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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

Authors

  • Lily S. Subrata,

    1. Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences,
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  • Kim N. Lowes,

    1. Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences,
    2. The Western Australian Institute for Medical Research, UWA Centre for Medical Research, and
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  • John K. Olynyk,

    1. The Western Australian Institute for Medical Research, UWA Centre for Medical Research, and
    2. School of Medicine & Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
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  • George C. T. Yeoh,

    1. Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences,
    2. The Western Australian Institute for Medical Research, UWA Centre for Medical Research, and
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  • Elizabeth A. Quail,

    1. Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences,
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  • Lawrence J. Abraham

    1. Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences,
    2. The Western Australian Institute for Medical Research, UWA Centre for Medical Research, and
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Lawrence J. Abraham, PhD, Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, Crawley 6009, Western Australia, Australia.
Tel: +61 8 6488 3041
Fax: +61 8 6488 1148
e-mail: labraham@cyllene.uwa.edu.au

Abstract

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.

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