Mechanisms of transcriptional activation of lipopolysaccharide binding protein (LBP).
The Lipopolysaccharide Binding Protein (LBP) is of high importance for endotoxin recognition, presentation and subsequent cytokine induction in immune cells. LBP, which is a member of a growing family of structurally and functionally related proteins, is synthesized in hepatocytes and secreted into the blood stream constitutively. During the acute phase response, however, LBP levels rise substantially and here the mechanisms of induction of LBP protein synthesis were reviewed. The induction of LBP in hepatocytes is due to transcriptional and posttranscriptional mechanisms as we have shown by nuclear run-on and RNA half-life experiments. Cloning of the 5'-flanking region of the LBP gene, furthermore revealed 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, named APRE/STAT-3 is essential for activation of the LBP promoter. Elucidation of the transcriptional activation mechanism could point the way to a therapeutically lowering of LBP levels in high risk patients for reducing their susceptibility to Gram-negative septic shock.
Schumann
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Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Cancer Center, University Hospital Rudolf-Virchow, Free University of Berlin, Germany.
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000517:prevention & control; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000378:metabolism; D008562:Membrane Glycoproteins; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000517:prevention & control; D014115:Toxemia / Q000517:prevention & control; D015533:Transcriptional Activation; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D000099231:Lipopolysaccharide-Binding Protein