NF-κB regulation of endothelial cell function during LPS-induced toxemia and cancer
Tatiana Kisseleva, … , Jan Kitajewski, Christian Schindler
Tatiana Kisseleva, … , Jan Kitajewski, Christian Schindler
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):2955-2963. https://doi.org/10.1172/JCI27392.
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Research Article Vascular biology

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

Abstract

The transcription factor NF-κB is an important regulator of homeostatic growth and inflammation. Although gene-targeting studies have revealed important roles for NF-κB, they have been complicated by component redundancy and lethal phenotypes. To examine the role of NF-κB in endothelial tissues, Tie2 promoter/enhancer–IκBαS32A/S36A transgenic mice were generated. These mice grew normally but exhibited enhanced sensitivity to LPS-induced toxemia, notable for an increase in vascular permeability and apoptosis. Moreover, B16-BL6 tumors grew significantly more aggressively in transgenic mice, underscoring a new role for NF-κB in the homeostatic response to cancer. Tumor vasculature in transgenic mice was extensive and disorganized. This correlated with a marked loss in tight junction formation and suggests that NF-κB plays an important role in the maintenance of vascular integrity and response to stress.

Authors

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

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Figure 6

Enhanced EC leakiness in the transgenic mice.

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Enhanced EC leakiness in the transgenic mice. (A) Vascular permeability ...
(A) Vascular permeability in transgenic (line 4; n = 4) and the WT mice (n = 4) was measured in response to mustard oil with Evans blue dye. Local vascular permeability was increased 4.5-fold in transgenic (P < 0.009) and 2-fold in WT mice (P < 0.0001). No difference was observed in unstimulated mice (n = 4 for each genotype). Similar results were obtained with Tie-Tg line 2. (B) TJs of pulmonary endothelium were evaluated by EM. Lung tissue was harvested from WT or transgenic mice either before (None) or after LPS (2 μg/ml, 18 hours) treatment or 14 days after B16-BL6 tumor injection. Specimens prepared for EM were initially screened at a magnification of ×3,320 (see Supplemental Figure 3C). Areas with adjoining ECs (as indicated in Supplemental Figure 3C) were then examined at a magnification of ×9,960 and are presented in 8 panels, as indicated. Electron-dense TJs are marked with arrows. Other features are marked as EC (endothelial cells), Ly (white blood cells), BV (blood vessels), and B16 (B16–BL6 melanoma cells). EMs are representative images from 3–8 random ×3,320 fields per sample and represent tissues from Tie-Tg lines 2 and 4.