Tumor necrosis factor-α and interleukin-1β mediate endothelial permeability induced by lipopolysaccharide-stimulated whole blood

Nooteboom, A; Linden, C. J. Van Der; Hendriks, T.

doi:10.1097/00003246-200209000-00019

Cited by 50 publications

(52 citation statements)

References 36 publications

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“…Importantly, inflammatory cytokines, such as tumor necrosis factor α, IL-1β, or IL-6, have been demonstrated to increase the permeability of the endothelial barrier in a concentration and time-dependent manner. [24][25][26] Therefore in the present study, we ruled out that the concentration of IL-6 used enhances transport by increasing the permeability of the endothelial barrier. Also unlike in human peripheral monocytes, 27 IL-6 stimulation did not cause any changes in RNA or protein levels of SR-BI or ABCG1 in endothelial cells.…”

Section: Discussionmentioning

confidence: 94%

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Robert

Lehner

Frank

et al. 2013

ATVB

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Objective-In the reverse cholesterol transport pathway, high-density lipoprotein (HDL) passes the endothelial cell barrier by mechanisms involving the scavenger receptor class B type I and the ATP-binding cassette G1. However, little is known on how inflammation influences this transendothelial transport. Approach and Results-On stimulation with interleukin-6, cultivated primary endothelial cells showed increased binding and transport of 125 I-HDL without changing the expression of scavenger receptor class B type I and ATP-binding cassette G1. Therefore, we analyzed the involvement of endothelial lipase (EL), a known HDL-binding protein expressed by endothelial cells. Here, we show an increased EL expression after interleukin-6 stimulation. Moreover, using pharmacological inhibitors or RNA interference against EL, we demonstrated its participation in HDL binding and transport through the endothelium. Furthermore, adenovirus-mediated transfection of endothelial cells with either catalytically active or nonactive EL revealed that EL facilitates the endothelial binding and transport by both bridging and lipolysis of HDL. EL was also found responsible for the reduction of HDL particle size occurring during the specific transport through a monolayer of endothelial cells. Finally, pharmacological inhibition of EL reversed the inducing effect of interleukin-6 on HDL binding and transport.Conclusions-Interleukin-6 stimulates the translocation of HDL through the endothelium, the first step in reverse cholesterol transport pathway, by enhancing EL expression. In addition, we demonstrated the role of EL in the transendothelial transport of HDL. [13][14][15][16] Moreover, several groups demonstrated the upregulation of EL on inflammatory stimulation both in vitro and in vivo. [17][18][19][20] In this study, we provide evidence that EL participates in endothelial binding, cell association, and transport of HDL. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results IL-6 Induces HDL Binding, Cell Association, and TransportTo investigate whether the interaction of HDL with endothelial cells is changed by the inflammatory cytokine IL-6, we stimulated aortic endothelial cells with IL-6. The interaction of HDL with the endothelial cells was characterized as binding at 4°C, cell association and transport at 37°C. IL-6 induced HDL binding to endothelial cells in a dose-and timedependent manner ( Figure IA and IB in the online-only Data Supplement). HDL binding was significantly increased after incubation with 1-or 10-ng/mL IL-6. Because of the maximal effects seen, all subsequent experiments were performed on cells that were stimulated without 0-or 10-ng/mL IL-6 for 24 hours. After 24 hours of IL-6 stimulation, specific binding was induced by 200±67% compared with not stimulated cells (100±28%; Figure 1A). Conversely, the specific cellularassociated HDL and the transported HDL were also increased by 144±21% and 178±39%, respectively, compared with not stimulated cells (100±17%; Figure 1B a...

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Section: Discussionmentioning

confidence: 94%

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Robert

Lehner

Frank

et al. 2013

ATVB

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“…LPS as well as TNF-␣ are considered as important factors that induce endothelial permeability, leading to circulatory collapse (Nooteboom et al, 2002). Compared with TNF-␣ and IL-1␤, no other cytokine has been shown to reproduce the dramatic hypotension and pathophysiological changes associated with septic shock.…”

Section: Discussionmentioning

confidence: 99%

Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality

Birkenmeier

Nicklisch²,

Pockelt³

et al. 2006

J Pharmacol Exp Ther

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A drug targeting both the inflammatory initiators (lipopolysaccharide; LPS) and mediators [tumor necrosis factor-␣ (TNF-␣)]should have advantage over a "single-factor targeting strategy" in sepsis prevention trials. We have prepared conjugates of polymyxin B (PMB) and the cytokine binding protein ␣2-macroglobulin (A2M). The conjugate binds TNF-␣ as well as LPS as studied by electrophoresis and phase partitioning. Compared with free PMB, the conjugate is nontoxic to cells and does not affect the viability of human monocytes. The A2M-PMB conjugate binds to the A2M receptor (CD91/low-density lipoprotein receptor-related protein 1) with affinity similar to that of the nonmodified protein. Fluorescein isothiocyanate-labeled LPS in the presence of A2M-PMB is rapidly transported into fibroblasts for degradation via receptor-mediated endocytosis. In vitro, A2M-PMB demonstrated inhibition of LPS-induced secretion of TNF-␣ from isolated monocytes as well as in the whole blood assay. The efficacy of the drug was tested in mice after induction of acute inflammation (LPS model) and after induction of a polymicrobial sepsis by cecal ligation and puncture (CLP) model. Treatment of mice with A2M-PMB up to 250 g/g body weight was not toxic to the animal. When the drug was administered 30 min before or 30 min after the LPS challenge, a survival rate of 90 and 70%, respectively, was obtained compared with the placebo control group (5%). A2M-PMB also protected mice after induction of polymicrobial sepsis when administered 30 min before CLP. These results support our hypothesis that A2M-PMB acts as a polyvalent drug to target different host mediators as well as sepsis inducer at the same time.In the past several years, mortality in patients with sepsis syndrome has decreased somewhat, but in those patients with septic shock and multiple organ failure, mortality still exceeds 50% (Danai and Martin, 2005). This high mortality is observed despite ventilatory, hemodynamic, metabolic, and renal support. Some patients-in particular, patients with genetic polymorphisms associated with low or moderate TNF response-survive the ordeal more often, but it remains frustrating not being able to stop the downhill course leading to multiple organ failure and death in other patients that results from overwhelming inflammation. New therapies have been sought and tested, including those preventing the biological activity of pathogen-associated molecular patterns, such as endotoxin or the downhill host response, most notably TNF-␣. Based on a wealth of animal studies, anti-inflammatory strategies, such as neutralizing TNF-␣, have been advocated to provide adjunctive therapy to the patient who continues to deteriorate in the face of considerable support in the intensive care unit. Unfortunately, these anticytokine therapies have not dramatically reduced mortality in doubleblind, placebo-controlled trials involving thousands of patients, although there is a consistent but statistically non-

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“…Blood-borne TNF-␣ and interleukin (IL)-1␤ seem to mediate LPS-induced endothelial permeability. 3 Endothelial cells recognize the presence of microbial components such as LPS via a receptor complex that contains at least three cell surface components: CD14, Toll-like receptor-4 (TLR-4), and MD-2. Endothelial cell contact with LPS or TNF-␣ initiates nuclear factor (NF)-B activation, which results in protein expression.…”

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confidence: 99%

“…Endothelial cell contact with LPS or TNF-␣ initiates nuclear factor (NF)-B activation, which results in protein expression. 3 There is little evidence of direct toxicity of LPS on cultured human endothelial cells. 4,5 When transcriptional products are inhibited by cycloheximide (CHX), 5 endothelial cells become sensitized to apoptotic signals.…”

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confidence: 99%

C5a-Induced Gene Expression in Human Umbilical Vein Endothelial Cells

Albrecht¹,

Chinnaiyan²,

Varambally³

et al. 2004

The American Journal of Pathology

155

106

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Tumor necrosis factor-α and interleukin-1β mediate endothelial permeability induced by lipopolysaccharide-stimulated whole blood

Cited by 50 publications

References 36 publications

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality

C5a-Induced Gene Expression in Human Umbilical Vein Endothelial Cells

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