2004 Fiscal Year Final Research Report Summary
The roles of pro-inflammatory cytokines on induction of acute phase proteins in inflammatory diseases
| 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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| Keywords | Serum amyloid A(SAA) / Interleukin 6(IL-6) / Anti-IL-6R antibody / STAT3 / C / EBPβ / NF-κB / Chronic inflammatory disease / AA amyloidosis |
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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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[Journal Article] A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.2004
Author(s)
Ito A, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, Matsumoto T, Yamamura T, Azuma J, Nishimoto N, Yoshizaki K, Shimoyama T, Kishimoto T.
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Journal Title
Gastroenterology 126
Pages: 989-996
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Toxicity, pharmacokinetics, and dose finding study of repetitive treatment with humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis : phase I/II clinical study.2003
Author(s)
Nishimoto N, Yoshizaki K, Maeda, K, Kuritani T, Deguchi H, Sato B, Imai N, Kakehi T, Takagi N, Suemura M, Kishimoto T.
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Journal Title
J.Rheum. 30
Pages: 1426-1435
Description
「研究成果報告書概要(欧文)」より
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