| Project/Area Number |
18370056
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
MUTA Tatsushi Tohoku University, Tohoku University, Grad, Sch. Life Sci., Professor (60222337)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,510,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2007: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
Fiscal Year 2006: ¥8,800,000 (Direct Cost: ¥8,800,000)
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| Keywords | regulation of expression / gene / infectious disease / immunology / signal transduction / transcriptional regulation / innate immunity / induction of expression |
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| Research Abstract |
IκB-ζ, which was discovered by the head investigator, is a key molecule playing dual roles in regulation of inflammatory reactions. IκB-ζ is induced by various microbial substances stimulating the innate immune system and is essential for transcription of secondary response genes such as interleukin (IL)-6, IL-12, and the transcription factor C/EBP-δ and suppresses those of primary response genes represented by tumor necrosis factor (TNF)-α. In the present study, we investigated mechanisms for transcriptional regulation by IκB-ζ. We found that both an NF-κB binding site and a C/EBP binding site in the promoter region are essential for the transcriptional activation by IκB-ζ in the human β-defensin 2 and neutrophil gelatinase-associated lipocalin genes. On the other hand, IκB-ζ inhibited transcription of a promoter harboring canonical NF-κB binding sites. These results indicated that IκB-ζ induced on stimulation forms a complex with NF-κB and binds to the promoters harboring an NF-κB binding site and a C/EBP sites, where it activates transcription. Induction of IκB-ζ is induced by IL-1β stimulation as well as LPS, but not by TNF-α. We have analyzed mechanisms for IκB-ζ induction and have shown that IκB-ζ mRNA is specifically stabilized upon LPS/IL-1β stimulation. In the present study, we searched for an element in the IκB-ζ mRNA that is essential for the post-transcriptional regulation, and found that a 165-nucleotide sequence in the 3'-untranslated region is essential and sufficient for the regulation. We furthermore examined induction of IκB-ζ in B cells and found that it is induced upon stimulation of B cell antigen receptor. We also found that the induction was inhibited by co-stimulation of the inhibitory Fc receptor. These results strongly suggest that IκB-ζ plays a critical role in the adaptive immune system.
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