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

• Published in: The FASEB journal 2013-12, Vol.27 (12), p.4940-4953
• Main Authors: 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, El‐Osta, Assam, Ohara, Osamu, Miyoshi, Ichiro
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; Animals; aP2; Cell Line; Chromatin - metabolism; Chromatin Assembly and Disassembly; diabetes; Endopeptidases - genetics; Endopeptidases - metabolism; Epigenesis, Genetic; epigenetic control; Histones - metabolism; Humans; Inflammation - genetics; Inflammation - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Myeloid Cells - metabolism; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Serum Amyloid A Protein - genetics; Serum Amyloid A Protein - metabolism; Transcription Factor AP-2 - genetics; Transcription Factor AP-2 - metabolism; Transcription, Genetic; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.13-233528

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 (P2.1‐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