immobilized peptide, and amino acid sequencing of the precipitated protein revealed that EFLNRWIT exerts its function via a cell surface-expressed moesin-like moiety, whose constitutive expression on T cells was increased after activation. This notion was further supported by our findings that: 1) anti-moesin mAb inhibited the binding of T cells to the immobilized EFLNRWIT peptide, 2) immobilized recombinant moesin bound the IL-2 peptide, and 3) soluble moesin inhibited the EFLNRWIT-induced T cell adhesion to fibronectin. Interestingly, moesin appears to be generally involved in T cell responses to adhesion-regulating signals. Thus, the IL-2 peptide EFLNRWIT appears to exert its modulating capacities via an adhesion-regulating moesin-like receptor.

Adjuvants, Immunologic↗
PubMed2001

Disaccharides derived from heparin or heparan sulfate regulate IL-8 and IL-1 beta secretion by intestinal epithelial cells.

BACKGROUND & AIMS: Intestinal epithelial cells can produce cytokines and chemokines that play an important role in the mucosal immune response. Regulation of this secretion is important to prevent inflammatory tissue damage. Disaccharides derived from heparan sulfate and heparin have been shown to down-regulate inflammation in vivo. We tested the effect of such disaccharides on cytokine secretion by intestinal epithelial cells. METHODS: Spontaneous and tumor necrosis factor (TNF)-alpha-stimulated interleukin (IL)-8 and IL-1 beta secretion and mRNA expression were assessed in HT-29 and Caco-2 intestinal epithelial cell lines in the presence of a panel of heparin and heparan sulfate disaccharides. RESULTS: Specific disaccharides suppressed spontaneous and TNF-alpha-induced mediator secretion in a dose-dependent manner. Disaccharide activity was structurally restricted. Preincubation of cells with nonsuppressing disaccharides blocked the activity of suppressing disaccharides. The number of sulfate moieties determined the ability of nonsuppressing disaccharides to block the effect of suppressive disaccharides. No suppression of mRNA expression was noted, and intracellular mediator levels were not reduced. CONCLUSIONS: Disaccharides derived from heparin and heparan sulfate regulate proinflammatory mediator secretion from intestinal epithelial cells. Dose dependence and competition by structurally diverging disaccharides suggest a receptor-mediated mechanism. Unchanged mRNA and intracellular mediator levels suggest that the disaccharides act at posttranscriptional stages.

Adjuvants, Immunologic↗
PubMed2000

Extracellular K(+) and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and beta1 integrins.

Elevated extracellular K(+) ([K(+)](o)), in the absence of "classical" immunological stimulatory signals, was found to itself be a sufficient stimulus to activate T cell beta1 integrin moieties, and to induce integrin-mediated adhesion and migration. Gating of T cell voltage-gated K(+) channels (Kv1.3) appears to be the crucial "decision-making" step, through which various physiological factors, including elevated [K(+)](o) levels, affect the T cell beta1 integrin function: opening of the channel leads to function, whereas its blockage prevents it. In support of this notion, we found that the proadhesive effects of the chemokine macrophage-inflammatory protein 1beta, the neuropeptide calcitonin gene-related peptide (CGRP), as well as elevated [K(+)](o) levels, are blocked by specific Kv1.3 channel blockers, and that the unique physiological ability of substance P to inhibit T cell adhesion correlates with Kv1.3 inhibition. Interestingly, the Kv1.3 channels and the beta1 integrins coimmunoprecipitate, suggesting that their physical association underlies their functional cooperation on the T cell surface. This study shows that T cells can be activated and driven to integrin function by a pathway that does not involve any of its specific receptors (i.e., by elevated [K(+)](o)). In addition, our results suggest that undesired T cell integrin function in a series of pathological conditions can be arrested by molecules that block the Kv1.3 channels.

Cell Adhesion↗
PubMed2000

Induction of interactions between CD44 and hyaluronic acid by a short exposure of human T cells to diverse pro-inflammatory mediators.

Migration of T cells into extravascular sites of inflammation is mediated by cell-cell and cell-matrix adhesion receptors, including the hyaluronan-binding glycoprotein, CD44. The biochemical nature of CD44 variants and the ligand specificity, function and the regulation of activation of CD44 expressed on various cell types have been extensively studied. However, little is still known about the short-term influence of cytokines and chemokines on the activation of CD44 on human T cells. Therefore, we studied the role of inflammatory mediators in regulating the adhesion of T cells from human peripheral blood to immobilized hyaluronan under static or shear stress conditions. We found that the CD44-dependent adhesion, under static and shear stress (i.e. relative gradual resistance to flow of 150 and 1500 s-1) conditions, of T cells to hyaluronan requires a T-cell activation of 2-3 hr and is regulated by the cross-linking of CD3, cytokines (e.g. interleukin-2 and tumour necrosis factor-alpha), and chemokines (e.g. MIP-1beta, interleukin-8, and RANTES). This T-cell adhesion was manifested by polarization, spreading and co-localization of cell surface CD44 with a rearranged actin cytoskeleton in hyaluronan-bound T cells. Thus, cytokines and chemokines present in the vicinities of blood vessel walls or present intravascularly in tissues where immune reactions take place, can rapidly activate the CD44 molecules expressed on T cells.

Antibodies, Monoclonal↗
PubMed2000

Disaccharides generated from heparan sulphate or heparin modulate chemokine-induced T-cell adhesion to extracellular matrix.

We have found previously that disaccharides (DS) enzymatically generated from heparin or heparan sulphate can modulate tumour necrosis factor-alpha (TNF-alpha) secretion from immune cells in vitro and cell-mediated immune reactions in vivo. Here, we show that such DS can modulate the adhesion and migration of human T cells. We found that certain heparin- and heparan sulphate-derived DS induced, in a dose-dependent manner, the adhesion of human T cells to both extracellular matrix (ECM) and immobilized fibronectin (FN); maximal T-cell adhesion occurred with 1 ng/ml of DS. The levels of T-cell adhesion to ECM that were induced by the tested DS molecules resembled those induced by the prototypic chemokine, macrophage inflammatory protein 1beta (MIP-1beta). However, the kinetics of DS-induced T-cell adhesion to FN resembled that induced by phorbol myristate acetate (PMA), but not that induced by MIP-1beta. This adhesion appeared to involve beta1 integrin recognition and activation, and was associated with specific intracellular activation pathways. Although a first exposure of T cells to certain DS molecules appeared to result in cell adhesion, a subsequent exposure of T cells to pro-adhesive chemokines, such as MIP-1beta or RANTES, but not to other pro-adhesive stimuli, for example interleukin-2 or CD3 cross-linking, resulted in inhibition of T-cell adhesion to and chemotactic migration through FN. Hence, we propose that the breakdown products of tissues generated by inflammatory enzymes are part of an intrinsic functional programme, and not necessarily molecular waste. Moreover, because the DS molecules exert their modulatory functions within a limited time, it appears that the historical encounters of the tissue-invading cells with the constituents of inflamed loci may dictate the cells' behaviour upon subsequent exposure to proinflammatory mediators.

Antibodies, Monoclonal↗
PubMed1999

Specific inhibition of T-cell adhesion to extracellular matrix and proinflammatory cytokine secretion by human recombinant galectin-1.

The migration of immune cells through the extracellular matrix (ECM) towards inflammatory sites is co-ordinated by receptors recognizing ECM glycoproteins, chemokines and proinflammatory cytokines. In this context, galectins are secreted to the extracellular milieu, where they recognize poly-N-acetyllactosamine chains on major ECM glycoproteins, such as fibronectin and laminin. We investigated the possibility that galectin-1 could modulate the adhesion of human T cells to ECM and ECM components. T cells were purified from human blood, activated with interleukin-2 (IL-2), labelled, and incubated further with intact immobilized ECM and ECM glycoproteins in the presence of increasing concentrations of human recombinant galectin-1, or its more stable, related, C2-S molecule obtained by site-directed mutagenesis. The presence of galectin-1 was shown to inhibit T-cell adhesion to intact ECM, laminin and fibronectin, and to a lesser extent to collagen type IV, in a dose-dependent manner. This effect was specifically blocked by anti-galectin-1 antibody and was dependent on the lectin's carbohydrate-binding properties. The inhibition of T-cell adhesion by galectin-1 correlates with the ability of this molecule to block the re-organization of the activated cell's actin cytoskeleton. Furthermore, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) production was markedly reduced when IL-2-activated T cells were incubated with galectin-1 or its mutant. This effect was prevented by beta-galactoside-related sugars. The present study reveals an alternative inhibitory mechanism for explaining the suppressive properties of the galectin-1 subfamily on inflammatory and autoimmune processes.

Cell Adhesion↗
PubMed1998

IL-2 induces T cell adherence to extracellular matrix: inhibition of adherence and migration by IL-2 peptides generated by leukocyte elastase.

Migration of inflammatory cells requires cell adhesion and their subsequent detachment from the extracellular matrix (ECM). Leukocyte activation and migration must be terminated to stop inflammation. Here, we report that IL-2 enhances human T cell adherence to laminin, collagen type IV, and fibronectin (FN). In contrast, neutrophil elastase, an enzyme activated during inflammation, degrades IL-2 to yield IL-2 fractions that inhibit IL-2-induced T cell adhesion to FN. The amino acid composition of two of these IL-2 fractions, which appear to block T cell adherence to FN, were analyzed, and three peptides were consequently synthesized. The three peptides IVL, RMLT, and EFLNRWIT, but not the corresponding inversely synthesized peptides, inhibited T cell adhesion to FN induced by a variety of activators: IL-2, IL-7, macrophage inflammatory protein (MIP)-1beta, and PMA, as well as anti-CD3 and anti-beta1 integrin-activating mAb. Moreover, these IL-2 peptides inhibited T cell chemotaxis via FN-coated membranes induced by IL-2 and MIP-1beta. Inhibition of T cell adherence and migration apparently involves abrogation of the rearrangement of the T cell actin cytoskeleton. Thus, the migrating immune cells, the cytokines, and the ECM can create a functional relationship in which both inflammation-inducing signals and inhibitory molecules of immune responses can coexist; the enzymatic products of IL-2 may serve as natural feedback inhibitors of inflammation.

Actins↗
PubMed1997

Induction of T cell adhesion to extracellular matrix or endothelial cell ligands by soluble or matrix-bound interleukin-7.

The putative effects of interleukin (IL)-7, operating in the context of extracellular matrix (ECM), on the adhesion of human T cells were examined. Recombinant human, IL-7 was found to bind ECM or fibronectin (FN) with IC50 values of 10-100 nM. Nanogram amounts of both soluble and, especially, FN- or ECM-bound IL-7, which differentially affected the morphologies of FN-adherent T cells, induced the adhesion of resting CD4+ and CD8+ T cells in dose-dependent and beta 1 integrin-dependent manners. Under static and flow conditions, soluble IL-7 also induced the binding of unstimulated T cells to vascular cell adhesion molecule-1, suggesting that this cytokine can also modulate integrin binding to endothelial cell ligands. The effects of affinity modulation by IL-7 of FN-specific beta 1 integrins depend on the presence of soluble FN, which inhibited T cell adhesion to FN induced by FN-bound IL-7 or by an integrin-specific affinity-modulating monoclonal antibody, but not by soluble IL-7 or phorbol 12-myristate 13-acetate. These findings provide an example of a major ECM integrin ligand, FN, which is capable of modulating its adhesive interactions with specific immune cells by associating with and presenting a cytokine in a bio-active state.

Cell Adhesion↗
PubMed1997

Effects on pulmonary function of daily exposure to dry or humidified hyperbaric oxygen.

The purpose of this study was to examine the effects of breathing dry or humidified hyperbaric oxygen on pulmonary function. Pulmonary function tests were performed before and after each of 10 hyperbaric oxygen exposures at 2.5 atmospheres absolute (ATA) for 95 min in a group of 13 patients treated daily by hyperbaric oxygen for problem wounds. Patients breathed dry oxygen during five successive sessions and humidified oxygen during the remaining five. No differences were found between forced vital capacities (FVC) and maximal expiratory flows before and after hyperbaric oxygen exposure while breathing dry or humidified oxygen. Significant differences were found for the changes in the percentage of FVC expired in 1 s (FEV1%) and mean forced mid-expiratory flow rate during the middle half of the FVC (FEF25-75%) on day 1 alone: decrements of 1.42 and 2.96%, respectively, under dry oxygen, vs. increments of 3.93 and 34.4%, respectively, for humidified oxygen. Day-to-day decrements in the percent changes in FEV1% and FEF25-75% were observed while breathing humidified hyperbaric oxygen. These results demonstrate that repeated daily exposure to humidified hyperbaric oxygen abolishes the initial beneficial effect of humidification on peripheral airways flow characteristics.

Adult↗
PubMed1986

Necrotizing fasciitis.

Necrotizing fasciitis was diagnosed in 16 patients during the years 1980 to 1984. All patients were managed by a uniform protocol consisting of radical excisional surgery, intravenous antibiotics, and hyperbaric oxygen therapy. An overall mortality rate of 12.5% was achieved. In view of the encouraging results, this therapeutic regimen is highly recommended.

Adult↗