急性期蛋白による自己免疫疾患・感染症の制御

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 22021029
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 村上 正晃 大阪大学, 生命機能研究科, 准教授 (00250514)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥9,600,000 (Direct Cost: ¥9,600,000); Fiscal Year 2011: ¥4,800,000 (Direct Cost: ¥4,800,000); Fiscal Year 2010: ¥4,800,000 (Direct Cost: ¥4,800,000)
• Keywords: サイトカイン / 急性期蛋白 / CD4+T細胞

Research Abstract

本研究はT細胞の生体内での反応性を肝臓などの非免疫臓器からのサイトカイン発現を起点に検討することを目的としている。この目的のために以下の3つの実験を行った。
1. IL-7を肝臓特異的に欠損させたマウスでの自己免疫疾患の発症
IL-7floxマウスを京都大学の生田先生からいただきアルブミンCreマウスとかけ合わせて肝臓特異的にIL-7が欠損した変異マウスを作製した。多発性硬化症モテルの実験的脳脊髄炎(EAE)を誘導したところ有意にその発症か抑制された。この結果は研究代表者が2009年にImmunlty誌に発表したハイドロダイナミック法とshRNAを用いた方法を同様のものであった。すでにIL-7を肝細胞から誘導する1型IFN受容体の欠損でも同様な表現型を得ることができた。
2. 脊髄の血管内皮細胞に存在する病原T細胞の中枢神経系への侵入口
第5腰椎の背側の血管の内皮細胞にサイトカインIL-6と神経刺激によるノルアドレナリンの刺激にてSTAT3とNFkBが活性化してケモカインの過剰発現系IL-6アンプが活性化し免疫細胞の中枢神経系への入り口となっていることが判った。血液中に中枢神経系の抗原に対する自己反応性T細胞が存在すればこの部位から侵入して病気を発症した(Cell 2012)。
3. 血管内皮細胞でのケモカイン発現機構IL-6アンプの制御潰伝子のゲノムワイドな解析
実験2にて解析したIL-6アンプの活性化制御遺伝子を同定する目的でshRNAを搭載したレンチウイルスを用いたゲノムワイドな解析を行った。その結果、IL-6アンプの活性化は1000個以上の遺伝子にて制御されていることが判った。これらの遺伝子にはこれまで遺伝学的に病気、病態との関運か証明されたのもが10%以上存在して疾患関連遺伝子が濃縮されていることが判った(under revlsion)。

Research Products

• [Journal Article] Intestinal CX3C chemokine receptor 1high (CX3CR1high) myeloid cells prevent T-cell-dependent colitis (2012)
  • Author(s): Kayama, H., M.Murakami, et al
  • Journal Title: PNAS Volume: (in press)
  • Peer Reviewed
• [Journal Article] Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier (2012)
  • Author(s): 有馬康伸
  • Journal Title: Cell Volume: 148(3) Issue: 3 Pages: 447-457
  • DOI: 10.1016/j.cell.2012.01.022
  • Peer Reviewed
• [Journal Article] Zinc in Allergy, Autoimmune, and Hard and Connective Tissue Diseases (2012)
  • Author(s): Nishida, K., M.Murakami, et al
  • Journal Title: Journal of Biological Inorganic Chemistry Volume: (in press)
  • Peer Reviewed
• [Journal Article] Zinc signaling in health and diseases (2012)
  • Author(s): Fukada, T., M.Murakami, et al
  • Journal Title: Metallomics Volume: (in press)
  • Peer Reviewed
• [Journal Article] SIRPalpha/CD172a Regulates Eosinophil Homeostasis (2011)
  • Author(s): Verjan Garcia, M.Murakami., et al
  • Journal Title: J.Immunol. Volume: 187 Pages: 2268-2277
  • Peer Reviewed
• [Journal Article] Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells (2011)
  • Author(s): Murakami, M., D.Kamimura, et al
  • Journal Title: J.Exp.Med. Volume: 208 Pages: 103-114
  • Peer Reviewed
• [Journal Article] Zinc in Allergy, Autoimmune, and Hard and Connective Tissue Diseases (2011)
  • Author(s): Fukada, T., M.Murakami, et al
  • Journal Title: Journal of Biological Inorganic Chemistry Volume: 16 Pages: 1123-1134
  • Peer Reviewed
• [Journal Article] A four step model for the IL-6 amplifier, a regulator of chromic inflammations in tissue specific MHC class II-associated autoimmune diseases (2011)
  • Author(s): Murakami, M. and T. Hirano
  • Journal Title: Front. Immun Volume: 2 Pages: 22-22
  • DOI: 10.3389/fimmu.2011.00022
  • Peer Reviewed
• [Journal Article] Local microbleeding and IL-6/IL-7 dependent arthritis MHCクラス2にリンクした炎症性疾患の4ステップモデルとは? (2011)
  • Author(s): 村上正晃
  • Journal Title: 感染・炎症・免疫 Volume: 32 Pages: 72-74
  • Peer Reviewed
• [Journal Article] Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells. (2011)
  • Author(s): Murakami, M., D.Kamimura, T.Hirano, et al.
  • Journal Title: J.Exp.Med. Volume: 208 Pages: 103-114
  • Peer Reviewed
• [Journal Article] IL-6 positively regulates Foxp3+CD8+ T cells in vivo. (2010)
  • Author(s): Nakagawa T., T.Hirano, M.Murakami, et al.
  • Journal Title: Int.Immunol. Volume: 22 Pages: 129-139
  • NAID: 10027391497
  • Peer Reviewed
• [Journal Article] Zinc suppresses Th17 development via inhibition of STAT3 activation. (2010)
  • Author(s): Kitabayashi C., M.Murakam, T.Hirano, et al.
  • Journal Title: Int.Immunol. Volume: 22 Pages: 375-386
  • Peer Reviewed
• [Presentation] Zinc finger motif containing protein A, ZFA regulates IL-6 amplifier activation via regulating NF-kB activity and promotes an autoimmune arthritis (2011)
  • Author(s): K, Katsunuma, D.Kamimura, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-29
• [Presentation] A zinc finger motif containing protein, ZFZ regulates IL-6 amplifier activation via regulating NF-kB activity and promotes an autoimmune arthritis (2011)
  • Author(s): H.Ogura, D.Kamimura, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-29
• [Presentation] Neural stimulation accelerates the IL-6 amplifier activation, which is critical for pathogenic CD4+ T cell accumulation in the central nervous system (2011)
  • Author(s): Y.Arima, D.Kamimura, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-29
• [Presentation] IL-6 amplifier activation in donors plays a role in allogenic rejections (2011)
  • Author(s): J.Lee, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-29
• [Presentation] The IL-6 amplifier activation, a key player of inflammation, in human diseases and disorders (2011)
  • Author(s): M.Murakami
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)(招待講演)
  • Year and Date: 2011-11-29
• [Presentation] An ENU-mutant mouse, which increased a stress signaling in naive T cells (2011)
  • Author(s): D.Kamimura, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-28
• [Presentation] A Four-step Model for MHC Class II-Associated Autoimmune Diseases (2011)
  • Author(s): Y, Okuyama, D.Kamimura, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-28
• [Presentation] Enhancement of IL-6 amplifier activation by a soluble factor, SFX, which accelerates the development of autoimmune diseses (2011)
  • Author(s): M.Harda, D.Kamimura, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-28
• [Presentation] A Zinc finger protein, ZFX is critical for IL-6 amplifier activation via NF-kB activation (2011)
  • Author(s): R.Singh, Kamimura, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-28
• [Presentation] A MTF-1target, which regulates the IL-6 amplifier activation (2011)
  • Author(s): R.Otsubo, M.Murakami, et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉)
  • Year and Date: 2011-11-28
• [Presentation] Identification of molecules, which move from the nuclear to cytoplasm by extracellular zinc treatment (2011)
  • Author(s): S.Kobayashi, M.Murakami, et al
  • Organizer: The 5^<th> International Conference on Metals and Genetics (ICMG2011)
  • Place of Presentation: 神戸国際カンファレンスセンター
  • Year and Date: 2011-09-06
• [Presentation] Identification of a critical MTF-1target gene for NFkB activation (2011)
  • Author(s): R.Otsubo, M.Murakami, et al
  • Organizer: The 5^<th> International Conference on Metals and Genetics (ICMG2011)
  • Place of Presentation: 神戸国際カンファレンスセンター
  • Year and Date: 2011-09-06
• [Presentation] Zinc signaling and Inflammation (2011)
  • Author(s): M.Murakami
  • Organizer: The 5^<th> International Conference on Metals and Genetics (ICMG2011)
  • Place of Presentation: 神戸国際カンファレンスセンター
  • Year and Date: 2011-09-05
• [Presentation] IL-17A-triggered positive-feedback for IL-6-signaling, a key player for inflammation, is associated with various human diseases (2011)
  • Author(s): M.Murakami
  • Organizer: RCAI-CGM Joint Meeting
  • Place of Presentation: 理化学研究所免疫アレルギー科学総合研究センター(横浜)(招待講演)
  • Year and Date: 2011-08-26
• [Presentation] A 4 Step Model in MHC Class II-Associated Autoimmune Diseases (2011)
  • Author(s): 奥山祐子、上村大輔、平野俊夫、村上正晃, 他
  • Organizer: International Symposium "Towards Comprehensive Understanding of Immune Dynamism"
  • Place of Presentation: 千里阪急ホテル
  • Year and Date: 2011-03-01
• [Presentation] Zinc Prevents Th17 Cell-Mediated Autoimmune Disease by Directly Inhibiting STAT3 (2011)
  • Author(s): 北林知佳、村上正晃、平野俊夫, 他
  • Organizer: International Symposium "Towards Comprehensive Understanding of Immune Dynamism"
  • Place of Presentation: 千里阪急ホテル
  • Year and Date: 2011-03-01
• [Presentation] Foxp3^+CD8^+ T Cells Developed in an IL-6-Dependent Manner Control an Autoimmune Arthritis. (2011)
  • Author(s): 鶴岡峰子、平野俊夫、村上正晃, 他
  • Organizer: International Symposium "Towards Comprehensive Understanding of Immune Dynamism"
  • Place of Presentation: 千里阪急ホテル
  • Year and Date: 2011-03-01
• [Presentation] 亜鉛と亜鉛トランスポーター:サイトカイン/増殖因子の情報伝達と病態形成への関与 (2010)
  • Author(s): 深田俊幸、村上正晃、平野俊夫, 他
  • Organizer: 第75回インターフェロン・サイトカイン学会・学術集会
  • Place of Presentation: 北九州国際会議場(招待講演)
  • Year and Date: 2010-06-26
• [Presentation] 亜鉛と免疫・アレルギー・炎症:亜鉛はシグナル伝達分子である (2010)
  • Author(s): 平野俊夫、村上正晃, 他
  • Organizer: 第109回日本皮膚科学会
  • Place of Presentation: 大阪国際会議場(招待講演)
  • Year and Date: 2010-04-17
• [Presentation] IL-6-meidated positive regulation of Foxp3+CD8+ T cells is critical for the development of autoimmune diseases. (2010)
  • Author(s): 鶴岡峰子、平野俊夫、村上正晃, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] IFN-γ from CD8+ T cells, which is regulated by IL-6 signal, is involved in superantigen-mediated CD4+ T cell death. (2010)
  • Author(s): 熱海徹、平野俊夫、村上正晃, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Specific antigen recognition by CD4+ T cells is not required for a MHC class II-associated autoimmune arthritis. (2010)
  • Author(s): 奥山祐子、上村大輔、村上正晃、平野俊夫, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Hepatic IL-7, which is Induced by TLR-Type I IFN Signaling, Promotes T cell Responses. (2010)
  • Author(s): 澤幸久、上村大輔、平野俊夫、村上正晃, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Zinc-mediated STAT3 suppression is involved in inhibition of autoimmune disease development via regulating Th17 differentiation. (2010)
  • Author(s): 北林知佳、村上正晃、平野俊夫, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Homeostatic proliferation of CD4+ T cells is involved in the pathogenesis of a mouse model of Omenn syndrome. (2010)
  • Author(s): 上村大輔、平野俊夫、村上正晃, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] IL-6 plays roles not only for developing Th17 but also for inducing an IL-6 amplifier in autoimmue diseases. (2010)
  • Author(s): 小椋英樹、村上正晃、平野俊夫, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] IL-6-mediated STAT3 signaling in T cells directs the development of Th17 with a minimum effect on that of Treg in vivo. (2010)
  • Author(s): 原田誠也、村上正晃、平野俊夫, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Combination of IL-2 plus anti-IL-2 mAbs reduces cancer metastasis through activation of NK cells. (2010)
  • Author(s): 有馬康伸、平野俊夫、村上正晃, 他
  • Organizer: 第14回国際免疫学会議
  • Place of Presentation: 神戸国際会議場他
• [Presentation] Zinc and Th17-mediated autoimmune diseases (2010)
  • Author(s): 村上正晃、平野俊夫, 他
  • Organizer: The 60th Fujihara Seminar Zinc Signaling and Cellular Functions
  • Place of Presentation: 大阪国際会議場
• [Presentation] Regulation of T cell Activation via a Metal Transporter (2010)
  • Author(s): 諸井亜理沙、上村大輔、平野俊夫、村上正晃, 他
  • Organizer: The 60th Fujihara Seminar Zinc Signaling and Cellular Functions
  • Place of Presentation: 大阪国際会議場
• [Presentation] An attempt to identify molecules, which intracellular localizations are regulated by Zinc. (2010)
  • Author(s): 小林翔平、村上正晃、平野俊夫, 他
  • Organizer: The 60th Fujihara Seminar Zinc Signaling and Cellular Functions
  • Place of Presentation: 大阪国際会議場
• [Presentation] A zinc finger motif containing protein regulates the activation of the IL-6 amplifier, which is a critical for the development of an autoimmune arthritis. (2010)
  • Author(s): 小椋英樹、上村大輔、平野俊夫、村上正晃, 他
  • Organizer: The 60th Fujihara Seminar Zinc Signaling and Cellular Functions
  • Place of Presentation: 大阪国際会議場
• [Presentation] Zinc and CD4+ T cell-mediated autoimmune diseases (2010)
  • Author(s): 村上正晃、平野俊夫, 他
  • Organizer: The 60th Fujihara Seminar Zinc Signaling and Cellular Functions
  • Place of Presentation: 大阪国際会議場
• [Book] 第5項IL-16 (2011)
  • Author(s): 村上正晃・平野俊夫
  • Publisher: 免疫疾患-疾患モデルの作製と利用
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/molonc/www/index.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/molone/www/index.html