Transcription factors modulating angiotensinogen gene expression in hepatocytes

Abstract

The gene encoding angiotensinogen is regulated at the transcriptional level in hepatocytes in response to glucocorticoids and inflammatory cytokines (IL-1 and TNF). These hormones activate transcription of the angiotensinogen gene by changing the abundance of DNA binding proteins that interact with a multihormone-inducible enhancer located between nucleotides -615 to -440 upstream of the major transcription start site. Activation of this enhancer in hepatocytes is effected by glucocorticoid- and cytokine-inducible DNA binding proteins. Cytokine induction is mediated through the interaction of two classes of transcription factors that bind to the acute-phase response element (APRE): nuclear factor-kappa B (NF-kappa B), and CCAAT-Box/Enhancer Binding Protein (C/EBP). NF-kappa B is a multiprotein DNA binding complex sequestered in the cytoplasm that is induced in the nucleus by cytokines, whereas C/EBP is a nuclear transcription factor family implicated in the expression of differentiated hepatic proteins. During the acute-phase response, individual C/EBP family members are discordinately regulated: C/EBP alpha levels fall, whereas another C/EBP family member termed nuclear factor IL6 (NF-IL6), is induced. We investigated the interaction between the two acute-phase induced APRE-binding proteins: NF-kappa B and NF-IL6. Both proteins bind to overlapping nucleotides in a mutually exclusive fashion with similar affinities for the APRE. NF-IL6, a less potent transactivator, attenuates NF-kappa B mediated transcription late in the evolution of the acute-phase response. These observations argue for a temporal model of sequentially-expressed transcription factors occupying the APRE during the evolution of the inflammatory process.