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インターロイキン-19の病態生理学的役割解明に関する研究

東 泰孝 大阪府立大学 DOI:info:doi/10.24729/00017816

2022.10.03

概要

インターロイキン-19(IL-19)は2000年にIL-10の新規ホモログとして発見され,現在はIL-20,IL-22,IL-24,IL-26と共にIL-10ファミリーに分類されている.IL-19は主として単球およびマクロファージから産生されるが,他の免疫系細胞であるB細胞およびミクログリア細胞からも産生される.加えて,非免疫系細胞であるケラチノサイト,上皮細胞,および血管平滑筋細胞など,様々な細胞から産生される.IL-19のシグナル伝達はIL-20受容体1およびIL-20受容体2のヘテロ二量体受容体(以下,IL-20R)を介して行われる.一方,IL-10は免疫反応全般を抑制する重要なサイトカインであり,IL-10遺伝子欠損マウス(IL-10KO)は,小腸および結腸に炎症性病変を自然発症する.IL-19遺伝子欠損マウス(IL-19KO)を作製し,消化器炎症を自然発症するかどうか解析したところ,IL-19KOはIL-10KOとは異なり消化器に炎症性病変を自然発症することはなかった.以上の背景を踏まえ,IL-19KOを用いて各種疾患モデルを解析することで,IL-19の病態生理学的役割を明らかにすることを全体の大きな目的とした.第1章では,IL-19KOを用いて大腸炎モデルの病態を解析してIL-19の役割を追究した.マウスの系統には大きくC57BL/6とBALB/cの2つの系統が存在する.C57BL/6とBALB/cはヘルパーT細胞1(Th1)型とTh2型の免疫反応に違いがある.C57BL/6マウスでは,Th1型免疫応答とIFN-の応答が支配的であるが,BALB/cでは,感染症やアレルギー反応に多く見られるTh2型の免疫応答を誘発しやすい.第2章では,BALB/c背景のIL-19KOを用いて感染性炎症反応モデルを解析することで,IL-19の役割を追求した.IL-19は広範囲な疾患の発症あるいは病態進展に関与することが報告されるが,肝疾患とIL-19に関する報告は見当たらない.IL-19の主たる産生細胞はマクロファージであり,肝臓にはクッパー細胞が存在することを考え合わせて,IL-19が肝疾患においても何らかの重要な役割を担う可能性は高い.第3章では,IL-19KOを用いて特に生活習慣病の病態として近年患者数が増加している非アルコール性脂肪性肝炎(NASH)モデルの病態を解析してIL-19の役割を追究した.

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