Z Gastroenterol 2019; 57(01): e83-e84
DOI: 10.1055/s-0038-1677270
5. Viral Hepatitis, Immunology
Georg Thieme Verlag KG Stuttgart · New York

The Hippo signalling is induced by Toll-like receptor 4 activation and regulatory balance innate immune responses in liver cells

X Luo
1   University Duisburg-Essen, Medical faculty, Dept. of Gastroenterology and Hepatology, Germany
,
M Lu
2   University Duisburg-Essen, Medical faculty, Institute of Virology, Germany
,
HA Baba
3   University Duisburg-Essen, Medical faculty, Dept. of Pathology, Germany
,
G Gerken
1   University Duisburg-Essen, Medical faculty, Dept. of Gastroenterology and Hepatology, Germany
,
H Wedemeyer
1   University Duisburg-Essen, Medical faculty, Dept. of Gastroenterology and Hepatology, Germany
,
R Broering
1   University Duisburg-Essen, Medical faculty, Dept. of Gastroenterology and Hepatology, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Background & aims:

Chronic hepatitis B virus (HBV) infection is a key risk factor for the development of hepatocellular carcinoma. Our previous work showed that immune genes as well as oncogenes are induced in primary murine hepatocytes (PMH) exposed to HBV particles. Another remarkable study showed that Hippo signalling is activated by Toll receptor in Drosophila and regulates innate immune response. We here investigated the effect of Hippo signalling on innate immune response in liver cells.

Methods:

Reanalysis ofGEO data was performed to search for eligible pathways associated with HBV infection. In murine hepatoma cell line and PMH LPS-induced changes in the expression of Hippo and NF-κB signalling-relevant mRNA and proteins as well as protein trans-localizations were analyzed. By knocking-down key components of these pathways using short-hairpin RNA, the interplay between TLR and Hippo signalling was elucidated. Binding of Yap/Tead4 complex and associated promoter activity were investigated and proven by dual-lucifersae reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay and immunocytochemistry.

Results:

Gene Set Enrichment Analysis showed Hippo and NF-κB signalling are induced in the context of HBV infection. Immune activation by LPS treatment led to dephosphorylation and nuclear translocation of Yap. The Yap/Tead4 transcription factor complex, which is the downstream of Hippo signaling, had been shown to bind to the Tead4 binding sites in the promoter region of Nfkbia. Moreover, knocking-down Yap and Tead4 also showed that the complex promotes IκBα expression, which was further confirmed by gain-of-function experiments and analysis of DNA/protein interaction. Increased IκBα, the inhibitor of NF-κB signalling, regulatory balanced the rapid immune response in hepatocytes.

Conclusions:

Here, LPS-sensitive Yap/Tead4 transcription factor complex regualted IκBα expression and thereby regulatory balanced innate immune response in hepatocytes. The growth-controlling Hippo signaling pathway might link inflammation and tumourigenesis in HBV infection.