NF-kappaB regulation of endothelial cell function during LPS-induced toxemia and cancer.
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.
Kisseleva
Tatiana
T
Department of Microbiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Song
Li
L
Vorontchikhina
Marina
M
Feirt
Nikki
N
Kitajewski
Jan
J
Schindler
Christian
C
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D020022:Genetic Predisposition to Disease; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D018805:Sepsis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014115:Toxemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase