TRANSCRIPTION FACTORS MODULATING ANGIOTENSINOGEN GENE-EXPRESSION IN HEPATOCYTES

Transcripting factors modulating angiotensinogen gene expression in he patocytes. The gene encoding angiotensinogen is regulated at the trans criptional level in hepatocytes in response to glucocorticoids and inf lammatory cytokines (IL-1 and TNF). These hormones activate transcript ion of the angiotensinogen gene by changing the abundance of DNA bindi ng proteins that interact with a multihormone-inducible enhancer locat ed between nucleotides -615 to -440 upstream of the major transcriptio n start site. Activation of this enhancer in hepatocytes is effected b y glucocorticoid- and cytokine-inducible DNA binding proteins. Cytokin e induction is mediated through the interaction of two classes of tran scription factors that bind to the acute-phase response element (APRE) : nuclear factor-KB (NF-KB), and CCAAT-Box/Enhancer Binding Protein (C /EBP). NF-KB is a multiprotein DNA binding complex sequestered in the cytoplasm that is induced in the nucleus by cytokines, whereas C/EBP i s a nuclear transcription factor family implicated in the expression o f differentiated hepatic proteins. During the acute-phase response, in dividual C/EBP family members are discordinately regulated: C/EBP alph a levels fall, whereas another C/EBP family member termed nuclear fact or IL6 (NF-IL6), is induced. We investigated the interaction between t he two acute-phase induced APRE-binding proteins: NF-kappa B and NF-IL 6. Both proteins bind to overlapping nucleotides in a mutually exclusi ve fashion with similar affinities for the APRE. NF-IL6, a less potent transactivator, attenuates NF-KB mediated transcription late in the e volution of the acute-phase response. These observations argue for a t emporal model of sequentially-expressed transcription factors occupyin g the APRE during the evolution of the inflammatory process.