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

We utilized a line of transgenic mice expressing Photinus luciferase comple mentary DNA (cDNA) under the control of a nuclear factor kappa B (NF-kappa B)-dependent promoter (from the 5' human immunodeficiency virus-1 [HIV-1] l ong terminal repeat) to examine the role of NF-kappa B activation in the pa thogenesis of systemic inflammation induced by bacterial endotoxin (lipopol ysaccharide [LPS]). After intraperitoneal injection of E. coli LPS, these m ice displayed a time- and dose-dependent, organ-specific pattern of lucifer ase expression, showing that NF-kappa B-dependent gene transcription is tra nsiently activated in multiple organs by systemic LPS administration. Lucif erase expression in liver could be specifically blocked by intravenous admi nistration of replication-deficient adenoviral vectors expressing a dominan t inhibitor of NF-kappa B (I kappa B-alpha DN), confirming that luciferase gene expression is a surrogate marker for NF-kappa B activation in this lin e 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-kappa B-dependent, as well as elevated serum concentrations of presumed NF-kappa B-dependent cytokines. In lung t issue homogenates, a close correlation was identified between luciferase ac tivity and KC levels. These studies show that systemic treatment with LPS o rchestrates a multiorgan NF-kappa B-dependent response that likely regulate s the pathobiology of systemic inflammation.