Omega‐3 but not omega‐6 fatty acids protect against TNF‐α induced endothelial cell activation

ABSTRACT Ebola virus causes severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. Vascular instability and dysregulation are disease-decisive symptoms during severe infection. While the transmembrane glycoprotein GP1,2 has been shown to cause endothelial cell destruction, the role of the soluble glycoproteins in pathogenesis is largely unknown; however, they are hypothesized to be of biological relevance in terms of target cell activation and/or increase of endothelial permeability. Here we show that virus-like particles (VLPs) consisting of the Ebola virus matrix protein VP40 and GP1,2 were able to activate endothelial cells and induce a decrease in barrier function as determined by impedance spectroscopy and hydraulic conductivity measurements. In contrast, the soluble glycoproteins sGP and Δ-peptide did not activate endothelial cells or change the endothelial barrier function. The VLP-induced decrease in barrier function was further enhanced by the cytokine tumor necrosis factor alpha (TNF-α), which is known to induce a long-lasting decrease in endothelial cell barrier function and is hypothesized to play a key role in Ebola virus pathogenesis. Surprisingly, sGP, but not Δ-peptide, induced a recovery of endothelial barrier function following treatment with TNF-α. Our results demonstrate that Ebola virus GP1,2 in its particle-associated form mediates endothelial cell activation and a decrease in endothelial cell barrier function. Furthermore, sGP, the major soluble glycoprotein of Ebola virus, seems to possess an anti-inflammatory role by protecting the endothelial cell barrier function.

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Comparative Analysis of Vascular Endothelial Cell Activation by TNF-α and LPS in Humans and Baboons

Cell Biochemistry and Biophysics ◽

10.1385/cbb:40:3:289 ◽

2004 ◽

Vol 40 (3) ◽

pp. 289-304 ◽

Cited By ~ 23

Author(s):

Qiang Shi ◽

Jian Wang ◽

Xing Li Wang ◽

John L. VandeBerg

Keyword(s):

Comparative Analysis ◽

Endothelial Cell ◽

Cell Activation ◽

Vascular Endothelial Cell ◽

Vascular Endothelial ◽

Endothelial Cell Activation ◽

Tnf Α

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In vitro endothelial cell activation and inflammatory responses in end-stage heart failure

Journal of Applied Physiology ◽

10.1152/japplphysiol.01497.2005 ◽

2006 ◽

Vol 101 (5) ◽

pp. 1466-1473 ◽

Cited By ~ 5

Author(s):

Ginette S. Hoare ◽

Emma J. Birks ◽

Christopher Bowles ◽

Nandor Marczin ◽

Magdi H. Yacoub

Keyword(s):

Heart Failure ◽

Endothelial Cells ◽

Endothelial Cell ◽

Cell Activation ◽

Endothelial Cell Activation ◽

Tnf Α ◽

Patients With Heart Failure ◽

End Stage Heart Failure ◽

End Stage ◽

Iκbα Degradation

Background: vascular endothelial cell activation and dysfunction are observed in patients with severe heart failure and may contribute to systemic manifestations of this syndrome. It remains unknown whether inflammatory activation of these cells occurs in these patients because of increased circulating proinflammatory mediators. Aim: to determine whether the serum from patients with heart failure possesses a net proinflammatory bioactivity to active proinflammatory pathways in cultured endothelial cells. Methods: serum was obtained from stable patients with end-stage heart failure undergoing elective cardiac transplantation (Tx) and severely decompensated patients with heart failure requiring emergency left ventricular assist device (LVAD) implantation. Net proinflammatory bioactivity of serum was investigated by monitoring IκBα degradation and E-selectin expression in cultured human pulmonary artery endothelial cells (HPAEC) following incubation with serum samples. Serum cytokine concentrations were measured by ELISA and neutralizing antibodies were used to determine the role of specific factors in the observed bioactivity. Result: serum from both patient groups induced HPAEC IκBα degradation. Low basal HPAEC E-selectin expression significantly increased following treatment with Tx but not LVAD serum. Serum tumor necrosis factor-α (TNF-α) and IL-10 concentrations were higher in patients with LVAD than those with Tx, and soluble TNF-α receptor expression was high in both groups. Neither TNF-α nor IL-10 blocking experiments altered either bioassay result. Conclusion: activation of a specific profile of pro- and anti-inflammatory mediators is associated with heart failure resulting in HPAEC nuclear factor (NF)-κB activation. However, E-selectin expression is further regulated by unidentified factors. TNF-α is upregulated but appears to play no part in NFκB activation in these patients. These findings could have important therapeutic implications.

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Inhibition of the endothelial cell activation by antithrombin in vitro

Thrombosis and Haemostasis ◽

10.1160/th04-03-0139 ◽

2004 ◽

Vol 92 (12) ◽

pp. 1420-1427 ◽

Cited By ~ 19

Author(s):

Mitsuhiro Uchiba ◽

Christoph Kaun ◽

Johann Wojta ◽

Bernd Binder ◽

Kenji Okajima

Keyword(s):

Endothelial Cell ◽

Protein Kinase ◽

Protein Kinase A ◽

Cell Activation ◽

Binding Protein ◽

Inhibitory Effect ◽

Inflammatory Activity ◽

Endothelial Cell Activation ◽

Tnf Α ◽

Kinase A

SummaryWe examined whether antithrombin (AT) inhibits tumor necrosis factor (TNF)-α-induced endothelial cell activation to elucidate molecular mechanism(s) of the anti-inflammatory activity of AT. AT inhibited the increase in E-selectin expression in cultured human umbilical vein endothelial cells (HUVECs) stimulated with TNF-α. In contrast, chemically modified AT that lacks affinity for heparin did not. AT inhibited the TNF-αinduced interaction of NF-κB p65 with p300, a homologue of cAMP-responsive element binding protein (CREB)-binding protein (CBP). AT increased both intracellular levels of cAMP and binding of phosphorylated-CREB to DNA in HUVECs. Forskolin showed the inhibitory effect similar to that of AT and pretreatment of HUVECs with KT-5720, an inhibitor of protein kinase A, reversed the inhibitory effect of AT. These observations suggested that AT inhibited the TNF-α-induced increase in E-selectin expression in HUVECs by inhibiting the interaction of NF-κB with CBP/p300 through cAMP-dependent protein kinase A-induced CREB activation. This inhibitory activity of AT might depend on its binding to heparin-like substances on the endothelial cell. Such an inhibitory effect of AT on TNF-α-induced endothelial cell activation might at least partly contribute to its anti-inflammatory activity.

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Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination

Blood ◽

10.1182/blood.v97.7.2121 ◽

2001 ◽

Vol 97 (7) ◽

pp. 2121-2129 ◽

Cited By ~ 160

Author(s):

Anne Stucki ◽

Anne-Sophie Rivier ◽

Milica Gikic ◽

Natacha Monai ◽

Marc Schapira ◽

...

Keyword(s):

Endothelial Cell ◽

Cell Activation ◽

Molecular Mechanisms ◽

Leukemic Cell ◽

Leukemic Cells ◽

Adhesion Assay ◽

Endothelial Cell Activation ◽

Adhesion Receptors ◽

Tnf Α ◽

Blast Cells

Abstract Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-α. Inhibition studies showed that multiple adhesion receptors—including L-selectin, E-selectin, VCAM-1, and CD11/CD18—were involved in blast cell adhesion to TNF-α–activated endothelium. Leukemic cells were then cocultured at 37°C on unactivated endothelial cell monolayers for time periods up to 24 hours. A time-dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. Additional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-α and IL-1β, and direct contacts between adhesion receptors expressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells.

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