Identification of the new function of TNF induced by intramembrane proteases and the application to regulate inflammatory diseases.

• Project/Area Number: 24591465
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kyushu University
• Principal Investigator: TSUKAMOTO Hiroshi 九州大学, 医学(系)研究科(研究院), 准教授 (70304772)
• Co-Investigator(Kenkyū-buntansha): HORIUCHI Takahiko 九州大学, 大学病院, 教授 (90219212)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膜内蛋白分解酵素 / TNF-α / TNF-α変換酵素 / SPPL / 細胞内ドメイン / 関節リウマチ / TNF / TNF変換酵素 / TACE

Outline of Final Research Achievements

The aim of this study is to investigate the effect of intramembrane proteases such as signal peptide peptidase like proteases (SPPL) on Tumor necrosis factor-α(TNF).After SPPLcDNA was transfected into TNF-producing 293T cells, fragments of TNF in cell lysate were analyzed by Western blotting. In this study, we demonstrated that only SPPL2a is able to cleave TNF into TNF-intracellular domain. We also demonstrated that SPPL3 has enzymatic activity like TNF converting enzyme.

Research Products

• [Journal Article] Serum progranulin levels are elevated in dermatomyositis patients with acute interstitial lung disease, predicting prognosis. (2015)
  • Author(s): Tanaka A, Tsukamoto H, Mitoma H, Kiyohara C, Ueda N, Ayano M, Ohta S, Kimoto Y, Akahoshi M, Arinobu Y, Niiro H, Tada Y, Horiuchi T and Akashi K.
  • Journal Title: Arthritis research & therapy Volume: 17 Issue: 1 Pages: 27-27
  • DOI: 10.1186/s13075-015-0547-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Longterm Safety and Efficacy of Subcutaneous Tocilizumab Monotherapy: Results from the 2-year Open-label Extension of the MUSASHI Study. (2015)
  • Author(s): Ogata A, Amano K, Dobashi H, Inoo M, Ishii T, Kasama T, Kawai S, Kawakami A, Koike T, Miyahara H, Miyamoto T, Munakata Y, Murasawa A, Nishimoto N, Ogawa N, Ojima T, Sano H, Shi K, Shono E, Suematsu E, Takahashi H, Tanaka Y, Tsukamoto H, Nomura A and Investigators MS.
  • Journal Title: The Journal of rheumatology Volume: 42 Issue: 5 Pages: 799-809
  • DOI: 10.3899/jrheum.140665
  • Peer Reviewed
• [Journal Article] Evaluation of the extent of ground-glass opacity on high-resolution CT in patients with interstitial pneumonia associated with systemic sclerosis: Comparison between quantitative and qualitative analysis. (2014)
  • Author(s): Yabuuchi H, Matsuo Y, Tsukamoto H, Horiuchi T, Sunami S, Kamitani T, Jinnouchi M, Nagao M, Akashi K and Honda H.
  • Journal Title: Clinical radiology Volume: 69 Issue: 7 Pages: 758-64
  • DOI: 10.1016/j.crad.2014.03.008
  • Peer Reviewed
• [Journal Article] Reduced carotid intima-media thickness in systemic lupus erythematosus patients treated with cyclosporine A. (2013)
  • Author(s): Oryoji K, Kiyohara C, Horiuchi T, Tsukamoto H, Niiro H, Shimoda T, Akashi K, Yanase T
  • Journal Title: Mod Rheumatol Volume: 24 Issue: 1 Pages: 86-92
  • DOI: 10.3109/14397595.2013.852838
  • Peer Reviewed
• [Journal Article] The cytotoxic effects of certolizumab pegol and golimumab mediated by transmembrane tumor necrosis factor α. (2013)
  • Author(s): Ueda N, Tsukamoto H, Mitoma H, Ayano M, Tanaka A, Ohta S, Inoue Y, Arinobu Y, Niiro H, Akashi K, Horiuchi T.
  • Journal Title: Inflamm Bowel Dis. Volume: 19 Issue: 6 Pages: 1224-1231
  • DOI: 10.1097/mib.0b013e318280b169
  • Peer Reviewed
• [Journal Article] Association of hepatitis B with antirheumatic drugs: a case-control study. (2013)
  • Author(s): Oshima Y, Tojo A, et al.
  • Journal Title: Mod Rheumatol. Volume: 23 Issue: 4 Pages: 694-704
  • DOI: 10.1007/s10165-012-0709-7
  • NAID: 10031189163
  • Peer Reviewed
• [Journal Article] Prevalence and risk factors of vertebral fracture in Japanese females with systemic lupus erythematosus (2013)
  • Author(s): Furukawa M, Kiyohara C, Horiuchi T, Tsukamoto H, Mitoma H, Kimoto Y, Uchino A, Nakagawa M, Oryoji K, Shimoda T, Harada M, Akashi K
  • Journal Title: Mod. Rheumatol Volume: 23 Issue: 4 Pages: 765-773
  • DOI: 10.1007/s10165-012-0735-5
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in Japan: a review of the literature. (2013)
  • Author(s): Washio M, Nakano T, Kawaguchi Y, Takagi K, Kiyohara C, Tsukamoto H, Tokunaga S, Horiuchi T.
  • Journal Title: Mod Rheumatol Volume: 23 Pages: 210-7
  • DOI: 10.1007/s10165-012-0737-3
  • NAID: 10031167691
  • Peer Reviewed
• [Journal Article] Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity. (2012)
  • Author(s): Tanaka A, Tsukamoto H, Mitoma H, Kiyohara C, Ueda N, Ayano M, Ohta SI, Inoue Y, Arinobu Y, Niiro H, Horiuchi T, Akashi K.
  • Journal Title: Arthritis Res Ther. Volume: 14 Issue: 6
  • DOI: 10.1186/ar4087
  • Peer Reviewed
• [Journal Article] CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells (2012)
  • Author(s): Niiro H,…, Tsukamoto H, et al(16名中12番目)
  • Journal Title: Blood Volume: 119 Issue: 10 Pages: 2263-2273
  • DOI: 10.1182/blood-2011-04-351965
  • Peer Reviewed
• [Journal Article] Hereditary Angioedema in Japan: Genetic Analysis of 13 Unrelated Cases (2012)
  • Author(s): Yamamoto, T. Horiuchi, T. Miyahara, H. Yoshizawa, S. Inagaki, N. Umegaki, N. Kasamatsu, Y. Hara, A. Arinobu, Y. Inoue, Y. Niiro, H. Tsukamoto, H. Akashi, K.
  • Journal Title: Am J Med Sci Volume: 343 Issue: 3 Pages: 210-214
  • DOI: 10.1097/maj.0b013e31822bdb65
  • Peer Reviewed
• [Presentation] 感染を繰り返した先天性補体C3欠損症の遺伝子解析 (2014)
  • Author(s): 塚本 浩、藤健太郎、三苫弘喜、新納宏昭、有信洋二郎、赤星光輝、赤司浩一、北野悦子、畑中道代、北村 肇、堀内孝彦
  • Organizer: 第51回補体シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2014-08-21 – 2014-08-22
• [Presentation] Comparison of CD34-selected and unmanipulated autologous hematopoietic stem cell transplantation for systemic sclerosis: Four-year follow-up results (2014)
  • Author(s): Tsukamoto H, Ayano M, Miyamoto T, Niiro H, Arinobu Y, Akahoshi M, Akashi K
  • Organizer: Annual European Congress of Rheumatology 2014
  • Place of Presentation: Paris, France
  • Year and Date: 2014-06-11 – 2014-06-14
• [Presentation] 造血幹細胞移植による全身性強皮症の治療 (2014)
  • Author(s): 塚本 浩
  • Organizer: 第58回日本リウマチ学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Seven-year follow-up of autologous hematopoietic stem cell transplantation for severe systemic sclerosis (2013)
  • Author(s): Tsukamoto H, Horiuchi H, Miyamoto T, Niiro H, Arinobu Y, Akahosh Mi, Masahiro Ayano, Atsushi Tanaka, Naoyasu Ueda, Koichi Akashi
  • Organizer: Annual European Congress of Rheumatology 2013
  • Place of Presentation: Madrid, Spain
• [Presentation] 全身性硬化症に対するCD34陽性細胞純化及び非純化自己造血幹細胞移植 ：4年間の比較 (2013)
  • Author(s): 塚本 浩、堀内孝彦、綾野雅宏、新納宏昭、有信洋二郎1、赤星光輝、上田尚靖、田中 淳、大田俊一郎、植木尚子、久本仁美、上田 彰、廣崎友里、押領司大助、赤司浩一
  • Organizer: 第58回日本リウマチ学会
  • Place of Presentation: 京都
• [Presentation] 難治性自己免疫疾患に対する 造血幹細胞移植療法 ーその基礎と臨床ー (2013)
  • Author(s): 塚本 浩、堀内孝彦
  • Organizer: 第41回日本臨床免疫学会
  • Place of Presentation: 下関
• [Presentation] 全身性硬化症に対する自己造血幹細胞移植の長期成績 (2012)
  • Author(s): 塚本 浩、堀内孝彦、綾野雅宏、新納宏昭、有信洋二郎1、井上 靖、上田尚靖、田中 淳、大田俊一郎、植木尚子、久本仁美、上田 彰、古川牧緒、原田実根2、赤司浩一
  • Organizer: 第57回日本リウマチ学会
  • Place of Presentation: 東京
• [Presentation] Long-term follow-up of autologous hematopoietic stem cell transplantation for severe systemic sclerosis (2012)
  • Author(s): Hiroshi Tsukamoto, Takahiko Horiuchi, Toshihiro Miyamoto, Hiroaki Niiro, Yojiro Arinobu, Yasushi Inoue, Masahiro Ayano, Atsushi Tanaka, Naoyasu Ueda, Mine Harada1, Koichi Akashi
  • Organizer: Annual European Congress of Rheumatology 2012
  • Place of Presentation: Berlin, Germany
• [Book] 見逃すと怖い膠原病100の質問 (2014)
  • Author(s): 塚本 浩
  • Total Pages: 230
  • Publisher: メディカルビュー社
• [Book] 免疫・アレルギー疾患イラストレイテッド (2013)
  • Author(s): 田中良哉、渥美達也、塚本浩、他
  • Total Pages: 358
  • Publisher: 羊土社