Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease

Ulbrich, Holger; Eriksson, Einar E.; Lindbom, Lennart

doi:10.1016/j.tips.2003.10.004

Cited by 324 publications

(229 citation statements)

References 59 publications

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“…The preservation of neutrophil activation status in co-treatments of R-roscovitine and the stimuli GM-CSF, LPS, leukotriene B 4 and TNF-a also infers important information regarding the recruitment and migration of neutrophils from the circulation to sites of inflammation as the neutrophil surface molecules CD11b and CD62L are important regulators of cell adhesion to vascular endothelium. It is pertinent that neutrophils are recruited to sites of infection and inflammation, as dysregulation in this process is associated with increased susceptibility to infection [36].…”

Section: Discussionmentioning

confidence: 99%

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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Successful resolution of inflammation requires inflammatory cells such as neutrophils to undergo apoptosis prior to non-inflammatory phagocytosis by professional phagocytes. Recently, cyclin-dependent kinase (CDK) inhibitors (e.g. R-roscovitine) have been shown to induce neutrophil apoptosis and enhance the resolution of inflammation. Interestingly, NF-jB and MAPK pathways and key endogenous survival proteins (typified by Mcl-1) are involved in the regulation of neutrophil apoptosis and, in cancer-cell lines, have been implicated as possible targets of CDK inhibitors. Here, we demonstrate that R-roscovitine over-rides TNF-a and LPS-induced survival (determined by morphological examination and binding of fluorescently labelled annexin-V) of isolated peripheral blood neutrophils. This effect did not appear to be mediated via effects on early markers of neutrophil activation (e.g. surface marker expression, shape change, aggregation and superoxide anion generation), by direct inhibition of NF-jB activation (assessed by cytoplasmic IjBa proteolysis and NF-jB p65 subunit translocation) and ERK activation (determined by specific ERK phosphorylation) but due to down-regulation (at protein and mRNA level) of the survival protein Mcl-1 but not the pro-apoptotic bcl-2 homologue Bim. These findings suggest that key endogenous survival proteins may be the targets of CDK inhibitors and consequently may be of critical importance in the resolution of inflammation.

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Section: Discussionmentioning

confidence: 99%

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

et al. 2010

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“…Integrins are heterodimeric molecules expressed on the surface of leukocytes that facilitate a strong association with cell-adhesion molecules (CAMs) on the surface of cytokinestimulated endothelial cells (ICAM-1, VCAM-1). 19 LPS directly increases expression of E-selectin and integrin counter receptors, 20 and the upregulation of this adhesion molecule expression requires the nuclear localization of nuclear factor-kappa B (NFkB). 21,22 In septic patients, elevated levels of endothelial selectins correlate with poor prognosis.…”

Section: Leukocyte Recruitment and Adhesionmentioning

confidence: 99%

Lipopolysaccharide signaling in endothelial cells

Dauphinee

Karsan

2006

Laboratory Investigation

534

433

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Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gramnegative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-jB (NF-jB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-jB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.

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Section: Leukotriene (Lt) B4 Is a Powerful Chemotactic And Immune Modmentioning

confidence: 99%

“…Discussion LTB 4 is a classical chemoattracting agent that also promotes neutrophil adhesion and diapedesis through the endothelial cell barrier, a key sequence of events during vascular inflammatory responses and host defense. However, the molecular mechanisms of LTB 4 -induced transendothelial migration of neutrophils is not fully understood, but seems to involve soluble factors as well as activation of both leukocyte and endothelial cell adhesion molecules (23). Direct effects of LTB 4 on endothelial cells have also been discussed, although these cells have appeared only weakly, if at all, reactive to this mediator (24,25).…”

Section: Effects Of Ltb4 On Nitrite Generation and Mcp-1 Release Frommentioning

confidence: 99%

“…LTB 4 is very active in the microcirculation and promotes adhesion of leukocytes to the endothelium, followed by diapedesis and migration into surrounding tissues. Although it has been reported that LTB 4 can induce CD54 (or ICAM-1) expression in endothelial cells (20,21), the prevailing notion is that adhesive and migratory effects of LTB 4 primarily originate from its action on the leukocyte, where chemoattractants induce up-regulation of cell-adhesion molecules that can interact with their cognate receptors on endothelial cells (22,23).Here, we report that LPS, TNF-␣, IL-1␤, and LTB 4 itself, differentially increase the expression of BLT 1 and͞or BLT 2 on HUVEC, which in turn allows LTB 4 mediated Ca 2ϩ signaling. We also show that LTB 4 can increase the release of monocyte chemoattractant protein-1 (MCP-1) and generation of nitrite (presumably from NO) from these cells.…”

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confidence: 99%

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Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B₄

Qiu

Johansson

Sjöström

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Leukotriene (LT) B4 is a powerful chemotactic and immune modulating agent that signals via two receptors denoted BLT1 and BLT2.Here we report that BLT1 and BLT2 are expressed at low levels in an apparently silent state in human umbilical vein endothelial cells (HUVEC). However, treatment with LPS leads to a >10 fold increase in the levels of BLT1 mRNA without any significant effects on BLT2 mRNA. In parallel, LPS also increases the amounts of BLT1 protein.Tumor necrosis factor-␣ (TNF-␣) increases the expression of BLT2 mRNA Ϸ6 times above basal levels with only a modest increase in BLT1 mRNA. Interleukin-1␤ causes variable and parallel increases of both BLT1 and BLT2 mRNA. The natural ligand LTB4 also increases BLT1, but not BLT2, mRNA and protein expression. Along with the induction of BLT1 and͞or BLT2, HUVEC acquire the capacity to respond to LTB4 with increased levels of intracellular calcium and these signals can be blocked by isotype selective BLT antagonists, CP-105696 and LY-255283. In addition, treatment of HUVEC with LTB4 causes increased release of both nitrite, presumably reflecting nitric oxide (NO), and monocyte chemoattractant protein-1. Our data indicate that expression of functional BLT receptors may occur at the surface of endothelial cells in response to LPS, cytokines, and ligand, which in turn may have functional consequences during the early vascular responses to inflammation. Moreover, the results point to BLT receptors as potential targets for pharmacological intervention in LT-dependent inflammatory diseases such as asthma, rheumatoid arthritis, and arteriosclerosis.inflammation ͉ arteriosclerosis ͉ rheumatoid arthritis ͉ asthma ͉ nitric oxide T he leukotrienes (LTs) are a family of lipid mediators that play important roles in a variety of allergic and inflammatory reactions (1, 2). These molecules are divided into two classes, the spasmogenic cysteinyl-LTs (cys-LT) and LTB 4 , which is a classical nM chemotactic agent produced by neutrophils, macrophages, and mast cells. Thus, LTB 4 is a potent chemoattractant for polymorphonuclear leukocytes, comparable to complement peptide C5a and fMet-Leu-Phe (3, 4). Recent data also indicate that LTB 4 is a strong chemoattractant for T cells, creating a functional link between early innate and late adaptive immune responses (5-7). Because of these biological effects, LTB 4 is regarded as an important chemical mediator in a variety of acute and chronic inflammatory diseases and only recently, genetic and biochemical evidence strongly implicate LTB 4 as a mediator of vascular inflammation and arteriosclerosis (8-10). LTB 4 , is synthesized from arachidonic acid via the concerted action of 5-lipoxygenase, assisted by 5-lipoxygenase-activating protein and the terminal LTA 4 hydrolase (11), usually in a single cell or via transcellular routes; this mechanism has been shown to occur in vivo (12,13). LTB 4 signals primarily via a specific, high-affinity, G proteincoupled seven-transmembrane receptor, termed BLT 1 (14). The BLT 1 gene is located on the huma...

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Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease

Cited by 324 publications

References 59 publications

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

Lipopolysaccharide signaling in endothelial cells

Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B₄

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Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease

Cited by 324 publications

References 59 publications

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

Lipopolysaccharide signaling in endothelial cells

Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B4

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Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B₄