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
Subrata, L.S., Lowes, K.N., Olynyk, J.K., Yeoh, G.C.T., Quail, E.A. and Abraham, L.J. (2005) 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. Liver International, 25 (3). pp. 633-646.
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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.
|Publication Type:||Journal Article|
|Copyright:||2005 Blackwell Munksgaard|
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