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-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.


CONCLUSIONS
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.
Subrata
Lily S
LS
Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, Western Australia, Australia.
Lowes
Kim N
KN
Olynyk
John K
JK
Yeoh
George C T
GC
Quail
Elizabeth A
EA
Abraham
Lawrence J
LJ
D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors; D008113:Liver Neoplasms; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000378:metabolism; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D011401:Promoter Regions, Genetic / Q000235:genetics; D011498:Protein Precursors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D015398:Signal Transduction / Q000276:immunology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D015850:Interleukin-6; C501168:KLF3 protein, human; D051741:Kruppel-Like Transcription Factors; C505886:LTB protein, human; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D016329:Sp1 Transcription Factor; D051996:Transcription Factor RelA; D014157:Transcription Factors