Interleukin-6-induced tethering of STAT3 to the LAP/C/EBP beta promoter suggests a new mechanism of transcriptional regulation by STAT3

LAP/C/EBP beta is a member of the C/EBP family of transcription factors and contributes to the regulation of the acute phase response in hepatocytes. Here we show that IL-6 controls LAP/C/EBP beta gene transcription and ident ify an IL-6 responsive element in the LAP/C/EBP beta promoter, which contai ns no STAT3 DNA binding motif. However, luciferase reporter gene assays sho wed that STAT3 activation through the gp130 signal transducer molecule is i nvolved in mediating IL-6-dependent LAP/C/EBP beta transcription. Southwest ern analysis indicated that IL-6 induces binding of a 68-kDa protein to the recently characterized CRE-like elements in the LAP/C/EBP beta promoter. T ransfection experiments using promoter constructs with mutated CRE-like ele ments revealed that these sites confer IL-6 responsiveness. Further analysi s using STAT1/STAT3 chimeras identified specific domains of the protein tha t are required for the IL-6-dependent increase in LAP/C/EBP beta gene trans cription; Overexpression of the amino-terminal domain of STAT3 blocked the IL-6-mediated response, suggesting that the STAT3 amino terminus has an imp ortant function in IL-8-mediated transcription of the LAP/C/EBP beta gene. These data lead to a model of how tethering STAT3 to a DNA-bound complex co ntributes to IL-6-dependent LAP/C/EBP beta gene transcription. Our analysis describes a new mechanism by which STAT3 controls gene transcription and w hich has direct implication for the acute phase response in liver cells.