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

J Clin Invest. 2006 Nov;116(11):2955-63. doi: 10.1172/JCI27392. Epub 2006 Oct 19.


The transcription factor NF-kappaB is an important regulator of homeostatic growth and inflammation. Although gene-targeting studies have revealed important roles for NF-kappaB, they have been complicated by component redundancy and lethal phenotypes. To examine the role of NF-kappaB in endothelial tissues, Tie2 promoter/enhancer-IkappaBalpha(S32A/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-kappaB 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-kappaB plays an important role in the maintenance of vascular integrity and response to stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Endothelial Cells / ultrastructure
  • Genetic Predisposition to Disease
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • NF-kappa B / metabolism*
  • Neoplasms / metabolism*
  • Permeability / drug effects
  • Sepsis / chemically induced
  • Sepsis / metabolism
  • Sepsis / pathology
  • Stress, Physiological / chemically induced
  • Stress, Physiological / genetics
  • Stress, Physiological / metabolism
  • Stress, Physiological / pathology
  • Toxemia / genetics
  • Toxemia / metabolism*
  • Toxemia / pathology
  • Tumor Necrosis Factor-alpha / pharmacology


  • Lipopolysaccharides
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • I-kappa B Kinase