Development of strategy to treat immune and allergic diseases targeting molecules associated with NF-kB activation

• Project/Area Number: 20590411
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Juntendo University
• Principal Investigator: NAKANO Hiroyasu Juntendo University, 大学院・医学研究科, 准教授 (70276476)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: TRAF / 腸炎 / NF-κB / アポトーシス / c-Flip / 肝炎 / c-FLIP(cellular FLICE-inhibitory protein) / 酸化ストレス / ノックアウトマウス / TNFα / Fas / TRAF2 / 炎症性腸炎 / Interleukin 10

Research Abstract

We characterized two deficient mice lacking TRAF2 or c-FLIP, both of which are critically involved in protection of cells from TNFα-induced apoptosis. TRAF2-deficient mice spontaneously developed severe hepatitis through enhanced apoptosis of the colonic epithelial cells and subsequent alterations of the commensal microbiota and upregulation of proinflammatory cytokines. To delete c-Flip gene, we injected poly I:C into interferon-inducible c-Flip-deficient (c-FlipF/F:Mx) mice. Upon poly I:C injection, c-FlipF/F:Mx mice developed severe hepatitis along with upregulation of IL-6, but not TNFα or IL-1β. Collectively, these results suggest that deletion of adaptor molecules associated with TNFα signalings promotes apoptosis along with inflammation.

Research Products

• [Journal Article] Sharpin is a component of the NF-κB activating linear ubiquitin chain assembly complex (2011)
  • Author(s): Tokunaga, et al.
  • Journal Title: Nature Volume: (In press)
  • Peer Reviewed
• [Journal Article] Crucial role for autophagy in degranulation of mast cells (2011)
  • Author(s): Ushio, et al.
  • Journal Title: J Allergy Clin Immunol Volume: (In press)
  • Peer Reviewed
• [Journal Article] 2010. Sharpin is a component of the NF-KB activating linear ubiquitin chain assembly complex. (2010)
  • Author(s): Tokunaga F., T.Nakagawa M.Nakahara, Y.Saeki, M.Taniguchi, S.Sakata, K.Tanaka, H.Nakano, K.Iwai
  • Journal Title: Nature (in press)
  • Peer Reviewed
• [Journal Article] Crucial role for autophagy in degranulation of mast cells. (2010)
  • Author(s): Ushio H., T.Ueno, Y.Kojima, M.Komatsu, S.Tanaka, A.Yamamoto, Y.Ichimura, J.Ezaki, K.Nishida, S.Komazawa-Sakon, F.Niyonsaba, T.Ishi, T.Yanagawa, E.Kominami, H.Ogawa, K.Okumura, H.Nakano
  • Journal Title: J Allergy Clin Immunol (in press)
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor receptor-associated factor (TRAF)2 controls homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease. (2010)
  • Author(s): Piao J.H., M.Hasegawa, B.Heissig, K.Hattori, K.Takeda, Y.Iwakura, K.Okumura, N.Inohara, H.Nakano
  • Journal Title: J Biol Chem (selected as "Paper of the Week") (in press)
  • Peer Reviewed
• [Journal Article] 2011. An unexpected role for autophagy in degranulation of mast cells. (2010)
  • Author(s): Nakano H., H.Ushio
  • Journal Title: Autophagy (in press)
  • Peer Reviewed
• [Journal Article] TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory cell recruitment and foam cell formation. (2010)
  • Author(s): Missiou A., P.Rudolf, P.Stachon, D.Wolf, N.Varo, P.Aichele, C.Colberg, N.Hoppe, S.Ernst, C.Munkel, C.Walter, B.Sommer, I.Hilgendorf, H.Nakano, C.Bode, A.Zirlik
  • Journal Title: Circ Res 107 Pages: 757-766
  • Peer Reviewed
• [Journal Article] Fate-determining mechanisms in epithelial-myofibroblast transition : major inhibitory role for Smad3. (2010)
  • Author(s): Masszi A., P.Speight, E.Charbonney, M.Lodyga, H.Nakano, K.Szaszi, A.Kapus
  • Journal Title: J Cell Biol 188 Pages: 383-399
  • Peer Reviewed
• [Journal Article] Human lactoferrin activates NF-KB through the Toll-like receptor 4 pathway while it interferes with the lipopolysaccharide-stimulated TLR4 signaling. (2010)
  • Author(s): Ando K., K.Hasegawa, K.Shindo, T.Furusawa, T.Fujino, K.Kikugawa, H.Nakano, O.Takeuchi, S.Akira, T.Akiyama, J.Gohda, J.Inoue, M.Hayakawa
  • Journal Title: FEBS J 277 Pages: 2051-2066
  • Peer Reviewed
• [Journal Article] Fate-determining mechanisms in epithelial-myofibroblast transition : major inhibitory role for Smad3 (2010)
  • Author(s): Masszi, et al.
  • Journal Title: J Cell Biol Volume: 188 Pages: 383-399
  • Peer Reviewed
• [Journal Article] TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory cell recruitment and foam cell formation (2010)
  • Author(s): Missiou, et al.
  • Journal Title: Circ Res Volume: 107 Pages: 757-766
  • Peer Reviewed
• [Journal Article] Human lactoferrin activates NF-kappaB through the Toll-like receptor 4 pathway while it interferes with the lipopolysaccharide-stimulated TLR4 signaling (2010)
  • Author(s): Ando, et al.
  • Journal Title: FEBS J Volume: 277 Pages: 2051-2066
  • Peer Reviewed
• [Journal Article] NF-KB2 (p100) limits TNF-alpha-induced osteoclastogenesis. (2009)
  • Author(s): Tanaka S., H.Nakano
  • Journal Title: J Clin Invest 119 Pages: 2879-2881
  • Peer Reviewed
• [Journal Article] TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. (2009)
  • Author(s): Kraus Z.J., H.Nakano, G.A.Bishop
  • Journal Title: Proc Natl Acad Sci U S A 106 Pages: 17140-17145
  • Peer Reviewed
• [Journal Article] TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis. (2009)
  • Author(s): Blackwell K., L.Zhang, G.S.Thomas, S.Sun, H.Nakano, H.Habelhah
  • Journal Title: Mol Cell Biol 29 Pages: 303-314
  • Peer Reviewed
• [Journal Article] NF-κB2(p100)limits TNF-alpha-induced osteoclastogenesis (2009)
  • Author(s): Tanaka, S., Nakano, H.
  • Journal Title: J Clin Invest 119 Pages: 2879-2881
  • Peer Reviewed
• [Journal Article] TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40 (2009)
  • Author(s): Kraus, Z.J., Nakano, H., Bishop, G.A.
  • Journal Title: Proc Natl Acad Sci USA 106 Pages: 17140-17145
  • Peer Reviewed
• [Journal Article] TRAF2 phosphorylation modulates tumor necrosis factor α-induced gene expression and cell resistance to apoptosis (2009)
  • Author(s): Blackwell, K., et al.
  • Journal Title: Mol Cell Biol 29 Pages: 303-314
  • Peer Reviewed
• [Journal Article] TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis (2009)
  • Author(s): Blackwell, et al.
  • Journal Title: Mol Cell Biol 29 Pages: 303-314
  • Peer Reviewed
• [Journal Article] Rac, PAK and p38 regulate cell contact-dependent nuclear translocation of myocardin-related transcription factor. (2008)
  • Author(s): Sebe A., A.Masszi, M.Zulys, T.Yeung, P.Speight, O.D.Rotstein, H.Nakano, I.Mucsi, K.Szaszi, A.Kapus
  • Journal Title: FEBS Lett 582 Pages: 291-298
  • Peer Reviewed
• [Journal Article] Fusion of OTT to BSAC Results in Aberrant Up-regulation of Transcriptional Activity. (2008)
  • Author(s): Sawada T., C.Nishiyama, T.Kishi, T.Sasazuki, S.Komazawa-Sakon, X.Xue, J.H.Piao, H.Ogata, J.Nakayama, T.Taki, Y.Hayashi, M.Watanabe, H.Yagita, K.Okumura, H.Nakano
  • Journal Title: J Biol Chem 283 Pages: 26820-26828
  • Peer Reviewed
• [Journal Article] Mitochondrial Extrusion through the cytoplasmic vacuoles during cell death. (2008)
  • Author(s): Nakajima A., H.Kurihara, H.Yagita, K.Okumura, H.Nakano
  • Journal Title: J Biol Chem 283 Pages: 24128-24135
  • Peer Reviewed
• [Journal Article] Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells. (2008)
  • Author(s): Nakajima A., Y.Kojima, M.Nakayama, H.Yagita, K.Okumura, H.Nakano
  • Journal Title: Oncogene 27 Pages: 76-84
  • Peer Reviewed
• [Journal Article] A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-KB activation. (2008)
  • Author(s): Hasegawa M., Y.Fujimoto, P.C.Lucas, H.Nakano, K.Fukase, G.Nunez, N.Inohara
  • Journal Title: EMBO J 27 Pages: 373-383
  • Peer Reviewed
• [Journal Article] Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells (2008)
  • Author(s): Nakajima, et al.
  • Journal Title: Oncogene 27 Pages: 76-84
  • Peer Reviewed
• [Journal Article] Mitochondrial Extrusion through the cytoplasmic vacuoles during cell death (2008)
  • Author(s): Nakajima, et al.
  • Journal Title: J Biol Chem 283 Pages: 24128-24135
  • Peer Reviewed
• [Journal Article] Fusion of OTT to BSAC Results in Aberrant Up-regulation of Transcriptional Activity (2008)
  • Author(s): Sawada, et al.
  • Journal Title: J Biol Chem 283 Pages: 26820-26828
  • Peer Reviewed
• [Journal Article] A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation. (2008)
  • Author(s): Hasegawa, et al.
  • Journal Title: EMBO J 27 Pages: 373-383
  • Peer Reviewed
• [Journal Article] Rac, PAK and p38 regulate cell contact-dependent nuclear translocation of myocardin-related transcription factor. (2008)
  • Author(s): Sebe, et al.
  • Journal Title: FEBS Lett 582 Pages: 291-298
  • Peer Reviewed
• [Presentation] Hepatocyte-specific c-Flip-deficient mice uncover a causal link between oxidative stress and tissue repair. (2010)
  • Author(s): Nakano H
  • Organizer: 8th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: Kyoto, Japan(招待講演)
• [Presentation] TRAF2による腸管内ホメオスタシスの制御 (2010)
  • Author(s): 中野裕康
  • Organizer: 第19回日本Cell Death学会学術集会
  • Place of Presentation: 名古屋(招待講演)
• [Presentation] 酸化ストレスと組織修復を仲介する因子の同定 (2010)
  • Author(s): 中野裕康
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学大会合同大会
  • Place of Presentation: 神戸
• [Presentation] Hepatocyte-specific deletion of c-Flip gene reveals a crucial role in protection of hepatocytes from apoptosis. (2010)
  • Author(s): Nakano, et al
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] A crucial role in c-FLIP in preventing TNF alpha- and Concanavalin A-induced hepatitis. (2010)
  • Author(s): 仁科隆史, 他
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学大会合同大会
  • Place of Presentation: 神戸
• [Presentation] Hepatocyte-specific c-Flip-deficient mice uncover a causal link between oxidative stress and tissue repair (2010)
  • Author(s): Nakano H.
  • Organizer: 8 th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: Kyoto, Japan.
• [Presentation] TRAF2による腸管内ホメオスタシスの制御 (2010)
  • Author(s): 中野裕康
  • Organizer: 第19回日本Cell Death学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] Hepatocyte-specific deletion of c-Flip gene reveals a crucial role in protection of hepatocytes from apoptosis (2010)
  • Author(s): Nakano, et al.
  • Organizer: 14 th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
• [Presentation] Downregulation of c-FLIP promotes caspase-dependent ROS and JNKactivation in tumor cells. (2009)
  • Author(s): Nakano, et al
  • Organizer: 12th International TNF conference
  • Place of Presentation: Madrid, Spain
• [Presentation] Downregulation of c-FLIP promotes caspase-dependent ROS and JNK activation in tumor cells (2009)
  • Author(s): Nakano, et al.
  • Organizer: 12th International TNF conference
  • Place of Presentation: Madrid, Spain
• [Presentation] A crucial role for constitutive autophagy in degranulation of mast cells (2009)
  • Author(s): Ushio, et al.
  • Organizer: 第39回日本免疫学会総会
  • Place of Presentation: 大阪
• [Presentation] Spontaneous development of severe inflammatory bowel disease in traf2-/-mice (2009)
  • Author(s): Piao, et al.
  • Organizer: 第39回日本免疫学会総会
  • Place of Presentation: 大阪
• [Presentation] Downregulation of c-FLIP promotes caspase-dependent ROS and JNK activation in tumor cells. (2008)
  • Author(s): Nakano, et al.
  • Organizer: 7th International cell death society meeting
  • Place of Presentation: Shanghai, China
• [Presentation] Spontaneous development of inflammatory bowel disease in traf2^<-/->mice (2008)
  • Author(s): Piao, et al.
  • Organizer: 7th International cell death society meeting
  • Place of Presentation: Shanghai, China
• [Presentation] Deletion of adaptor molecules implicated in TNF signaling promotes inflammation (2008)
  • Author(s): 中野 裕康
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学大会合同大会(シンポジウム)
  • Place of Presentation: 神戸
• [Presentation] traf2^<-/->マウスに見られる自然発症腸炎のメカニズムの解析 (2008)
  • Author(s): 朴将虎, 他
  • Organizer: 第38回日本免疫学会総会
  • Place of Presentation: 京都
• [Presentation] A crucial role for constitutive autophagy in degranulation of mast cells.
  • Author(s): Ushio, et al
  • Organizer: 第39回日本免疫学会総会
  • Place of Presentation: 大阪
• [Presentation] Spontaneous development of severe inflammatory bowel disease in traf2-/-mice.
  • Author(s): Piao, et al
  • Organizer: 第39回日本免疫学会総会
  • Place of Presentation: 大阪
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