NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancer

Kisseleva, Tatiana; Li, Song; Vorontchikhina, Marina; Feirt, Nikki; Kitajewski, Jan; Schindler, Christian

doi:10.1172/jci27392

Cited by 133 publications

(135 citation statements)

References 62 publications

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“…This information suggests that alveolar macrophages are required for initiation of LPSinduced inflammatory responses in the lungs, likely through activation of NF-B signaling. However, our data and another recent study (25) indicate that NF-B signaling in nonimmune cells is critical for determining the lung's response to injurious stimuli. Kisseleva et al (25) expressed a dominant inhibitor of the NF-B pathway in endothelial cells using the Tie2 promoter and found that NF-B blockade resulted in increased vascular permeability in the lungs, increased endothelial apoptosis, and increased mortality in response to systemic LPS.…”

Section: Discussioncontrasting

confidence: 41%

Airway Epithelium Controls Lung Inflammation and Injury through the NF-κB Pathway

Cheng

Han

Chen

et al. 2007

The Journal of Immunology

162

161

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Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-κB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-κB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IκB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-κB activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-κB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IκB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-κB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.

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Section: Discussioncontrasting

confidence: 41%

Airway Epithelium Controls Lung Inflammation and Injury through the NF-κB Pathway

Cheng

Han

Chen

et al. 2007

The Journal of Immunology

162

161

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“…Lipopolysaccharide (LPS) is an inflammatory agent that activates a wide range of responses partly mediated by TLR4 and NF B. In the liver, NF B plays an antiapoptotic role and provides protection against LPS-induced liver failure (26,27). Consistent with Sirt1 tg mice having lower levels of NF B activity, Sirt1-tg mice on SD revealed a marked LPS hypersensitivity compared with WT controls (Fig.…”

Section: Transgenic Sirt1 Mice Are Protected From Hepatic Inflammationmentioning

confidence: 92%

Sirt1 protects against high-fat diet-induced metabolic damage

Pfluger

Herranz

Velasco-Miguel

et al. 2008

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

846

777

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The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat dietinduced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipidinduced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1␣, and lower activation of proinflammatory cytokines, such as TNF␣ and IL-6, via downmodulation of NF B activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.inflammation ͉ metabolism ͉ NF B ͉ sirtuins ͉ steatosis D riven by the need for potent and safe options to treat obesity, diabetes, and the metabolic syndrome, numerous efforts are currently underway to achieve a better understanding of the molecular networks controlling cellular glucose, lipid, and energy metabolism (1-3). It is generally accepted that gene-environment interactions (such as the effect of high-fat diets on the molecular pathways that maintain energy homeostasis) play a key role in the pathogenesis of the metabolic syndrome (4). Intriguingly, several reports recently showed that specific dietary fatty acids can directly activate Toll-like receptors, which are better known as components of the innate immune system recognizing bacteria-derived fatty acids (5-7). The resulting immune response promotes the systemic activation of proinflammatory pathways including NF B, TNF␣, or IL-6 (5, 6). This chain of events is believed to ultimately lead to insulin resistance, setting in motion the vicious cycle of the metabolic syndrome (8).Recently, a series of studies in several organisms revealed multiple important links of the Sirtuin family of proteins with energy metabolism and inflammation (9-11). Also known as silent information regulator 2 (Sir2)-related enzymes, the Sirtuins have been well conserved throughout evolution and represent a family of nicotinamide adenine dinucleotide-dependent enzymes that deacetylate residues of acetylated lysine. The mammalian sirtuins Sirt1-Sirt7 are implicated in a number of cellular and physiological functions including gene sil...

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“…Treatment of zebrafish embryos with NF-κB inhibitors provoked vascular leakage and altered vessel morphology (38). Tie2 promoter/enhancer-IκB S32A-S36A transgenic mice, in which the endothelial-specific Tie2 promoter drives the expression of a trans-dominant-negative mutant of NF-κB and therefore present an inhibition of endothelial NF-κB signaling, developed normally and displayed, in particular, a normal pattern of vascular development (39). However, inoculated tumors grew faster in these mice, and histologic analysis revealed a striking increase in tumor vascularization.…”

Section: Molecular Cancer Therapeuticsmentioning

confidence: 99%

NF-κB activation in endothelial cells is critical for the activity of angiostatic agents

Tabruyn

Mémet

Avé

et al. 2009

Molecular Cancer Therapeutics

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In tumor cells, the transcription factor NF-κB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth factor. From these data, a protumorigenic role of NF-κB has emerged. Here, we examined in endothelial cells whether NF-κB signaling pathway is involved in mediating the angiostatic properties of angiogenesis inhibitors. The current report describes that biochemically unrelated agents with direct angiostatic effect induced NF-κB activation in endothelial cells. Our data showed that endostatin, anginex, angiostatin, and the 16-kDa N-terminal fragment of human prolactin induced NF-κB activation in endothelial cells in both cultured human endothelial cells and in vivo in a mouse tumor model. It was also found that NF-κB activity was required for the angiostatic activity, because inhibition of NF-κB in endothelial cells impaired the ability of angiostatic agents to block sprouting of endothelial cells and to overcome endothelial cell anergy. Therefore, activation of NF-κB in endothelial cells can result in an unexpected antitumor outcome. Based on these data, the current approach of systemic treatment with NF-κB inhibitors may therefore be revisited because NF-κB activation specifically targeted to endothelial cells might represent an efficient strategy for the treatment of cancer. [Mol Cancer Ther 2009;8(9):2645-54]

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NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancer

Cited by 133 publications

References 62 publications

Airway Epithelium Controls Lung Inflammation and Injury through the NF-κB Pathway

Airway Epithelium Controls Lung Inflammation and Injury through the NF-κB Pathway

Sirt1 protects against high-fat diet-induced metabolic damage

NF-κB activation in endothelial cells is critical for the activity of angiostatic agents

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