Abstract |
Mechanisms of hepatic fibrogenesis induced by hepatitis C virus (HCV), one of the leading causes of liver fibrosis, are not fully understood. We studied transcriptional up-regulation of transforming growth factor β (TGF-β), especially TGF-β2, which is mediated by activation of liver-enriched transcription factor cAMP-responsive element- binding protein, hepatocyte specific (CREBH) triggered by HCV infection and its functional significance for induction of profibrogenic phenotypes by interaction of HCV-infected cells with hepatic stellate cells (HSCs). Compared to TGF-β1, expression of TGF-β2 mRNA was induced faster and to a higher level upon HCV infection. Serum TGF-β2 levels in hepatitis C patients were higher compared to those in healthy individuals and were positively correlated with hepatic fibrosis stages F0-F2. TGF-β2 promoter activity was decreased and increased, respectively, by silencing and overexpression of CREBH. CREBH recognition sites were identified in the TGF-β2 promoter. CREBH binding to the promoter and its increase in cells expressing HCV Core-NS2 were shown by gel mobility shift and chromatin immunoprecipitation, respectively. The active form of CREBH was detectable in HCV-infected chimeric mice with human livers and cells expressing HCV proteins. Involvement of CREBH in HCV-induced fibrogenic response was further demonstrated in the CREBH null-mutant mouse model. Fibrogenic phenotypes were assessed using co-cultures of HCV-infected cells and HSCs. Expressions of fibrogenic factors and TGF-β1 increasing in the co-cultures was prevented by TGF-β2- or CREBH silencing. CONCLUSION: CREBH was identified as a key positive regulator of TGF-β2 transcription in HCV-infected cells. TGF-β2 released from infected cells potentially contributes to cross-induction of TGF-β in an autocrine manner through its own signaling pathway, leading to an increase in fibrogenic responses in adjacent HSCs. (Hepatology 2017;66:1430-1443).
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Authors | Takeshi Chida, Masahiko Ito, Kenji Nakashima, Yumi Kanegae, Takuya Aoshima, Shuji Takabayashi, Kazuhito Kawata, Yoshimi Nakagawa, Masahiro Yamamoto, Hitoshi Shimano, Tomokazu Matsuura, Yoshimasa Kobayashi, Takafumi Suda, Tetsuro Suzuki |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 66
Issue 5
Pg. 1430-1443
(11 2017)
ISSN: 1527-3350 [Electronic] United States |
PMID | 28621467
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2017 by the American Association for the Study of Liver Diseases. |
Chemical References |
- Creb3l3 protein, mouse
- Cyclic AMP Response Element-Binding Protein
- Transforming Growth Factor beta1
- Transforming Growth Factor beta2
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Topics |
- Animals
- Autocrine Communication
- Cyclic AMP Response Element-Binding Protein
(metabolism)
- Fibrosis
- Gene Expression Regulation
- Hepatic Stellate Cells
(pathology)
- Hepatitis C
(complications, metabolism, pathology)
- Liver
(pathology)
- Liver Cirrhosis
(metabolism, virology)
- Male
- Mice, Inbred C57BL
- Paracrine Communication
- Transforming Growth Factor beta1
(metabolism)
- Transforming Growth Factor beta2
(metabolism)
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