| Project/Area Number |
16K08630
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Teikyo Heisei University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | アミノペプチダーゼ / エキソソーム / 一酸化窒素 / 炎症 / ベーチェット病 / 貪食 / LPS / マクロファージ / ケモカイン / サイトカイン / HLA分子 / 自己免疫疾患 / 抗原提示 |
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| Outline of Final Research Achievements |
It has been known that ERAP1 mutation is associated with Behcet's disease. In this study, to elucidate the molecular mechanisms in the disease, roles of ERAP1 in inflammation were evaluated.
To construct a disease model, uveitis was induced by lipopolysaccharide(LPS) injection into peritoneal cavity of wild-type and ERAP1-knock out (KO) mice. Although nitric oxie（NO) in the blood was increased together with ERAP1 secretion therein after injection, ERAP1-KO caused the reduction of NO and Arg synthesis. These results suggest that secreted ERAP1 is involved in the NO synthesis via producing Arg. On the other hand, we found that secreted ERAP1 binds to exosome derived from activated macrophages and its complex lead to activation of naive macrophage mediating facilitaion of Arg production, iNOS expression and phagocytosis.
Our data provide the evidence that free ERAP1 and ERAP1 associated with exosomes plays important roles in inflammation through macrophage activation.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、LPS刺激に伴って分泌されたERAP1あるいは、ERAP1-エキソソーム複合体が、ERAP1活性を介してマクロファージの貪食や一酸化窒素合成を亢進することを見出すことができた。すなわち、ベーチェット病では、細菌感染などをきっかけにマクロファージから血中に分泌されたERAP1が炎症増悪の一因となる可能性が高い。従って、特異阻害剤などによる血中ERAP1活性の抑制が、ベーチェット病やその他の炎症性自己免疫疾患（ERAP1の関与が指摘されている強直性脊椎炎や乾癬など）に対する治療の手段となりえる。また、血中ERAP1活性がこれら疾患における炎症増悪の新しいマーカーとして利用が期待できる。
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