Hepatic expression of the tumor necrosis factor family member lymphotoxin-β is regulated by interleukin (IL)-6 and IL-1β: transcriptional control mechanisms in oval cells and hepatoma cell lines

Background: Lymphotoxin-beta (LT-beta) plays an important role in inflammation and its promoter contains a functional nuclear factor-kappa B (NF-kappa B) element, rendering it a likely target of pro-inflammatory cytokines. Inflammatory cytokines play a central role in liver regeneration resulting from acute or chronic liver injury, with interleukin (IL)-6 signaling essential for liver regeneration induced by partial hepatectomy. In hepatic oval cells observed following chronic liver injury, LT-beta levels are upregulated, suggesting a link between LT-beta and liver regeneration. Results: The expression of LT-beta in hepatic oval cell and hepatocellular carcinoma cell lines was further investigated, along with its responsiveness to IL-6 and IL-1 beta. Key regulatory cis-acting elements of the LT-beta promoter that mediate IL-6 responsiveness (Sp/BKLF, Ets, NF-kappa B and Egr-1/Sp1) and IL-1 beta responsiveness (NF-kappa B and Ets) of hepatic LT-beta expression were identified. The novel binding of basic Kruppel-like factor (BKLF) proteins to an apparent composite Sp/BKLF site of the LT-beta promoter was shown to mediate IL-6 responsiveness. Binding of NF-kappa B p65/p50 heterodimers and Ets-related transcription factors to their respective sites mediates responsiveness to IL-1 beta. Conclusion: The identification of IL-6 and IL-1 beta as activators of LT-beta supports their involvement in LT-beta signaling in liver regeneration associated. with chronic liver damage.