of which have been reported to reduce HBV core protein level. However, the molecular mechanisms by which these cytokines exert their inhibitory effects on the core promoter are not well investigated. Here, we suggested that HNF4a plays a crucial role in TGF-b1-mediated suppression of the HBV core promoter, which subsequently blocks HBc synthesis and HBV PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22180813 replication. Previous study of HBV infection in primary human liver cells suggested that Kupffer cells can secrete IL-6 upon viral recognition, and in turn inhibits HBV replication by downregulation of HNF-1a and HNF-4a. Moreover, the study of a natural helioxanthin analogue showed that the main antiviral mechanism triggered by this compound is also mediated by downregulation of HNF-3 and HNF-4a. Meanwhile, The inhibitory effects of TGF-b1 on the modulation of HBV transcription In this report, we continued our previous research on TGF-b1mediated HBV repression and explored the mechanism how TGF-b1 interferes with HBV replication. Our data suggested that the reduction of cellular HNF-4a by TGF-b1 treatment dramatically diminishes the expression level of HBV pgRNA, but not pre-C mRNA. Although the promoter regions of pgRNA and pre-C mRNA are highly overlapped and share the same transcription factor binding motifs, it has been indicated that the transcriptions of the pgRNA and pre-C mRNA are differentially regulated and are directed by two distinct promoters. The basal elements of these two promoters are similar but genetically separable, with each consisting of its own transcriptional 193022-04-7 initiator and a TATA box-like sequence. Furthermore, it has been reported that HNF-4 differentially regulates pgRNA and pre-C mRNA, of which HNF-4 specifically activates the transcription of pgRNA, but not pre-C mRNA. One possible explanation was provided by Yu et. al., they found that the 39 HNF-4 binding element was overlapped with the TATA-box of pre-C promoter, and the binding of HNF-4 on this region might interfere with the assembling of the initial transcription complex for pre-C mRNA production. As a consequence, it is not surprising that the reduction of HNF-4a by TGF-b1 has more impact on the suppression of pgRNA than pre-C mRNA. The Suppression of HBV Replication by TGF-b1 The Suppression of HBV Replication by TGF-b1 Scutellariae radix, one major component of traditional Chinese medicine Xiao-Chai-Hu-Tang, was suggested to suppress HBV production by compromising the binding between HNF-4a and HBV core promoter. In conclusion, HNF-4a is certainly one of the critical targets involved in viral clearance during the modulation of HBV replication. imply that TGF-b1 is able to alter the expression of several transcription factors and the differentiation status of hepatocytes. 
Thus, we suggested that TGF-b1 diminishes the expression of HNF4a, which may regulate HBV replication not only by directly reducing HBV core protein biosynthesis but also by indirectly affecting other hepatic genes and hepatocyte differentiation status. Down-regulation of HNF-4a by TGF-b1 treatment The repression of HNF-4a expression by TGF-b1 has been reported to be exerted through several distinct mechanisms. For example, TGF-b1 induced the expression of transcription repressor Snail in hepatocytes, which in turn reduced the transcription of HNF-4a gene through direct binding of Snail within the HNF-4a promoter region. In addition, another transcription repressor HMGA2 was activated through TGF-b1induced Smad3 signaling pathway in
