Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation

Hiroshi Kitamura, Shunsuke Kimura, Yoshinori Shimamoto, Jun Okabe, Masatoshi Ito, Tomomi Miyamoto, Yoshinori Naoe, Chisato Kikuguchi, Bob Meek, Chitoku Toda, Shiki Okamoto, Katsushi Kanehira, Koji Hase, Hiroshi Watarai, Mayumi Ishizuka, Assam El-Osta, Osamu Ohara, Ichiro Miyoshi

研究成果: Article査読

27 被引用数 (Scopus)


Macrophages play a critical role in chronic inflammation and metabolic diseases. We identified a longer splice variant of ubiquitin specific protease (USP) 2-69 as a novel molecule that modulates pathways implicated in metabolic disorders. Expression levels of aP2/ FABP4 and PAI-1/SERPINE1 genes were increased by 4- and 1.8-fold, respectively, after short hairpin RNA-mediated knockdown (KD) of the USP2 gene, and such expression was alleviated by overexpression of USP2-69 in human myeloid cell lines. Supernatants derived from USP2-KD cells induced IL6 (6-fold) and SAA3 (15-fold) in 3T3-L1 adipocytes to suggest the anti-inflammatory properties of USP2. In addition, we observed a 30% decrease in the number of macrophages in mesenteric adipose tissue derived from USP2-69 transgenic mice fed a high-fat diet for 14 wk compared with that in their C57BL/6 littermates (P<0.01), which was consistent with a 40% decrease in transcription of aP2 and PAI-1. The aP2 locus exhibited elevated chromatin accessibility (>2.1-fold), methylation of histone H3 lysine 4 (>4.5- fold), and acetylation of histone H4 (>2.5-fold) in USP2-KD cells. Transfection of isopeptidase-mutated USP2-69 did not alter chromatin conformation on the aP2 locus in USP2-KD cells. Our results suggest that USP2-69 suppresses meta-inflammatory molecules involved in the development of type-2 diabetes.-Kitamura, H., Kimura, S., Shimamoto, Y., Okabe, J., Ito, M., Miyamoto, T., Naoe, Y., Kikuguchi, C., Meek, B., Toda, C., Okamoto, S., Kanehira, K., Hase, K., Watarai, H., Ishizuka, M., El-Osta, A., Ohara, O., Miyoshi, I. Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation.

ジャーナルFASEB Journal
出版ステータスPublished - 2013 12月

ASJC Scopus subject areas

  • バイオテクノロジー
  • 生化学
  • 分子生物学
  • 遺伝学


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