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

doi:10.1096/fj.13-233528

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

Medicine Alfred Hospital

Research output: Contribution to journal › Article › Research › peer-review

30 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	4940 - 4953
Number of pages	14
Journal	The FASEB Journal
Volume	27
Issue number	12
DOIs	https://doi.org/10.1096/fj.13-233528
Publication status	Published - 2013

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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. (2013). Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation. The FASEB Journal, 27(12), 4940 - 4953. https://doi.org/10.1096/fj.13-233528

@article{764d278dd1144298bdf8736ef204dc2a,

title = "Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation",

abstract = "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.",

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

year = "2013",

doi = "10.1096/fj.13-233528",

language = "English",

volume = "27",

pages = "4940 -- 4953",

journal = "The FASEB Journal",

issn = "0892-6638",

publisher = "Federation of American Society for Experimental Biology",

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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 2013, 'Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation', The FASEB Journal, vol. 27, no. 12, pp. 4940 - 4953. https://doi.org/10.1096/fj.13-233528

TY - JOUR

T1 - Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation

AU - Kitamura, Hiroshi

AU - Kimura, Shunsuke

AU - Shimamoto, Yoshinori

AU - Okabe, Jun

AU - Ito, Masatoshi

AU - Miyamoto, Tomomi

AU - Naoe, Yoshinori

AU - Kikuguchi, Chisato

AU - Meek, Bob

AU - Toda, Chitoku

AU - Okamoto, Shiki

AU - Kanehira, Katsushi

AU - Hase, Koji

AU - Watarai, Hiroshi

AU - Ishizuka, Mayumi

AU - El-Osta, Assam

AU - Ohara, Osamu

AU - Miyoshi, Ichiro

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.fasebj.org/content/27/12/4940.full.pdf

U2 - 10.1096/fj.13-233528

DO - 10.1096/fj.13-233528

M3 - Article

SN - 0892-6638

VL - 27

SP - 4940

EP - 4953

JO - The FASEB Journal

JF - The FASEB Journal

IS - 12

ER -

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

Abstract

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