Abstract
Background:
Lymphotoxin-beta (LT-beta) plays an important role in inflammation and its promoter contains a functional nuclear factor-kappaB (NF-kappaB) 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-1beta. Key regulatory cis-acting elements of the LT-beta promoter that mediate IL-6 responsiveness (Sp/BKLF, Ets, NF-kappaB and Egr-1/Sp1) and IL-1beta responsiveness (NF-kappaB 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-kappaB p65/p50 heterodimers and Ets-related transcription factors to their respective sites mediates responsiveness to IL-1beta.
Conclusion:
The identification of IL-6 and IL-1beta as activators of LT-beta supports their involvement in LT-beta signaling in liver regeneration associated with chronic liver damage.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Base Sequence
-
Carcinoma, Hepatocellular
-
Cell Line, Transformed
-
Cell Line, Tumor
-
DNA-Binding Proteins / metabolism
-
Early Growth Response Protein 1
-
Gene Expression Regulation / drug effects*
-
Gene Expression Regulation / immunology
-
Hepatocytes / cytology
-
Hepatocytes / physiology*
-
Humans
-
Immediate-Early Proteins / metabolism
-
Interleukin-1 / pharmacology*
-
Interleukin-6 / pharmacology*
-
Kruppel-Like Transcription Factors
-
Liver Neoplasms
-
Lymphotoxin-alpha / genetics*
-
Lymphotoxin-alpha / metabolism
-
Lymphotoxin-beta
-
Membrane Proteins / genetics*
-
Membrane Proteins / metabolism
-
Molecular Sequence Data
-
Mutagenesis, Site-Directed
-
NF-kappa B / metabolism
-
NF-kappa B p50 Subunit
-
Promoter Regions, Genetic / genetics
-
Protein Precursors / metabolism
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-ets
-
Signal Transduction / immunology
-
Sp1 Transcription Factor / metabolism
-
Transcription Factor RelA
-
Transcription Factors / metabolism
-
Transcription, Genetic / drug effects
-
Transcription, Genetic / immunology
Substances
-
DNA-Binding Proteins
-
EGR1 protein, human
-
Early Growth Response Protein 1
-
Immediate-Early Proteins
-
Interleukin-1
-
Interleukin-6
-
KLF3 protein, human
-
Kruppel-Like Transcription Factors
-
LTB protein, human
-
Lymphotoxin-alpha
-
Lymphotoxin-beta
-
Membrane Proteins
-
NF-kappa B
-
NF-kappa B p50 Subunit
-
Protein Precursors
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-ets
-
Sp1 Transcription Factor
-
Transcription Factor RelA
-
Transcription Factors