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慢性呼吸器疾患におけるIL-17F及びNrf2の機能解析

中嶋, 真之 筑波大学

2020.07.27

概要

気管支喘息は、気道狭窄と気道過敏性の亢進、リモデリングによって特徴づけられる慢性炎症性疾患である。一般的に気管支喘息は、好酸球性の気道炎症を主体とするtype2型とそれ以外のnon-type2型に分類される[1]。Type2型の気道炎症には、ILC2や好酸球、肥満細胞やTh2細胞などが関与する。Type2型の気管支喘息は、通常吸入ステロイドをはじめとした既存の治療薬への反応が良好であり、IL-4、IL-5、IL-13、IgEなどを対象とした生物学的製剤の使用も可能なため、重症例においても複数の治療選択肢が残されている。一方、Non-type2型の気管支喘息は主に好中球主体の気道炎症を特徴とし、ILC3やTh1細胞、Th17細胞などが関与する。また気道の好中球浸潤と喘息の重症度は相関することが報告されている[2, 3]。さらに吸入ステロイドが奏功しない重症喘息に好中球性炎症の関与が示唆されている[4, 5]。重症喘息患者は全喘息患者の約10%を占めることから今後の喘息の治療・管理における最重要課題の一つとなっているが、好中球性炎症の病態は完全には明らかにされていない。これらのことからnon-type2型気管支喘息に対する有効な治療法は確立されておらず、新たな薬物療法の開発が期待されている。

 2001年に川口がクローニングしたIL-17FはIL-17ファミリーに属するサイトカインであり、IL-6やIL-8、GROαなどの産生を強力に誘導することで、好中球性炎症の発現に関与している[6-8]。IL-17Fをマウスの気道に過剰発現させると、気道の好中球性炎症が誘導される[9]。また、IL-17Fは喘息やCOPD患者の気道で増加し、重症度とも相関することが知られている[10-12]。IL-17Fの遺伝子多型の一つでアミノ酸変異を伴う一塩基多型(7188T/C)は有意に喘息患者に多く、かつ気管支喘息患者の肺機能の低下とも関連している[13]。これらの知見からIL-17Fは喘息の発症や病態に関与する重要な因子の一つであると考えられる。

 気道平滑筋は直接的に気道閉塞をきたすため、気管支喘息における気管平滑筋の役割は、これまで主に機械的な収縮能に着目されてきた。しかし、近年の研究から気道平滑筋細胞自身がIL-6を含む炎症性サイトカインを産生する、すなわちエフェクター細胞として気道炎症の病態に積極的に関与する事が報告されてきた[14, 15]。気道平滑筋細胞はIL-17Fの受容体であるIL-17RAとIL-17RCを発現していることから、IL-17Fによるサイトカイン分泌においても何らかの機能を有していることが推察されるが、その詳細は不明である[16]。IL-17Fの気道平滑筋細胞における役割を明らかにすることは、喘息、特に重症喘息の病態を解明し新たな創薬治療のターゲットになる可能性があると考えられる。

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