九州大学学術情報リポジトリ
Kyushu University Institutional Repository
神経障害性疼痛の慢性化におけるカテプシンSの役割
張, 馨文
http://hdl.handle.net/2324/1441136
出版情報：Kyushu University, 2013, 博士（歯学）, 課程博士 バージョン：
権利関係：Public access to the fulltext file is restricted for unavoidable reason (3)
論 文 審 査 の 結 果 の 要 ヒ日コ
Peripheral Role of Cathepsin Sin Thl Cell‑dependent Transition of Nerve Injury‑induced Acute Pain to a Chronic Pain State
There is increasing evidence that CD4+ T cell‑dependent responses are associated with the maintenance of neuropathic pain. However, little is known about the precise mechanisms underlying the activation of CD4+ T cells. This study showed that inhibition of cathepsin S (CatS) activity, either through genetic deletion or via a pharmacological inhibitor, significantly attenuated the maintenance of tactile allodynia, splenic hypertrophy, proliferation of splenic CD4+ T cells and the final cleavage step of the島1HC class II‑associated invariant chain following peripheral nerve injury. This study also found that splenectomy significantly attenuated the nerve injury‑induced tactile allodynia, whereas the adoptive transfer of CD4+ T cells prepared from splenocytes of neuropathic wild‑type mice significantly increased the pain level of splenectomized wild wild‑type or Cats‑1ー mice. In addition, CatS deficiency or treatment with CatS inhibitor significantly inhibited the infiltration of CD4+ T cells that expressed interferon‑y (IFN‑y) in the dorsal spinal cord. Signal transducer and activator of transcription 1, a molecule downstream of IFNY receptor activation, was activated exclusively in microglia 7days after peripheral nerve injury. Moreover, CatS deficiency, treatment with chemical inhibitor or splenectomy significantly attenuated the proliferation of microglia 14 days after peripheral nerve injury. These results show a peripheral critical role of CatS in the development of neuropathic pain through the antigen‑specific activation of CD4+ T cells. After activation, CD4+ T cells appear to infiltrate into the dorsal spinal cord and secrete INF‑y to reactivate microglia, which contribute to the transition of acute pain to a chronic pain state. Therefore, the result suggests that controlling CatS activity may represent a new strategy against the maintenance of chronic pain. This research contains novel findings, and therefore, the paper deserves a doctor of philosophy degree conferment.
博 士 学 位 論 文 審 査 結 果 の 要 旨 及 び そ の 担 当 者
（ふりがな） チ ョ ウ ケ イ ブ ン
氏 名
張 馨 文
主 査 九州大学 西 村 英 紀 教 授 論 文 調 査 委 員 リ高 査 九州大学 平 田 雅 人 教 授
高
リ 査 九州大学 山下 喜久 教 授
