口腔粘膜の自然免疫系;特に炎症・免疫応答抑制機構の解明

• Project/Area Number: 18689901
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Morphological basic dentistry
• Research Institution: Tohoku University
• Principal Investigator: 上原 亜希子 東北大, 歯学研究科(研究院), 助教 (00431510)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥22,920,000 (Direct Cost: ¥19,200,000、Indirect Cost: ¥3,720,000); Fiscal Year 2008: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2007: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2006: ¥6,800,000 (Direct Cost: ¥6,800,000)
• Keywords: 口腔上皮細胞 / 自然免疫 / NOD系分子 / TLR系分子 / 抗菌因子 / protease-activated receptor / NOD1 / NOD2 / TLR / MDP / diaminopimelic acid / popeptides / lipid A / NFkappaB

Research Abstract

1.様々な組織由来の上皮細胞の各種loll-like receptor (ILR)糸およびNOD1/2発現とりガンド刺激に対する応答性
これまでに口腔上皮細胞は各種TLR系およびNOD1/2分子を恒常的に発現しており、対応する各種リガンドで刺激するとベータディフェンシンやペプチドグリカン認識蛋白発現が増強される一方、過剰な炎症応答を避ける為か各種炎症性サイトカイン産生は増強されなかった。全身の臓器由来の上皮細胞(咽頭・食道・胃・腸管・子宮頚・皮膚など)に対象を広げて検討したところ、これら各種上皮細胞も口腔上皮細胞を同様に恒常的にこれらレセプター分子を発明していることを証明した。リガンド刺激に対してベータディフェンシン類の発現は明瞭に増強されたが、口腔上皮細胞とは異なりペプチドグリカン認識蛋白発現は増強されなかった。
2.Porphyromonas gingivalisのジンジパインと各種TLR系およびNOD系リガンド刺激による相乗作用
歯周病原性と目されるP. gingivalisの産生する酵素ジンジパインと各種TLR系およびNOD系リガンドで刺激するとプロテアーゼ活性化受容体(protease-activatedreceptor;PAR)および転写因子NF-kBを介して細胞を活性化することを明らかにした。

Research Products

• [Journal Article] Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines (2007)
  • Author(s): Akiko Uehara
  • Journal Title: Molecular Immunology 44 Pages: 3100-3111
  • Peer Reviewed
• [Journal Article] Antibodies to proteinase 3 prime human monocytic cells via protease-activated receptor-2 and NF-kB for Toll-like receptor-and NOD-dependent activation. (2007)
  • Author(s): Akiko Uehara
  • Journal Title: Molecular Immunology 44 Pages: 3552-3562
  • Peer Reviewed
• [Journal Article] Functional TLRs and NODs in human gingival fibroblasts. (2007)
  • Author(s): A Uehara, H Takada
  • Journal Title: The Journal of Dental Research 86 (3) Pages: 249-254
• [Journal Article] Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. (2007)
  • Author(s): A Uehara, Y Fujimoto, K Fukase, H Takada
  • Journal Title: Molecular Immunology (印刷中)
• [Journal Article] Antibodies to proteinase 3 prime human monocytic cells via protease-activated receptor-2 and NF-κB for Toll-like receptor- and NOD-dependent activation. (2007)
  • Author(s): A Uehara, A Iwashiro, T Sato, et al.
  • Journal Title: Molecular Immunology (印刷中)
• [Journal Article] Oral bacteria and periodontitis, with special reference to innate immune system in oral mucosa. (2007)
  • Author(s): A Uehara, H Takada
  • Journal Title: Clinical Calcium 17 (2) Pages: 173-178
• [Journal Article] Meso-diaminopimelic acid and meso-lanthionine, amino acids, specific to bacterial peptidoglycans, activates human epithelial cells through NOD1. (2006)
  • Author(s): A Uehara, Y Fujimoto, A Kawasaki, et al.
  • Journal Title: The Journal of Immunology 177 (3) Pages: 1796-1804
• [Journal Article] Toll-like receptors, NOD1 and NOD2 in oral epithelial cells. (2006)
  • Author(s): Y Sugawara, A Uehara, Y Fujimoto, et al.
  • Journal Title: The Journal of Dental Research 85 (6) Pages: 524-529
• [Journal Article] Promoter hypomethylation of Toll-like receptor-2 gene is associated with increased proinflammatory response towards bacterial peptidoglycan in cystic fibrosis bronchial epithelial cells. (2006)
  • Author(s): T Shuto, T Furuta, M Oba, et al.
  • Journal Title: FASEB Journal 20 (6) Pages: 782-784
• [Journal Article] Mouse and human cells activation by N-dodecanoyl-DL-homoserine lactone (C_<12>-HSL), a Chromobacterium violaceum autoinducer. (2006)
  • Author(s): K Gomi, K Toshiaki, Y Tokue, et al.
  • Journal Title: Infection and Immunity 74 (12) Pages: 7029-7031
• [Journal Article] Enhancement of TLR-mediated innate immune responses by peptidoglycans through NOD signaling. (2006)
  • Author(s): H Takada, A Uehara
  • Journal Title: Current Pharmaceutical Design 12 (32) Pages: 4163-4172
• [Presentation] プロテアーゼ活性化受容体と各種TLR系及びNOD系リガンド刺激はヒト単球系細胞を相乗的に活性化する (2007)
  • Author(s): 上原亜希子
  • Organizer: 第13回日本エンドトキシン研究会
  • Place of Presentation: 鹿児島
  • Year and Date: 2007-10-20
• [Presentation] Porphyromonas gingivalisの産生するジンジパインはヒトロ腔上皮細胞のIL-8産生を抑制する (2007)
  • Author(s): 上原亜希子
  • Organizer: 第49回歯科基礎医学会
  • Place of Presentation: 札幌
  • Year and Date: 2007-08-31
• [Presentation] Antibodies to proteinase 3 (PR3) prime human monocytic cells in a TLR2-, 3-, 4-, 7-, 8-, NOD1-, and NOD2-mediated activation. (2007)
  • Author(s): Akiko Uehara
  • Organizer: 1st Congress of the Society of Innate Immunity
  • Place of Presentation: Ankara (Turkey)
  • Year and Date: 2007-05-14
• [Remarks]
  • URL: http://portal.med.tohoku.ac.jp/index.html