C/EBPα and C/EBPβ binding proteins modulate hepatocyte apoptosis through iNOS signaling pathway

Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) involve many pathophysiologic conditions. The expression of iNOS is regulated at multiple stages. Presently, the regulatory details of iNOS signaling are still unclear. This study aimed to investigate the regulatory role of C/EBP alpha. and C/EBP beta, in iNOS signaling pathway. By employing the techniques such as EMSA, ChIP assay, site-directed mutagenesis, and siRNA silencing, the relationship between iNOS and C/EBP alpha/C/EBP beta in rat hepatocytes was clarified. iNOS promoter was the direct transcriptional targets of the C/EBP alpha, C/EBP beta, and NF-kappa B binding proteins. There was the interactive influence between NF-kappa B and C/EBP alpha/C/EBP beta. The expression of iNOS was modulated by C/EBP alpha/C/EBP beta transcription factors. Moreover, the iNOS expression mediated glycochenodeoxycholate (GCDC)-induced apoptosis in hepatocytes. C/EBP alpha/C/EBP beta binding proteins could affect the GCDC-induced apoptosis through iNOS cascade. These findings indicate that C/EBP alpha and C/EBP beta regulate the iNOS expression, which may further modify cell responses such as apoptosis and cell survival. (C) 2011 Elsevier B.V. All rights reserved.