| Project/Area Number |
15390314
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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 |
膠原病・アレルギー・感染症内科学
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| Research Institution | Osaka University |
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Principal Investigator |
YOSHIZAKI Kazuyuki Osaka University, School of Health and Sport Sciences, Professor, 健康体育部, 教授 (90144485)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥11,600,000 (Direct Cost: ¥11,600,000)
Fiscal Year 2004: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2003: ¥7,000,000 (Direct Cost: ¥7,000,000)
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| Keywords | Serum amyloid A(SAA) / Interleukin 6(IL-6) / Anti-IL-6R antibody / STAT3 / C / EBPβ / NF-κB / Chronic inflammatory disease / AA amyloidosis / NF-κB p65 / IL-6 / Serum amyloid A(SAA) / EMSA / DNA affinity chromatography / ルシフェラーゼプロモーター活性 / RA / 血清アミロイドA / IL-1 / TNF-α / 転写活性 |
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| Research Abstract |
According to the report by Betts et al. on induction of human SAA2 gene, the transcription factors of C/EBPβ and NF-κB are involved in the synergistic activation by IL-6 and IL-1. We established a SAA isoform real-time quantitative RT-PCR assay to estimate the mRNA expression of each of the SAA isoforms after cytokine stimulation. We demonstrate that IL-6 were necessary for the synergistic induction of SAA genes among IL-6,Il-1β and TNF-α and that IL-6 blockade (anti-IL-6R antibody) but not TNF-α or Il-1 blockade completely inhibits the synergistic induction of SAA1 and SAA2 genes in the triple stimulation. Our results indicate that IL-6 plays a critical role in the synergistic activation of human SAA gene by IL-6,IL-1 and TNF-α. Furthermore, we suggest that JAK/STAT3 pathway plays an important role than C/EBPβ through MAP kinase pathway.
Next we provide evidence STAT3 plays an essential role in the cytokine-driven of SAA expression, although the human SAA gene has no typical STAT3 response element(RE) in its promoters. STAT3 and NF-κB p65 first form a complex following IL-1 and IL-6(IL-1+6) stimulation, and STAT3 then interacts with no-consensus sequences at a 3'-site of the NF-κB RE of the SAA gene promoter. Moreover, co-expression of p300 with STAT3 dramatically enhanced the transcriptional activity of SAA. The formation of a complex with STAT3,NF-κB p65, and p300 is essential for the synergistic induction of the SAA gene by IL-1+6 stimulation. Our findings are expected to aid the understanding of the inflammatory status.
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