Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level.
Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the alpha 2-macroglobulin, fibrinogen, and alpha 1-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-kappa B, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.
Wegenka
U M
UM
Institute for Biochemistry, RWTH Aachen, Germany.
Buschmann
J
J
Lütticken
C
C
Heinrich
P C
PC
Horn
F
F
D000209:Acute-Phase Proteins / Q000235:genetics*; D000210:Acute-Phase Reaction; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D008070:Lipopolysaccharides / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000235:genetics
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008070:Lipopolysaccharides; D008222:Lymphokines; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000511:alpha-Macroglobulins