PMC:17829 / 9864-14490
Annnotations
2_test
{"project":"2_test","denotations":[{"id":"11178120-8345197-4390809","span":{"begin":1307,"end":1309},"obj":"8345197"},{"id":"11178120-7542307-4390810","span":{"begin":1310,"end":1312},"obj":"7542307"},{"id":"11178120-7934491-4390811","span":{"begin":2653,"end":2655},"obj":"7934491"},{"id":"11178120-10075615-4390812","span":{"begin":2656,"end":2658},"obj":"10075615"},{"id":"11178120-9870876-4390813","span":{"begin":2659,"end":2661},"obj":"9870876"},{"id":"11178120-8670315-4390814","span":{"begin":2820,"end":2822},"obj":"8670315"},{"id":"11178120-8530158-4390815","span":{"begin":2935,"end":2937},"obj":"8530158"},{"id":"11178120-9531282-4390816","span":{"begin":3744,"end":3746},"obj":"9531282"},{"id":"11178120-8774548-4390817","span":{"begin":4086,"end":4088},"obj":"8774548"},{"id":"11178120-10646482-4390818","span":{"begin":4089,"end":4091},"obj":"10646482"},{"id":"11178120-11001373-4390819","span":{"begin":4092,"end":4094},"obj":"11001373"},{"id":"11178120-8345197-4390809","span":{"begin":1307,"end":1309},"obj":"8345197"},{"id":"11178120-7542307-4390810","span":{"begin":1310,"end":1312},"obj":"7542307"},{"id":"11178120-7934491-4390811","span":{"begin":2653,"end":2655},"obj":"7934491"},{"id":"11178120-10075615-4390812","span":{"begin":2656,"end":2658},"obj":"10075615"},{"id":"11178120-9870876-4390813","span":{"begin":2659,"end":2661},"obj":"9870876"},{"id":"11178120-8670315-4390814","span":{"begin":2820,"end":2822},"obj":"8670315"},{"id":"11178120-8530158-4390815","span":{"begin":2935,"end":2937},"obj":"8530158"},{"id":"11178120-9531282-4390816","span":{"begin":3744,"end":3746},"obj":"9531282"},{"id":"11178120-8774548-4390817","span":{"begin":4086,"end":4088},"obj":"8774548"},{"id":"11178120-10646482-4390818","span":{"begin":4089,"end":4091},"obj":"10646482"},{"id":"11178120-11001373-4390819","span":{"begin":4092,"end":4094},"obj":"11001373"}],"text":"Discussion:\nOur experiments characterised the immuno-phenotype of monocytes that migrated through EC monolayers. Several surface molecules (CD11a, CD33, CD45RO, ICAM-1 and HLA-DR) were significantly increased on the migrated monocytes in comparison with the nonadherent population. The differences in the immunophenotype between migrating and nonadherent monocytes could be explained either by the preferential migration of a particular subset of monocytes or as a result of the interaction of monocytes with the endothelium. If the observed alterations in the immunophenotype of migrating monocytes had been due to the preferential migration of a particular subset, we would have expected a depletion of this subset in the nonadherent population. This did not occur; all surface markers studied were expressed to similar extents on the nonadherent and initial populations (see Table 2). The notion that the process of transendothelial migration leads to an upregulation of certain surface markers on monocytes is also supported by the fact that the expression of most markers was significantly higher in the migrated cells than in the bound cells (see Table 2). Taken together, our results suggest that transendothelial migration induces the activation or maturation of monocytes.\nAs described previously [19,20], we found that pretreatment of the endothelium with certain chemokines or cytokines enhanced transendothelial migration. The most striking phenotypic changes were seen for ICAM-1 expression, when ECs were pretreated with TNF-α and IL-1α (see Table 3 and Figs 3 and 4). In contrast, MIP-1α pretreatment did not change the monocyte phenotype investigated here. In the light of enhanced migration through MIP-1α-prestimulated endothelium, these results suggest a dichotomy of cytokine/chemokine effects on migration compared with surface marker expression: ECs activated with TNF-α and IL-1α seem to lead to an upregulation of both monocyte migration and surface marker expression, whereas MIP-1α only enhances migration, a finding that is compatible with the chemotactic chemokine nature of MIP-1α. Alternatively, MIP-1α could have been trapped in the collagen gel, acting as a chemotactic gradient directly on monocytes rather than via ECs. Thus TNF-α and IL-1α seem to mediate different proinflammatory events from those mediated by MIP-1α.\nOur observations of increased expression of ICAM-1 on migrated monocytes after the pretreatment of ECs with TNF-α and IL-1α are especially remarkable because these cytokines are important in the pathogenesis of inflammation. In RA, TNF-α and IL-1 blockade showed an unequivocal therapeutic effect [21,22,23]. In addition, ICAM-1 and E-selectin levels of patients with RA who had received anti-TNF-α therapy decreased within a few days of the initiation of therapy [24].\nPrevious findings indicate that TNF-α and IL-1α induce an upregulation of the ICAM-1 counter-receptor on ECs [25]. This is consistent with the increase in cell migration found in our experiments and the altered expression of ICAM-1 on monocytes. Because the classic ICAM-1 counter-receptors LFA-1 and Mac-1 have not been detected on ECs, the existence of another ICAM-1 ligand, one that facilitates the transendothelial migration of monocytes, remains possible.\nThe reported changes indicate that, after migration, monocytes could become more liable to interact with T cells (which are known to enhance LFA-1 expression in the presence of TNF-α). This interaction might lead to a further mutual stimulation of T cells and macrophages. In fact the ligand-counterligand system consisting of LFA-1 and ICAM-1 also is one co-stimulatory pathway involved in interactions between antigen-presenting cells (APCs) and T cells [26]. Because our results demonstrate that both ICAM-1 and HLA-DR are upregulated on migrated monocytes, their function as APCs and possible ability to communicate with T cells, might be facilitated after transendothelial migration. Thus, this observation also supports previous notions on the importance of T cells in the pathogenesis of RA [27,28,29].\nIn summary, our findings indicate that monocyte migration is accompanied by changes in function-associated surface antigens and that TNF-α and IL-1α in particular increase the number of migrating monocytes and lead to an enhanced expression of certain surface markers involved in cell-cell interactions. These events might not only be partly responsible for the high inflammatory activity in RA synovium; they also suggest that ECs have a pivotal role in these processes and thus might constitute an important therapeutic target."}
Colil
{"project":"Colil","denotations":[{"id":"T39","span":{"begin":3744,"end":3746},"obj":"9531282"},{"id":"T40","span":{"begin":3744,"end":3746},"obj":"9531282"},{"id":"T41","span":{"begin":1307,"end":1309},"obj":"8345197"},{"id":"T42","span":{"begin":1310,"end":1312},"obj":"7542307"},{"id":"T43","span":{"begin":1307,"end":1309},"obj":"8345197"},{"id":"T44","span":{"begin":1310,"end":1312},"obj":"7542307"},{"id":"T45","span":{"begin":2820,"end":2822},"obj":"8670315"},{"id":"T46","span":{"begin":2820,"end":2822},"obj":"8670315"},{"id":"T47","span":{"begin":4086,"end":4088},"obj":"8774548"},{"id":"T48","span":{"begin":4089,"end":4091},"obj":"10646482"},{"id":"T49","span":{"begin":4092,"end":4094},"obj":"11001373"},{"id":"T50","span":{"begin":4086,"end":4088},"obj":"8774548"},{"id":"T51","span":{"begin":4089,"end":4091},"obj":"10646482"},{"id":"T52","span":{"begin":4092,"end":4094},"obj":"11001373"},{"id":"T53","span":{"begin":2653,"end":2655},"obj":"7934491"},{"id":"T54","span":{"begin":2656,"end":2658},"obj":"10075615"},{"id":"T55","span":{"begin":2659,"end":2661},"obj":"9870876"},{"id":"T56","span":{"begin":2653,"end":2655},"obj":"7934491"},{"id":"T57","span":{"begin":2656,"end":2658},"obj":"10075615"},{"id":"T58","span":{"begin":2659,"end":2661},"obj":"9870876"},{"id":"T59","span":{"begin":2935,"end":2937},"obj":"8530158"},{"id":"T60","span":{"begin":2935,"end":2937},"obj":"8530158"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/docs/sourcedb/PubMed/sourceid/"}],"text":"Discussion:\nOur experiments characterised the immuno-phenotype of monocytes that migrated through EC monolayers. Several surface molecules (CD11a, CD33, CD45RO, ICAM-1 and HLA-DR) were significantly increased on the migrated monocytes in comparison with the nonadherent population. The differences in the immunophenotype between migrating and nonadherent monocytes could be explained either by the preferential migration of a particular subset of monocytes or as a result of the interaction of monocytes with the endothelium. If the observed alterations in the immunophenotype of migrating monocytes had been due to the preferential migration of a particular subset, we would have expected a depletion of this subset in the nonadherent population. This did not occur; all surface markers studied were expressed to similar extents on the nonadherent and initial populations (see Table 2). The notion that the process of transendothelial migration leads to an upregulation of certain surface markers on monocytes is also supported by the fact that the expression of most markers was significantly higher in the migrated cells than in the bound cells (see Table 2). Taken together, our results suggest that transendothelial migration induces the activation or maturation of monocytes.\nAs described previously [19,20], we found that pretreatment of the endothelium with certain chemokines or cytokines enhanced transendothelial migration. The most striking phenotypic changes were seen for ICAM-1 expression, when ECs were pretreated with TNF-α and IL-1α (see Table 3 and Figs 3 and 4). In contrast, MIP-1α pretreatment did not change the monocyte phenotype investigated here. In the light of enhanced migration through MIP-1α-prestimulated endothelium, these results suggest a dichotomy of cytokine/chemokine effects on migration compared with surface marker expression: ECs activated with TNF-α and IL-1α seem to lead to an upregulation of both monocyte migration and surface marker expression, whereas MIP-1α only enhances migration, a finding that is compatible with the chemotactic chemokine nature of MIP-1α. Alternatively, MIP-1α could have been trapped in the collagen gel, acting as a chemotactic gradient directly on monocytes rather than via ECs. Thus TNF-α and IL-1α seem to mediate different proinflammatory events from those mediated by MIP-1α.\nOur observations of increased expression of ICAM-1 on migrated monocytes after the pretreatment of ECs with TNF-α and IL-1α are especially remarkable because these cytokines are important in the pathogenesis of inflammation. In RA, TNF-α and IL-1 blockade showed an unequivocal therapeutic effect [21,22,23]. In addition, ICAM-1 and E-selectin levels of patients with RA who had received anti-TNF-α therapy decreased within a few days of the initiation of therapy [24].\nPrevious findings indicate that TNF-α and IL-1α induce an upregulation of the ICAM-1 counter-receptor on ECs [25]. This is consistent with the increase in cell migration found in our experiments and the altered expression of ICAM-1 on monocytes. Because the classic ICAM-1 counter-receptors LFA-1 and Mac-1 have not been detected on ECs, the existence of another ICAM-1 ligand, one that facilitates the transendothelial migration of monocytes, remains possible.\nThe reported changes indicate that, after migration, monocytes could become more liable to interact with T cells (which are known to enhance LFA-1 expression in the presence of TNF-α). This interaction might lead to a further mutual stimulation of T cells and macrophages. In fact the ligand-counterligand system consisting of LFA-1 and ICAM-1 also is one co-stimulatory pathway involved in interactions between antigen-presenting cells (APCs) and T cells [26]. Because our results demonstrate that both ICAM-1 and HLA-DR are upregulated on migrated monocytes, their function as APCs and possible ability to communicate with T cells, might be facilitated after transendothelial migration. Thus, this observation also supports previous notions on the importance of T cells in the pathogenesis of RA [27,28,29].\nIn summary, our findings indicate that monocyte migration is accompanied by changes in function-associated surface antigens and that TNF-α and IL-1α in particular increase the number of migrating monocytes and lead to an enhanced expression of certain surface markers involved in cell-cell interactions. These events might not only be partly responsible for the high inflammatory activity in RA synovium; they also suggest that ECs have a pivotal role in these processes and thus might constitute an important therapeutic target."}