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Ubiquitin‐specific protease 2‐69 in macrophages potentially modulates metainflammation
Author(s) -
Kitamura Hiroshi,
Kimura Shunsuke,
Shimamoto Yoshinori,
Okabe Jun,
Ito Masatoshi,
Miyamoto Tomomi,
Naoe Yoshinori,
Kikuguchi Chisato,
Meek Bob,
Toda Chitoku,
Okamoto Shiki,
Kanehira Katsushi,
Hase Koji,
Watarai Hiroshi,
Ishizuka Mayumi,
ElOsta Assam,
Ohara Osamu,
Miyoshi Ichiro
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-233528
Subject(s) - chemistry , microbiology and biotechnology , chromatin , inflammation , histone , xbp1 , gene , biology , biochemistry , rna , immunology , rna splicing
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. FASEB J. 27, 4940–4953 (2013). www.fasebj.org