| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2000: ¥6,300,000 (Direct Cost: ¥6,300,000)
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| Research Abstract |
We studied effects of bile acids on immune response through regulation of transcription factor such as NF-κB and farnesoid X receptor (FXR). NF-κB played a pivotal role in immune response and cell survival. In addition, FXR is an orphan nuclear transcription factor that has been identified as a negative regulator of cholesterol 7α-hydroxylase, the rate-limiting enzyme in the classic bile acid synthesis pathway. However, little is known about bile acid-induced immune responses in human normal hepatocytes. First, we studied functional analysis of both transcription factors induced by bile acids. Our results showed that transactivational domain, nuclear localization signal, and ligand-binding domain were existed in N-terminal region, hinge, and C-terminal region in FXR, respectively. Moreover, we presented transcriptional regulation of FXR was modulated by its splicing variants. In contrast, bile acids degradated IκBα and IκBβ, which are inhibitory molecules of NF-κB, and activated p65 an
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d p50 heterodimer, indicating that bile acids induced biphasic NF-κB activation. Furthermore, bile acids induced reactive oxygen, MEKK1, and p38 MAP kinase in human normal hepatocytes. Thus, we presented that bile acids regulated NF-κB activation via reactive oxygen, MEKK1, and p38 MAP kinase. Second, we examined effect of bile acids on transcriptional interaction of NF-κB and FXR. Our data showed that FXR up-regulated bile acid-induced NF-κB activation via interaction of p65. Therefore, bile acids more strongly activated NF-κB and regulated immune responses and cell survival through interaction between NF-κB and FXR. In fact, we clarified that bile acids directly induced RANTES chemokine and inhibitor of apoptosis protein-1 (IAP-1) expression. Collectively, we presented for the first time that bile acids modulated immune responses and cell survival via interaction between NF-κB and FXR, possibly indicating that bile acids are the therapeutic agents in hepato-biliary autoimmune diseases. Less
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