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

Background: Lymphotoxin-β (LT-β) plays an important role in inflammation and its promoter contains a functional nuclear factor-κB (NF-κB) 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-β levels are upregulated, suggesting a link between LT-β and liver regeneration. Results: The expression of LT-β in hepatic oval cell and hepatocellular carcinoma cell lines was further investigated, along with its responsiveness to IL-6 and IL-1β. Key regulatory cis-acting elements of the LT-β promoter that mediate IL-6 responsiveness (Sp/BKLF, Ets, NF-κB and Egr-1/Sp1) and IL-1β responsiveness (NF-κB and Ets) of hepatic LT-β expression were identified. The novel binding of basic Kruppel-like factor (BKLF) proteins to an apparent composite Sp/BKLF site of the LT-β promoter was shown to mediate IL-6 responsiveness. Binding of NF-κB p65/p50 heterodimers and Ets-related transcription factors to their respective sites mediates responsiveness to IL-1β. Conclusion: The identification of IL-6 and IL-1β as activators of LT-β supports their involvement in LT-β signaling in liver regeneration associated with chronic liver damage.