Roles of Rho/ROCK and MLCK in TNF‐α‐induced changes in endothelial morphology and permeability

McKenzie, J.; Ridley, Anne J.

doi:10.1002/jcp.21114

Cited by 220 publications

(243 citation statements)

References 41 publications

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“…It was reported that the low TEER was associated with irregular cell shape, when studied morphologically (Tretiach et al, 2003), and alterations in the permeability of the vascular endothelium (Bucana et al, 1988). McKenzie & Ridley (2007) found that TNF-a subsequently caused a progressive increase in permeability and in stress fibre reorganization, cell elongation and intercellular gap formation over 8-24 h. Consistent with the increased permeability, occludin and JAM-A were removed from tight junctions and ZO-1 was partially redistributed (McKenzie & Ridley, 2007). Similar results were obtained in the present study.…”

Section: Permeability Of Dengue Virus-infected Endothelial Cellssupporting

confidence: 90%

Peripheral blood mononuclear cells increase the permeability of dengue virus-infected endothelial cells in association with downregulation of vascular endothelial cadherin

Dewi

Takasaki

Kurane

2008

Journal of General Virology

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Plasma leakage is one of the characteristic features of dengue haemorrhagic fever. The interaction among peripheral blood mononuclear cells (PBMCs), dengue virus and endothelial cells was analysed in vitro. Human umbilical vein endothelial cells (HUVECs) were infected with dengue-2 virus (DV-2) at an m.o.i. of 0.5 p.f.u. per cell. PBMCs were added to DV-2-infected HUVECs, and transendothelial electrical resistance (TEER) and transalbumin permeability were assessed. Dengue virus infection at an m.o.i. of 0.5 p.f.u. per cell alone did not decrease the TEER, but addition of PBMCs decreased the TEER, increased the albumin permeability and induced morphological changes of HUVECs. The extent of the decrease was more profound with adherent PBMCs than with non-adherent PBMCs. The expression of vascular endothelial cadherin (VE-cadherin) was examined using real-time RT-PCR and immunofluorescence. Addition of PBMCs to DV-2-infected HUVECs decreased the levels of mRNA transcripts and cell-surface expression of VE-cadherin. The results indicate that PBMCs increased the permeability of DV-2-infected HUVECs and that the increased permeability was concomitant with morphological change and the decrease in VE-cadherin expression. The results suggest that functional impairment of the DV-2-infected HUVEC monolayer was caused by interaction with PBMCs.

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Section: Permeability Of Dengue Virus-infected Endothelial Cellssupporting

confidence: 90%

Peripheral blood mononuclear cells increase the permeability of dengue virus-infected endothelial cells in association with downregulation of vascular endothelial cadherin

Dewi

Takasaki

Kurane

2008

Journal of General Virology

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“…Previous studies have shown that MLCK plays a central role in the regulation of intestinal epithelial TJ barrier function (41,49,55,56). MLCK activation has been shown to be a central mechanism that regulates both pharmacologic (39 -41) and physiologic (42) induced opening of intestinal TJ barrier.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of IL-1β-Induced Increase in Intestinal Epithelial Tight Junction Permeability

Al–Sadi

Dokładny

et al. 2008

The Journal of Immunology

361

295

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The IL-1β-induced increase in intestinal epithelial tight junction (TJ) permeability has been postulated to be an important mechanism contributing to intestinal inflammation of Crohn’s disease and other inflammatory conditions of the gut. The intracellular and molecular mechanisms that mediate the IL-1β-induced increase in intestinal TJ permeability remain unclear. The purpose of this study was to elucidate the mechanisms that mediate the IL-1β-induced increase in intestinal TJ permeability. Specifically, the role of myosin L chain kinase (MLCK) was investigated. IL-1β caused a progressive increase in MLCK protein expression. The time course of IL-1β-induced increase in MLCK level correlated linearly with increase in Caco-2 TJ permeability. Inhibition of the IL-1β-induced increase in MLCK protein expression prevented the increase in Caco-2 TJ permeability. Inhibition of the IL-1β-induced increase in MLCK activity also prevented the increase in Caco-2 TJ permeability. Additionally, knock-down of MLCK protein expression by small interference RNA prevented the IL-1β-induced increase in Caco-2 TJ permeability. The IL-1β-induced increase in MLCK protein expression was preceded by an increase in MLCK mRNA expression. The IL-1β-induced increase in MLCK mRNA transcription and subsequent increase in MLCK protein expression and Caco-2 TJ permeability was mediated by activation of NF-κB. In conclusion, our data indicate that the IL-1β increase in Caco-2 TJ permeability was mediated by an increase in MLCK expression and activity. Our findings also indicate that the IL-1β-induced increase in MLCK protein expression and Caco-2 TJ permeability was mediated by an NF-κB-dependent increase in MLCK gene transcription.

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“…Indeed, in primary cultures of retinal endothelial cells, TNF-a induces changes in protein levels of ZO-1 and claudin-5 as early as 6 h after treatment (59), and long-term exposure to TNF-a correlates with redistribution of junctional adhesion molecule, occludin, and ZO-1 proteins from the cell-cell junction (30). In addition, treatment of peripheral microvascular endothelium with TNF-a and IFN-g results in focal loss of VE-cadherin-mediated intercellular adhesion in areas of endothelial barrier breakdown (12).…”

Section: Discussionmentioning

confidence: 99%

“…TNF-a and IFN-g modulate paracellular permeability and transendothelial electrical resistance of hCMEC/D3 cells Previous studies have shown that treatment of human peripheral microvascular endothelial cells with either TNF-a alone or in combination with IFN-g induces an increase in paracellular permeability (28)(29)(30). To evaluate the capacity of proinflammatory cytokines to disrupt the gate properties in hCMEC/D3 cells, we performed paracellular permeability studies using the hydrophilic tracer 70 kDa FITC-dextran.…”

Section: Expression Of Tnf-a and Ifn-g Receptors By Hcmec/d3 Cellsmentioning

confidence: 99%

Role of Caspases in Cytokine-Induced Barrier Breakdown in Human Brain Endothelial Cells

Lopez-Ramirez

Fischer

Torres-Badillo

et al. 2012

The Journal of Immunology

110

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During neuroinflammation, cytokines such as TNF-α and IFN-γ secreted by activated leukocytes and/or CNS resident cells have been shown to alter the phenotype and function of brain endothelial cells (BECs) leading to blood–brain barrier breakdown. In this study, we show that the human BEC line hCMEC/D3 expresses the receptors for TNF-α, TNF receptor 1 and TNF receptor 2, and for IFN-γ. BEC activation with TNF-α alone or in combination with IFN-γ induced endothelial leakage of paracellular tracers. At high cytokine concentrations (10 and 100 ng/ml), this effect was associated with caspase-3/7 activation and apoptotic cell death as evidenced by annexin V staining and DNA fragmentation (TUNEL) assays. In addition, inhibition of JNK and protein kinase C activation at these doses partially prevented activation of caspase-3/7, although only JNK inhibition was partially able to prevent the increase in BEC paracellular permeability induced by cytokines. By contrast, lower cytokine concentrations (1 ng/ml) also led to effector caspase activation, increased paracellular flux, and redistribution of zonula occludens-1 and VE-cadherin but failed to induce apoptosis. Under these conditions, specific caspase-3 and caspase-9, but not caspase-8, inhibitors partially blocked cytokine-induced disruption of tight and adherens junctions and BEC paracellular permeability. Our results suggest that the concentration of cytokines in the CNS endothelial microenvironment determines the extent of caspase-mediated barrier permeability changes, which may be generalized as a result of apoptosis or more subtle as a result of alterations in the organization of junctional complex molecules.

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Roles of Rho/ROCK and MLCK in TNF‐α‐induced changes in endothelial morphology and permeability

Cited by 220 publications

References 41 publications

Peripheral blood mononuclear cells increase the permeability of dengue virus-infected endothelial cells in association with downregulation of vascular endothelial cadherin

Peripheral blood mononuclear cells increase the permeability of dengue virus-infected endothelial cells in association with downregulation of vascular endothelial cadherin

Mechanism of IL-1β-Induced Increase in Intestinal Epithelial Tight Junction Permeability

Role of Caspases in Cytokine-Induced Barrier Breakdown in Human Brain Endothelial Cells

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