(1→3)-β-D-グルカン受容体 Dectin-1 の自然免疫及び抗腫瘍免疫活性作用と真菌感染防御における役割
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概要
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Candida albicans などの真菌の細胞壁には (1→3)-β-D-グルカンが含まれており、樹状細胞やマクロファージに発現するC型レクチンに属するDectin-1はβ-グルカンに結合する膜タンパク質としてそれら菌体の認識に関わっている。しかし、真菌感染あるいは真菌に対応する免疫機構が関連する疾患においてDectin-1がどのような役割を演じているかは明確ではなく、これらを明らかにすることは感染防御や炎症性疾患の発症と対策を考慮するために重要であると考えられる。そこで、Dectin-1のβ-グルカン認識能と細胞活性化における分子機構を解析するために、Dectin-1変異体およびDectin-1モノクローナル抗体の作製、及びDectin-1ノックアウトマウスを使用して、細胞機能への影響を検討した。その結果Dectin-1はmannose/galactose結合性C型レクチンとは全く異なるアミノ酸残基を用いて、β-グルカンを認識することが示された。Dectin-1はTLR2発現細胞においてZymosanによるNF-κB活性化能を促進した。この促進作用はβ-グルカン非結合性Dectin-1変異体では起こらず、また細胞内ITAMモチーフの変異体でも観察されないことから、β-グルカンの認識とチロシンリン酸化が細胞内シグナルに重要であることが示された。一方、チロシンキナーゼSyk、CARD9、Bcl10などのシグナリング分子をさらに遺伝子導入するとTLR2が無くてもDectin-1依存的にNF-κBは活性化された。以上のことから、Dectin-1によるβ-グルカン結合シグナルのみではNF-κBを活性化するには不十分で、Dectin-1以外の受容体からのNF-κB活性化シグナル誘導あるいは細胞内Syk、CARD9の経路も重要であることが示唆された。In vivo 実験モデルにおいて、Dectin-1中和モノクローナル抗体の投与により (1→3)-β-D-グルカンによる抗腫瘍活性は有意に低下した。さらに、Dectin-1KOマウスを用いた研究により、(1→3)-β-D-グルカンの白血球活性化作用は低下し、真菌に対する防御能が低下した。これらのことから、Dectin-1は、(1→3)-β-D-グルカンの認識と自然免疫活性化及び真菌に対する防御因子として極めて重要な受容体であることが示された。
- FCCA(Forum: Carbohydrates Coming of Age)の論文
- 2007-09-02
著者
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Adachi Yoshiyuki
Laboratory Far Immunopharmacology Of Microbial Products School Of Pharmacy Tokyo University Of Pharm
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Adachi Yoshiyuki
Laboratory For Immunopharmacology Of Microbial Products Tokyo University Of Pharmacy And Life Scienc
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