病原体センサー活性化に伴う選択的遺伝子発現誘導機構とその破綻

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 21117004
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University
• Principal Investigator: 牟田 達史 東北大学, 生命科学研究科, 教授 (60222337)
• Project Period (FY): 2009-07-23 – 2014-03-31
• Project Status: Discontinued (Fiscal Year 2013)
• Budget Amount: ¥151,970,000 (Direct Cost: ¥116,900,000、Indirect Cost: ¥35,070,000); Fiscal Year 2013: ¥29,380,000 (Direct Cost: ¥22,600,000、Indirect Cost: ¥6,780,000); Fiscal Year 2012: ¥30,290,000 (Direct Cost: ¥23,300,000、Indirect Cost: ¥6,990,000); Fiscal Year 2011: ¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000); Fiscal Year 2010: ¥28,470,000 (Direct Cost: ¥21,900,000、Indirect Cost: ¥6,570,000); Fiscal Year 2009: ¥36,400,000 (Direct Cost: ¥28,000,000、Indirect Cost: ¥8,400,000)
• Keywords: IκB-ζ / 慢性炎症 / 自己免疫疾患 / シェーグレン症候群 / 自然炎症 / 転写制御因子 / アポトーシス / 上皮細胞 / 遺伝子発現 / シグナル伝達 / 炎症 / NF-κB / 病原体センサー / 皮膚炎

Research Abstract

IκB-ζ遺伝子を欠損するマウスは、specific pathogen-free (SPF)環境下で、目の周囲に慢性炎症を自然発症する。今回我々は、この慢性炎症の発症機序に取り組み、このマウスでは、涙腺にリンパ球の浸潤を伴う炎症があり、涙の分泌量が低下していること、血清中には自己抗体が存在することを明らかにした。自己抗体の中でも特に、シェーグレン症候群の鑑別診断に用いられる抗SSA抗体、抗SSB抗体価が上昇していることが明らかとなり、このマウスの症状は、ヒトのシェーグレン症候群に酷似していることが判明した。
細胞移植実験や遺伝子欠損マウスを用いた解析を行ったところ、この炎症の発症には、リンパ球の存在が必須であることが判明したが、正常マウスのリンパ球を移植したIκB-ζ遺伝子欠損マウスでも炎症が観察され、リンパ球以外の別の細胞種の異常が原因と考えられた。各種の細胞で特異的にIκB-ζ遺伝子を欠損するマウスを作製して解析を進めたところ、上皮細胞において同遺伝子が欠損するマウスで炎症が発症することが明らかになった。また、IκB-ζ遺伝子を欠損するマウスの涙腺ではアポトーシスが過剰に誘導されていること、この細胞死は炎症とは無関係に誘導されることがわかった。さらに、アポトーシスを抑制する薬剤をIκB-ζ遺伝子欠損マウスの目に投与したところ、炎症が抑えられ、涙の分泌量も回復することが明らかになった。つまり、涙腺上皮細胞では、IκB-ζがアポトーシスを抑制するはたらきをもっており、この遺伝子が欠損するとアポトーシスが過剰に誘導されること、この過剰なアポトーシスによって、自己反応性の異常なリンパ球が産生され、局所的な炎症が誘導されることが明らかになった。
本研究成果は、今なお、多くの患者がドライアイ、ドライマウスに苦しむシェーグレン症候群の発症機序の理解とその治療に大きく貢献すると考えられる。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

IκB-ζ遺伝子欠損マウスが自然発症する慢性炎症の病因について検討したところ、このマウスが、ヒトの自己免疫疾患の一種であるシェーグレン症候群様の慢性炎症を自然発症すること、この慢性炎症の原因が涙腺上皮細胞で起きる過剰な細胞死によることを明らかにするとともに、さらにこの慢性炎症及び、それに付随する病態が、細胞死を阻害する薬剤で治療可能なことを示すことができた。
当初予想できなかったこれらの結果は、シェーグレン症候群などの組織特異的自己免疫疾患の発症機序の解明とその治療ヘ向けた取り組みに新たな視点をもたらす画期的な研究成果と注目され、米国科学誌「Immunity」にてFeatured Articleとして発表されるとともに、Previewで紹介された。また、当該分野において特別な意義をもつ論文として、F1000Primeに選出された。

Strategy for Future Research Activity

涙腺上皮においてIκB-ζを誘導する内因性リガンドの同定、アポトーシスの自発的な誘導機構、さらに、IκB-ζによるアポトーシス回避機構の解明が次の重要な課題となると考えられる。これらはいずれも容易な課題ではないが、解明された場合、上皮組織の恒常性維持の理解とシェーグレン症候群の治療にさらに大きな貢献をもたらすと予想される。

Research Products

• [Journal Article] Essential role for Toll-like receptor 7 (TLR7)-unique cysteines in an intramolecular disulfide bond, proteolytic cleavage and RNA sensing (2013)
  • Author(s): Kanno A, Yamamoto C, Onji M, Fukui R, Saitoh SI, Motoi Y, Shibata T, Matsumoto F, Muta T, Miyake K
  • Journal Title: International immunology Volume: 25 Pages: 413-422
  • DOI: 10.1093/intimm/dxt007
  • Peer Reviewed
• [Journal Article] Enhanced Apoptosis by Disruption of the STAT3-IκB-ζ Signaling Pathway in Epithelial Cells Induces Sj#246;gren's Syndrome-like Autoimmune Disease. (2013)
  • Author(s): 大熊敦史
  • Journal Title: Induces Sjogren's Syndrome-like Autoimmune Disease Volume: 38 Pages: 450-460
  • DOI: 10.1016/j.immuni.2012.11.016
  • Peer Reviewed
• [Journal Article] Cross-species Analysis Reveals Evolving And Conserved Features of the NF-kB Proteins. (2013)
  • Author(s): Ryzhakov, G. et al.
  • Journal Title: Journal of Biological Chemistry Volume: 印刷中
  • DOI: 10.1074/jbc.m113.451153
  • Peer Reviewed
• [Journal Article] Thioredoxin-interacting protein gene expression via MondoA is rapidly and transiently suppressed during inflammatory responses (2013)
  • Author(s): Kanari, Y. et al.
  • Journal Title: PLoS One Volume: 8
  • DOI: 10.1371/journal.pone.0059026
  • Peer Reviewed
• [Journal Article] Transcriptional and Post-transcriptional Regulation of IkB-ζ upon Engagement of BCR, TLR, and Fey Receptor (2013)
  • Author(s): Hanihara, F. et al.
  • Journal Title: TLRand FcγreceptorInt Immunol Volume: 印刷中
  • DOI: 10.1093/intimm/dxt017
  • Peer Reviewed
• [Journal Article] Interleukin- 10-induced neutrophil gelatinase-associated lipocalin production in macrophages with consequences for tumor growth. (2012)
  • Author(s): Jung, M. et al.
  • Journal Title: Molecular and Cellular Biology Volume: 32 Pages: 3938-3948
  • DOI: 10.1128/mcb.00413-12
  • Peer Reviewed
• [Journal Article] Sadaaki Iwanaga : Discovery of the Lipopolysaccharide- and β-1,3-D-glucan-mediated Proteolytic Cascade and Unique Proteins in Invertebrate Immunity (2010)
  • Author(s): Kawabata, S., Muta, T.
  • Journal Title: Journal of Biochemistry Volume: VOL.147 Pages: 611-618
  • Peer Reviewed
• [Journal Article] IκBζ regulates T_H17 Development by Cooperating with ROR Nuclear Receptors (2010)
  • Author(s): Okamoto, et al
  • Journal Title: Nature Volume: VOL.464 Pages: 1381-1385
  • Peer Reviewed
• [Journal Article] Identification of BCAP-L as A Negative Regulator of the TLR Signaling-induced Production of IL-6 and IL-10 in Macrophages by Tyrosine Phosphoproteomics (2010)
  • Author(s): Matsumura, et al
  • Journal Title: Biochemical and Biopbysical Research Communicsitions Volume: VOL.400 Pages: 265-270
  • Peer Reviewed
• [Journal Article] IκBζ is Essential for Natural Killer Cell Activation in Response to IL-12 and IL-18 (2010)
  • Author(s): Miyake, et al
  • Journal Title: Proceedinga of National Academy of Science U.S.A. Volume: VOL.107 Pages: 17680-17685
  • Peer Reviewed
• [Journal Article] IκBζ is Essential for Natural Killer Cell Activation in Response to IL-12 and IL-18. (2010)
  • Author(s): Miyake, et al.
  • Journal Title: Proceedings of National Academy of Science U.S.A. Volume: 107 Pages: 17680-17685
  • Peer Reviewed
• [Journal Article] Identification of BCAP-L as A Negative Regulator of the TLR Signaling-induced Production of IL-6 and IL-10 in Macrophages by Tyrosine Phosphoproteomics. (2010)
  • Author(s): Matsumura, et al.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 400 Pages: 265-270
  • Peer Reviewed
• [Journal Article] IκBζ Regulates TH17 Development by Cooperating with ROR Nuclear Receptors. (2010)
  • Author(s): Okamoto, et al.
  • Journal Title: Nature Volume: 464 Pages: 1381-1385
  • Peer Reviewed
• [Journal Article] Sadaaki Iwanaga : discovery of the lipopolysaccharide- and β-1,3-D-glucan-mediated proteolytic cascade and unique proteins in invertebrate immunity. (2010)
  • Author(s): Kawabata, S., Muta, T.
  • Journal Title: Journal of Biochemistry Volume: 174 Pages: 611-618
• [Journal Article] 炎症における転写制御とその破綻 (2010)
  • Author(s): 牟田達史
  • Journal Title: 炎症と免疫 Volume: 18 Pages: 228-233
• [Journal Article] 核内IκB蛋白質IκB-ζを介したサイトカイン産生制御 (2010)
  • Author(s): 牟田達史
  • Journal Title: 医学のあゆみ Volume: 234 Pages: 372-378
• [Journal Article] 核内IκBタンパク質IκB-ζを介したサイトカイン産生制御 (2010)
  • Author(s): 牟田達史
  • Journal Title: 実験医学 Volume: 28 Pages: 1863-1868
• [Journal Article] MAPK-activated Protein Kinase 2 Differentially Regulates Plasmodium falciparum Glycosylphosphatidylinositol induced Production of Tumor Necrosis Factor-α and Interleukin-12 in Macrophages. (2009)
  • Author(s): Zhu, et al.
  • Journal Title: Journal of Biological Chemistry Volume: 284 Pages: 15750-15761
  • Peer Reviewed
• [Presentation] 感染防御応答における多段階遺伝子発現制御機構 (2012)
  • Author(s): 牟田 達史
  • Organizer: 第85回日本細菌学会総会
  • Place of Presentation: 長崎
  • Invited
• [Presentation] Regulation of inflammatory gene expression by the nuclear IκB family protein IκB-ζ. (2012)
  • Author(s): Muta, T.
  • Organizer: The 12th Biennial International Endotoxin and Innate Immunity Society Meeting
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] Transcriptional and Post-transcriptional Activation of IκB-ζ by Toll-like Receptor and B Cell Antigen Receptor. (2012)
  • Author(s): Hanihara, F. et al.
  • Organizer: The 12th Biennial International Endotoxin and Innate Immunity Society Meeting
  • Place of Presentation: Tokyo
• [Presentation] IκB-ζ-deficient Mice Develop Sｊogren’s Syndrome-like Chronic Inflammation Caused by Dysregulation of Epithelial Homeostasis. (2012)
  • Author(s): Okuma, A. et al.
  • Organizer: The 12th Biennial International Endotoxin and Innate Immunity Society Meeting
  • Place of Presentation: Tokyo
• [Presentation] IκB-ζ-deficiency in Epithelial Cells Elicits Sjogren’s Syndrome-like Autoimmune Disease. (2012)
  • Author(s): Okuma, A. et al.
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸
• [Presentation] Roles for the nuclear IκB family protein IκB-ζ in inflammation. (2012)
  • Author(s): Muta, T.
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] ヤマアカガエル集団内における自然免疫遺伝子の多様性 (2011)
  • Author(s): 高柳真世, ら
  • Organizer: 日本生態学会第58回全国大会
  • Place of Presentation: 札幌
  • Year and Date: 2011-03-10
• [Presentation] Chemokine Induction in Macrophages as a Response to Necrotic Cells (2011)
  • Author(s): Muta, T. et al.
  • Organizer: Toll2011 Meeting-Decoding Innate Immunity
  • Place of Presentation: Riva del Garda, Italy
• [Presentation] 炎症応答における核内IκBファミリータンパク質IκB-ζの機能とその破綻 (2011)
  • Author(s): 牟田 達史
  • Organizer: The 7th Tsukuba Hematologic Disease Seminar in Autumn, 2011
  • Place of Presentation: つくば
  • Invited
• [Presentation] 壊死細胞由来の複数のDanger Signalに対するマクロファージの応答 (2011)
  • Author(s): 木村 俊文ら
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
• [Presentation] IκB-ζ-deficiency in Non-lympoid Cells Spontaneously Induces Autoimmune Reaction (2011)
  • Author(s): Okuma, A. et al.
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Presentation] B細胞抗原受容体刺激における転写制御と転写後制御を介したIκB-ζの発現誘導 (2011)
  • Author(s): 埴原 文人ら
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] Recognition of Necrotic Cells and Chemokine Induction in Macrophages via Nucleotide (2010)
  • Author(s): Kimura, et al
  • Organizer: 第83回日本生化学会大会第33回日本分子生物学会年会合同大会(BMB2010)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] Critical Roles of Non-hematopoietic Cells in Prevention of Autoimmune Reactions Revealed by the Studies on IκB-ζ-deficient Mice (2010)
  • Author(s): Okuma, et al
  • Organizer: International Forum for Adaptability Science II : Technologies for a Sustainable Society
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2010-12-02
• [Presentation] Stimulus-specific Post-transcriptional Regulation of IκB-ζ in Innate and Adaptive Immune Responses (2010)
  • Author(s): Hanihara, et al
  • Organizer: 2010 Joint Annual Meeting between the Society for Leukocyte Biology and the International Endotoxin & Innate Immunity Society
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-10-08
• [Presentation] Roles for Lymphocytes and Non-hematopoietic Cells in the Pathogenesis of Chronic Skin Inflammation in IκB-ζ-deficient Mice (2010)
  • Author(s): Okuma, et al
  • Organizer: 2010 Joint Annual Meeting between the Society for Leukocyte Biology and the International Endotoxin & Innate Immunity Society
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-10-08
• [Presentation] Analysis on the Pathogenesis of Chronic Skin Inflammation that Spontaneously Develops in IκB-ζ Gene-deficient Mice (2010)
  • Author(s): Okuma, et al
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-25
• [Presentation] Chemokines Induction of Maerophages in Response to Dead Cells (2010)
  • Author(s): Kimura, et al
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-25
• [Presentation] Identification of the Toll-like Receptor Signaling Components Involved in the Post-transcriptional Regulation of IκB-ζ. (2010)
  • Author(s): Ohba, et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] Analysis on the Pathogenesis of Chronic Skin Inflammation that Spontaneously Develops in IκB-ζ Gene-deficient Mice. (2010)
  • Author(s): Okuma, et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] Chemokines Induction of Macrophages in Response to Dead Cells. (2010)
  • Author(s): Kimura, et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] Identification of the Toll-like Receptor Signaling Components Involved in the Post-transcriptional Regulation of IκB-ζ (2010)
  • Author(s): Ohba, et al
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-23
• [Presentation] Stimulus-specific Post-transcriptional Regulation of IκB-ζ, an Essential Regulator on Inflammatory Responses (2010)
  • Author(s): Hanihara, et al
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-23
• [Presentation] IκBζ is Required for the Transcriptional Program in Th17 Development (2010)
  • Author(s): Okamoto, et al
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-23
• [Presentation] Stimulus-specific Post-transcriptional Regulation of IκB-ζ, an Essential Regulator on Inflammatory Responses. (2010)
  • Author(s): Hanihara, et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-23
• [Presentation] IκBζ Is Required for the Transcriptional Program in Th17 Development. (2010)
  • Author(s): Okamoto, et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-23
• [Presentation] Molecular Dissection of the MyD88-dependent Signaling that Leads to Specific mRNA Stabilization (2010)
  • Author(s): Muta, et al
  • Organizer: Keystone Symposium "Innate Immunity"
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2010-06-10
• [Presentation] Molecular Dissection of the MyD88-dependent Signaling that Leads to Specific mRNA Stabilization. (2010)
  • Author(s): Muta, et al.
  • Organizer: Keystone Symposium "Innate Immunity"
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2010-06-10
• [Presentation] 自然免疫における炎症応答制御とその破綻 (2010)
  • Author(s): 牟田達史
  • Organizer: 第33回日本血栓止血学会学術集会
  • Place of Presentation: 鹿児島
  • Year and Date: 2010-04-24
• [Presentation] ヤマアカガエル集団間集団内での免疫関連遺伝子の多様性 (2010)
  • Author(s): 高柳真世, ら
  • Organizer: 日本生態学会第57回全国大会
  • Place of Presentation: 東京
  • Year and Date: 2010-03-17
• [Presentation] Chronic Skin Inflammation Developed in Mice Lacking IκB-ζ, a Crucial NF-κB Regulator. (2010)
  • Author(s): Muta, et al.
  • Organizer: Keystone Symposium : "NF-κB in Inflammation and Disease"
  • Place of Presentation: Santa Fe, NM, USA
  • Year and Date: 2010-01-07
• [Presentation] An Essential Role of IκBζ in the Development of Osteoclastogenic Helper T Cells-Th17 cells (2010)
  • Author(s): Okamoto, et al
  • Organizer: 3rd International Conference on Osteoimmunology
  • Place of Presentation: Santorini, Greece
• [Presentation] An Essential Role of IκBζ in the Development of Osteoclastogenic Helper T Cells-Th17 cells. (2010)
  • Author(s): Okamoto, et al.
  • Organizer: 3rd International Conference on Osteoimmunology
  • Place of Presentation: Dublin, Ireland
• [Presentation] Mechanisms for stimulus-specific post-transcriptional regulation that determines induction of IκB-ζ, an essential regulator for selective gene expression on inflammatory responses. (2009)
  • Author(s): Hanihara, et al.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-12
• [Presentation] Identification of TAB2 as an IκB-ζ Binding Protein and Its Implication in the IκB-ζ-dependent Transcriptional Activation. (2009)
  • Author(s): Otsubo, et al.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-09
• [Presentation] The Establishment of a System to Manipulate the Activity of the Toll-like Receptor Signaling Component using Estrogen-Receptor Fusion Proteins. (2009)
  • Author(s): Ariga, et al.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-09
• [Presentation] Chronic Skin Inflammation of IκB-ζ-deficient Mice and Their Defective Epithelial Homeostatic Responses. (2009)
  • Author(s): Okuma, et al.
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-04
• [Presentation] 誘導型転写制御因子IκB-ζによる炎症応答制御とその破綻により自然発症する慢性炎症 (2009)
  • Author(s): 牟田達史
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] 炎症応答における選択的遺伝子発現を支配する転写制御因子IκB-ζの刺激特異的転写後制御機構 (2009)
  • Author(s): 埴原文人, ら
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Remarks] 東北大学大学院生命科学研究科牟田研究室ホームページ
  • URL: http://www.biology.tohoku.ac.jp/lab-www/muta_lab/
• [Remarks] 組織特異的自己免疫疾患の病因解明（上皮細胞の過剰な細胞死によってシェーグレン症候群が誘導される）
  • URL: http://www.tohoku.ac.jp/japanese/2013/03/press20130228-02.html
• [Remarks] 組織特異的自己免疫疾患の病因解明
  • URL: http://www.lifesci.tohoku.ac.jp/research_ja/14954/
• [Remarks]
  • URL: http://www.biology.tohoku.ac.jp/lab-www/inuta_lab/
• [Remarks]
  • URL: http://www.biology.tohoku.ac.jp/lab-www/muta_lab/