Inhibition of hepatic transcriptional induction of lipopolysaccharide-binding protein by transforming-growth-factor beta 1.
LPS-binding protein (LBP) is an acute-phase protein with the ability to bind and transfer LPS of Gram-negative bacteria, as well as cell wall compounds of other pathogenic bacteria. This soluble pattern-recognition molecule is present in high concentrations in serum and represents an important defense mechanism of the host. Regulation of the hepatic acute-phase response and its termination are important mechanisms for limiting systemic inflammatory activity of the host organism. We show here that TGF-beta 1, in a dose-dependent fashion, is able to inhibit LBP transcript accumulation and LBP protein synthesis induced by IL-6, IL-1 beta and dexamethasone in hepatoma cell lines. These data were confirmed employing primary human hepatocytes, where TGF-beta 1 also inhibited LBP protein synthesis. We identified and analyzed several Smad-binding sites (Smads are major regulatory elements of TGF-beta 1) within the LBP promoter, and found that one of them was active. We furthermore identified an AP-1-binding site clearly conferring inhibitory effects of TGF-beta 1 towards LBP promoter activity, shown by gel shift and promoter mutagenesis experiments. Further elucidating the mechanism of transcriptional regulation of proteins involved in innate immune responses may potentially help to develop novel intervention strategies for the acute-phase response, sepsis, and septic shock.
Hallatschek
Werner
W
Institut für Mikrobiologie und Hygiene, Charité Medical Center, Humboldt-University, Berlin, Germany.
Fiedler
Gesa
G
Kirschning
Carsten J
CJ
Creutzburg
Fränzi
F
Lamping
Norbert
N
Nüssler
Andreas
A
Schumann
Ralf R
RR
D000209:Acute-Phase Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008562:Membrane Glycoproteins; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018793:Interleukin-13; D015847:Interleukin-4; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D051785:Smad Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D000099231:Lipopolysaccharide-Binding Protein