Statins Decrease Lung Inflammation in Mice by Upregulating Tetraspanin CD9 in Macrophages

Yingji Jin, Isao Tachibana, Yoshito Takeda, Ping He, Sujin Kang, Mayumi Suzuki, Hanako Kuhara, Satoshi Tetsumoto, Kazuyuki Tsujino, Toshiyuki Minami, Takeo Iwasaki, Kaori Nakanishi, Satoshi Kohmo, Haruhiko Hirata, Ryo Takahashi, Koji Inoue, Izumi Nagatomo, Hiroshi Kida, Takashi Kijima, Mari ItoHideyuki Saya, Atsushi Kumanogoh

研究成果: Article査読

30 被引用数 (Scopus)

抄録

Tetraspanins organize protein complexes in tetraspanin-enriched membrane microdomains that are distinct from lipid rafts. Our previous studies suggested that reduction in the levels of tetraspanins CD9 and CD81 may be involved in the progression of inflammatory lung diseases, especially COPD. To search for agents that increase the levels of these tetraspanins, we screened 1,165 drugs in clinical use and found that statins upregulate CD9 and CD81 in RAW264.7 macrophages. The lipophilic statins, fluvastatin and simvastatin, reversed LPS-induced downregulation of CD9 and CD81, simultaneously preventing TNF-α and matrix metalloproteinase-9 production and spreading of RAW264.7 cells. These statins exerted anti-inflammatory effects in vitro in wild-type macrophages but not in CD9 knockout macrophages, and decreased lung inflammation in vivo in wild-type mice but not in CD9 knockout mice, suggesting that their effects are dependent on CD9. Mechanistically, the statins promoted reverse transfer of the LPS-signaling mediator CD14 from lipid rafts into CD9-enriched microdomains, thereby preventing LPS receptor formation. Finally, upregulation of CD9/CD81 by statins was related to blockade of GTPase geranylgeranylation in the mevalonate pathway. Our data underscore the importance of the negative regulator CD9 in lung inflammation, and suggest that statins exert anti-inflammatory effects by upregulating tetraspanin CD9 in macrophages.

本文言語English
論文番号e73706
ジャーナルPloS one
8
9
DOI
出版ステータスPublished - 2013 9月 9

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)
  • 農業および生物科学(全般)
  • 一般

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