Mol Cell Biol 1996,
PMID: 8668165
Schumann, R R; Kirschning, C J; Unbehaun, A; Aberle, H P; Knope, H P; Lamping, N; Ulevitch, R J; Herrmann, F
Acute-phase reactants (APRs) are proteins synthesized in the liver following induction by interleukin-1 (IL-1), IL-6, and glucocorticoids, involving transcriptional gene activation. Lipopolysaccharide-binding protein (LBP) is a recently identified hepatic secretory protein potentially involved in the pathogenesis of sepsis, capable of binding the bacterial cell wall product endotoxin and directing it to its cellular receptor, CD14. In order to examine the transcriptional induction mechanisms by which the LBP gene is activated, we have investigated the regulation of expression of its mRNA in vitro and in vivo as well as the organization of 5' upstream regulatory DNA sequences. We show that induction of LBP expression is transcriptionally regulated and is dependent on stimulation with IL-1beta, IL-6, and dexamethasone. By definition, LBP thus has to be viewed as a class 1 acute-phase protein and represents the first APR identified which is capable of detecting pathogenic bacteria. Furthermore, cloning of the LBP promoter revealed the presence of regulatory elements, including the common APR promoter motif APRE/STAT-3 (acute-phase response element/signal transducer and activator of transcription 3). Luciferase reporter gene assays utilizing LBP promoter truncation and point mutation variants indicated that transcriptional activation of the LBP gene required a functional APRE/STAT-3 binding site downstream of the transcription start site, as well as an AP-1 and a C/EBP (CCAAT enhancer-binding protein) binding site. Gel retardation and supershift assays confirmed that upon cytokine stimulation APRF/STAT-3 binds to its recognition site, leading to strong activation of the LBP gene. Unraveling of the mechanism of transcriptional activation of the LBP gene, involving three known transcription factors, may contribute to our understanding of the acute-phase response and the pathophysiology of sepsis and septic shock.
Diseases/Pathways annotated by Medline MESH: Carcinoma, Hepatocellular, Liver Neoplasms
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Text Mining Data
LBP → IL-1beta: "
We show that induction of
LBP expression is transcriptionally regulated and is
dependent on stimulation with
IL-1beta , IL-6, and dexamethasone
"
LBP → IL-6: "
We show that induction of LBP expression is transcriptionally regulated and is dependent on stimulation with IL-1beta, IL-6 , and dexamethasone
"
Manually curated Databases
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NCI Pathway Database IL6-mediated signaling events:
STAT3 (dimer ) complex (STAT3)
→
CEBPB (CEBPB)
(transcription, activates)
Evidence: mutant phenotype, reporter gene, physical interaction
-
NCI Pathway Database IL6-mediated signaling events:
STAT3 (dimer ) complex (STAT3)
→
LBP (LBP)
(transcription, activates)
Evidence: mutant phenotype, reporter gene, physical interaction
-
NCI Pathway Database IL6-mediated signaling events:
STAT3 (dimer ) complex (STAT3)
→
AP1 complex (FOS-JUN)
(transcription, activates)
Evidence: mutant phenotype, reporter gene, physical interaction
-
NCI Pathway Database IL6-mediated signaling events:
CEBPB (CEBPB)
→
LBP (LBP)
(transcription, activates)
Evidence: mutant phenotype, reporter gene, physical interaction
-
NCI Pathway Database IL6-mediated signaling events:
CEBPB (CEBPB)
→
AP1 complex (FOS-JUN)
(transcription, activates)
Evidence: mutant phenotype, reporter gene, physical interaction
In total, 8 gene pairs are associated to this article in curated databases