TNF-inducible expression of lymphotoxin-β in hepatic cells: An essential role for NF-κB and Ets1 transcription factors

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2012-11, Vol.60 (2), p.498-504
• Main Authors: Subrata, Lily S., Voon, Dominic C., Yeoh, George C.T., Ulgiati, Daniela, Quail, Elizabeth A., Abraham, Lawrence J.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Binding Sites; cytokines; Early Growth Response Protein 1 - metabolism; Ets1; Hep G2 Cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; liver; Lymphotoxin; Lymphotoxin-beta - genetics; Lymphotoxin-beta - metabolism; Mice; Molecular Sequence Data; NF-kappa B - metabolism; Oval cells; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Protein Binding - genetics; Protein Multimerization - drug effects; Protein Multimerization - genetics; Proto-Oncogene Protein c-ets-1 - metabolism; Sp1 Transcription Factor - metabolism; T-lymphocytes; Tetradecanoylphorbol Acetate - pharmacology; TNF; transcription (genetics); Transcription factor; Transcription Factor RelA - metabolism; transcription factors; Transcriptional Activation - drug effects; Transcriptional Activation - genetics; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2012.05.029

► TNF activates lymphotoxin-beta transcription. ► NF-κB and Ets cis-acting transcriptional elements mediate TNF activation. ► NF-κB p50 and p65 bind lymphotoxin-beta promoter sequences. ► Ets1 binds the promoter in vivo. ► Ets1 overexpression transactivates the lymphotoxin-beta gene. As TNF is one of the earliest signals that can be detected in the leukocyte-derived inflammatory cascade which drives subsequent cytokine production, we are interested in determining whether TNF is one of the initiating factors controlling liver remodeling and regeneration following chronic liver damage. One of the early responses is the expression of lymphotoxin-β by hepatic progenitor oval cells. The aim of this study was to determine whether hepatic expression of LT-β was controlled by TNF and to understand the basis of this regulation. We previously showed that LT-β expression is transcriptionally controlled via the TNF-induced, inflammatory NF-κB pathway in T lymphocytes. Here we show that TNF is able to upregulate LT-β expression in hepatic cells at the transcriptional level by the binding of NF-κB p50/p65 heterodimers and Ets1 to their respective sites in the LT-β promoter.