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Multiorgan nuclear factor kappa B activation in a transgenic mouse model of systemic inflammation.

Abstract
We utilized a line of transgenic mice expressing Photinus luciferase complementary DNA (cDNA) under the control of a nuclear factor kappa B (NF-kappaB)-dependent promoter (from the 5' human immunodeficiency virus-1 [HIV-1] long terminal repeat) to examine the role of NF-kappaB activation in the pathogenesis of systemic inflammation induced by bacterial endotoxin (lipopolysaccharide [LPS]). After intraperitoneal injection of E. coli LPS, these mice displayed a time- and dose-dependent, organ-specific pattern of luciferase expression, showing that NF-kappaB-dependent gene transcription is transiently activated in multiple organs by systemic LPS administration. Luciferase expression in liver could be specifically blocked by intravenous administration of replication-deficient adenoviral vectors expressing a dominant inhibitor of NF-kappaB (IkappaB-alphaDN), confirming that luciferase gene expression is a surrogate marker for NF-kappaB activation in this line of mice. After treatment with intraperitoneal LPS, the mice were found to have increased lung tissue messenger RNA (mRNA) expression of a variety of cytokines that are thought to be NF-kappaB-dependent, as well as elevated serum concentrations of presumed NF-kappaB-dependent cytokines. In lung tissue homogenates, a close correlation was identified between luciferase activity and KC levels. These studies show that systemic treatment with LPS orchestrates a multiorgan NF-kappaB-dependent response that likely regulates the pathobiology of systemic inflammation.
AuthorsT S Blackwell, F E Yull, C L Chen, A Venkatakrishnan, T R Blackwell, D J Hicks, L H Lancaster, J W Christman, L D Kerr
JournalAmerican journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 162 Issue 3 Pt 1 Pg. 1095-101 (Sep 2000) ISSN: 1073-449X [Print] UNITED STATES
PMID10988136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Cytokines
  • DNA, Complementary
  • Lipopolysaccharides
  • RNA, Messenger
  • Luciferases
Topics
  • Animals
  • Cytokines (genetics, metabolism)
  • DNA, Complementary (genetics)
  • HIV Enhancer (genetics)
  • Humans
  • Lipopolysaccharides (immunology)
  • Luciferases (genetics)
  • Lung (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • RNA, Messenger (genetics)
  • Systemic Inflammatory Response Syndrome (genetics, immunology)

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