Involvement of cathepsin B in the processing and secretion of interleukin-1β in chromogranin a-stimulated microglia

Kayo Terada, Jun Yamada, Yoshinori Hayashi, Zhou Wu, Yasuo Uchiyama, Christoph Peters, Hiroshi Nakanishi

研究成果: ジャーナルへの寄稿学術誌査読

76 被引用数 (Scopus)

抄録

Cathepsin B (CB) is a cysteine lysosomal protease implicated in a number of inflammatory diseases. Although it is now evident that caspase-1, an essential enzyme for maturation of interleukin-1b (IL-1β), can be activated through the inflammasome, there is still evidence suggesting the existence of lysosomal-proinflammatory caspase pathways. In the present study, a marked induction of pro-IL-1β, its processing to the mature form and secretion were observed in the primary cultured microglia prepared from wild-type mice after stimulation with chromogranin A (CGA). Although pro-IL-1β also markedly increased in microglia prepared from CB-deficient mice, CB-deficiency abrogated the pro-IL-1β processing. CA-074Me, a specific inhibitor for CB, inhibited the pro-IL-1β maturation and its release from microglia. Furthermore, the caspase-1 activation was also inhibited by CA-074Me and E-64d, a broad cysteine protease inhibitor. After treatment with CGA, CB was markedly induced at both protein and mRNA levels. The induced pro-CB was rapidly processed to its mature form. The immunoreactivity for CB co-localized with both that for caspase-1 and the cleaved IL-1β, in the acidic enlarged lysosomes. In consistent with these in vitro observations, the immunoreactivity for the cleaved IL-1β was markedly observed in microglia of the hippocampus from aged wild-type but not CB-deficient mice. These observations strongly suggest that CB plays a key role in the pro-IL-1βmaturation through the caspase-1 activation in enlarged lysosomes of CGA-treated microglia. Therefore, either pharmacological or genetic inhibition of CB may provide therapeutic intervention in inflammation-associated neurological diseases.

本文言語英語
ページ(範囲)114-124
ページ数11
ジャーナルGLIA
58
1
DOI
出版ステータス出版済み - 2010

!!!All Science Journal Classification (ASJC) codes

  • 神経学
  • 細胞および分子神経科学

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