Control of transcriptional activation of the lipopolysaccharide binding protein (LBP) gene by proinflammatory cytokines.
The lipopolysaccharide binding protein (BLP) is of major importance for endotoxin recognition, presentation and subsequent cytokine induction in immune cells. As a member of a growing family of structurally and functionally related proteins, LBP is synthesized in hepatocytes and constitutively secreted into the bloodstream. During the acute-phase response, however, LBP levels rise substantially. In this article the mechanisms of induction of LBP protein synthesis are highlighted. Induction of LBP in hepatocytes is the result of transcriptional and posttranscriptional mechanisms, as shown by nuclear run-on and RNA half-life experiments. Cloning of the 5' flanking region of the LBP gene gave results consistent with the LBP promoter as a typical acute-phase protein promoter. Reporter-gene assays employing the Luciferase gene and mutation variants of the LBP promoter revealed that integrity of a common acute-phase promoter motif, binding STAT-3, is essential for activation of the LBP promoter. Elucidating the transcriptional activation mechanism could show the way how to therapeutically lower LBP levels in high-risk patients in order to reduce their susceptibility to Gram-negative septic shock.
Kirschning
C
C
Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
Unbehaun
A
A
Lamping
N
N
Pfeil
D
D
Herrmann
F
F
Schumann
R R
RR
D000209:Acute-Phase Proteins; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein