title: 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.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Departments of Microbiology and Immunology, and Cell Biology, Vanderbilt University School of Medicine, Nashville, USA. timothy.blackwell@mcmail.vanderbilt.edu
authors.forename: T S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: F E
authors.initials: FE
authors.lastname: Yull
authors.forename: C L
authors.initials: CL
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Venkatakrishnan
authors.forename: T R
authors.initials: TR
authors.lastname: Blackwell
authors.forename: D J
authors.initials: DJ
authors.lastname: Hicks
authors.forename: L H
authors.initials: LH
authors.lastname: Lancaster
authors.forename: J W
authors.initials: JW
authors.lastname: Christman
authors.forename: L D
authors.initials: LD
authors.lastname: Kerr
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D016322:HIV Enhancer / Q000235:genetics*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008156:Luciferases / Q000235:genetics; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics* / Q000276:immunology
chemical_list: D016207:Cytokines; D018076:DNA, Complementary; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D008156:Luciferases