| Project/Area Number |
18591116
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Nagasaki University |
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Principal Investigator |
KAWAKAMI Atsushi Nagasaki University, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Lecturer (90325639)
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| Co-Investigator(Kenkyū-buntansha) |
ORIGUCHI Tomoki Nagasaki University, Graduate School of Biomedical Sciences, Professor (90295105)
IDA Hiroaki Nagasaki University, Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Lecturer (60363496)
TAMAI Mami Nagasald University, Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Post-doctoral fellow (60380862)
FUJIKAMA Keita Nagasaki University, Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Post-graduate student (90404285)
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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 |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | FLS / RA / CaMKII / Akt / apoptosis / HL-60 / citrullination / PADI4 / 関節リウマチ(RA) / 蛋白シトルリン化 / 細胞分化 / 関節リウマチ / CIA / 滑膜線維芽細胞 / TRAIL依存性アポトーシス / 治療ターゲット |
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| Research Abstract |
The remarkable proliferation as well as apoptosis resistance are crucial for rheumatoid arthritis (RA). Among them, we have focused on the importance of PI3K/Akt pathway, and in the current 2 years, we have tried to investigate the role of CaMKII pathway. FLS in culture expressed CaMKII γ and δ, especially δ isoform. The addition of CaMKII chemical inhibitor, KN93, significantly augmented apoptosis sensitivity of FLS in response to TRAIL and anti-Fas antibody. The additional experiment showed that CaMKII-induced phenomena of apoptosis sensitivity are mediated through Akt. CaMKII is an enzyme that is activated by Ca ion influx. Ca ion influx also activates PADI, which is an essential enzyme for post-transcriptional mechanism of peptide citrullination. Post-transcriptional mechanism of peptide citrullination is thought to be crucial for anti-CCP antibodies production in patients with RA, a RA-specific autoantibodies. However, we could not detect the citrullinated peptides in cultured FLS in response to Ca ion influx, pro-inflammatory cytoltines or pro-apoptotic stimuli. Thus, we conducted the experiment by the use of human cell line, HL-60. HL-60 expressed CaMKII γ isoform. A significant expression of PADI4, citrullinated peptides and Akt phosphorylation was found during the course of granulocyte-lineage differentiation of HL-60 by ATRA According to the results obtained in the current 2 years, an association between CaMKII and FLS apoptosis is demonstrated. Considering a possible cross-talk between CaMKII and Akt, another cross-talk among CaMKII, Akt and the peptide citrullination process appears to be present. These mechanisms are thought to be important research issue of RA that strengthens a role of CaMKII for a target molecule in RA.
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