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.
View: Text | PDF
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

×

Figure 5

Enhanced tumorigenesis in Tie-Tg mice is endothelial cell intrinsic.

Options: View larger image (or click on image) Download as PowerPoint
Enhanced tumorigenesis in Tie-Tg mice is endothelial cell intrinsic. (A)...
(A) WT and transgenic mice were engrafted with either transgenic or WT (from β-actin–GFP+ mice) BM. Quantification of tumor mass (percent metastasis per micrometer squared of lung tissue) demonstrated that mice with transgenic ECs (i.e., Tg, n = 4; Tg→Tg, n = 3; and β-actin→Tg, n = 6) exhibited considerably higher tumor burdens (respectively, 31%, 27%, and 23% versus 3.6%, 3.9%, and 5.2%; P < 0.0001, P < 0.007, and P < 0.001) than mice with WT ECs (i.e., WT, n = 3; WT→WT, n = 3; and Tg→WT, n = 6). Five fields were evaluated per mouse. Data represent mice from transgenic lines 2 and 4. (B) A significant increase in tumor vascularization in mice with transgenic ECs was revealed by PECAM-1 (CD31), CD34, and ICAM-1 immunostaining visualized under a ×20 objective. (C) Neovascularization in B16-BL6 cell–impregnated Matrigel was significantly increased when transplanted into Tg mice. Blood vessels were revealed by staining for PECAM-1 and visualized under ×4 and ×20 objectives, as indicated.