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Investigation regarding the role of MFG-E8 on NF-κB-dependent intestinal inflammation : Development of a new anti-inflammatory targeting MFG-E8

Research Project

Project/Area Number 20590723
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionShimane University

Principal Investigator

ISHIHARA Shunji  Shimane University, 医学部, 准教授 (80263531)

Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2010: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2008: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords炎症性腸疾患 / 自然免疫 / MFG-E8 / Toll受容体 / NF-κB / Tool受容体 / MF-κB / MF-кB
Research Abstract

MFG-E8 deficiency is associated with acquisition of immune-mediated disorders due to the loss of tissue homeostasis. We observed altered MFG-E8 expression in inflamed colons during the acute phase of murine experimental colitis and found that treatment with recombinant MFG-E8, but not its RGD mutant counterpart, ameliorated colitis by reducing inflammation and improving disease parameters. To reveal the MFG-E8-mediated anti-inflammatory mechanism, we employed an in vitro system, which showed the downregulation of NF-κB in an LPS dependent manner. In addition, MFG-E8 altered α_vβ_3-integrin-mediated FAK phosphorylation by impeding the binding of one of its potent ligands osteopontin, which becomes activated during colitis. Our results indicated that MFG-E8 has a novel therapeutic potential for treatment of colitis.
Recently, we also employed mfg-e8 KO mice for evaluating the function of MFG-E8 on intestinal inflammation. Acute experimental colitis was established by administrating of dextran sodium sulphate (DSS). We found that exacerbation of body weight loss, shorting of colon and histological inflammation in mfg-e8 KO mice during DSS-induced intestinal inflammation, as compared to those in wild mice. Additional investigations will be necessary to elucidate the role of MFG-E8 in chronic intestinal inflammation.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (48 results)

All 2011 2010 2009 2008 Other

All Journal Article (23 results) (of which Peer Reviewed: 12 results) Presentation (25 results)

  • [Journal Article] Autophagy is required for toll-like receptor-mediated interleukin-8 production in intestinal epithelial cells.2011

    • Author(s)
      Li YY, Ishihara S, Aziz MM, Oka A, Kusunoki R, Tada Y, Yuki T, Amano Y, Ansary MU, Kinoshita Y
    • Journal Title

      Int J Mol Med. 27

      Pages: 337-344

    • Related Report
      2010 Final Research Report
  • [Journal Article] Down-regulation of single immunoglobulin interleukin-1R-related molecule (SIGIRR)/TIR8 expression in intestinal epithelial cells during inflammation.2010

    • Author(s)
      Kadota C, Ishihara S, Aziz MM, Rumi MA, Oshima N, Mishima Y, Moriyama I, Yuki T, Amano Y, Kinoshita Y
    • Journal Title

      Clin Exp Immunol. 162

      Pages: 348-361

    • Related Report
      2010 Final Research Report
  • [Journal Article] Decreased production of interleukin-10 and transforming growth factor-β in Toll-like receptor-activated intestinal B cells in SAMP1/Yit mice.2010

    • Author(s)
      Mishima Y, Ishihara S, Aziz MM, Oka A, Kusunoki R, Otani A, Tada Y, Li YY, Moriyama I, Oshima N, Yuki T, Amano Y, Matsumoto S, Kinoshita Y
    • Journal Title

      Immunology. 131

      Pages: 473-487

    • Related Report
      2010 Final Research Report
  • [Journal Article] A20 is an early responding negative regulator of Toll-like receptor 5 signalling in intestinal epithelial cells during inflammation.2010

    • Author(s)
      Oshima N, Ishihara S, Rumi MA, Aziz MM, Mishima Y, Kadota C, Moriyama I, Ishimura N, Amano Y, Kinoshita Y
    • Journal Title

      Clin Exp Immunol 159

      Pages: 185-198

    • Related Report
      2010 Final Research Report
  • [Journal Article] Autophagy is required for toll-like receptor-mediated interleukin-8 production in intestinal epithelial cells2010

    • Author(s)
      Li YY, Ishihara S, et al
    • Journal Title

      Int J Mol Med.

      Volume: 27 Pages: 337-344

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Down-regulation of single immunoglobulin interleukin-1R-related molecule (SIGIRR)/TIR8 expression in intestinal epithelial cells during inflammation.2010

    • Author(s)
      Kadota C, Ishihara S, et al
    • Journal Title

      Clin Exp Immunol.

      Volume: 162 Pages: 348-361

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Decreased production of interleukin-10 and transforming growth factor-β in Toll-like receptor-activated intestinal B cells in SAMP1/Yit mice.2010

    • Author(s)
      Mishima Y, Ishihara S, et al
    • Journal Title

      Immunology.

      Volume: 131 Pages: 473-487

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A20 is an early responding negative regulator of Toll-like receptor 5 signalling in intestinal epithelial cells during inflammation.2010

    • Author(s)
      Oshima N, Ishihara S, et al
    • Journal Title

      Clin Exp Immunol

      Volume: 159 Pages: 185-198

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A20 is an early responding negative regulator of Toll-like receptor 5 signalling in intestinal epithelial cells during inflammation.2010

    • Author(s)
      Oshima N, et al
    • Journal Title

      Clin Exp Immunol. 159(2)

      Pages: 185-198

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inflammatory bowel disease : review from the aspect of genetics.2009

    • Author(s)
      Ishihara S, Aziz MM, Yuki T, Kazumori H, Kinoshita Y
    • Journal Title

      J Gastroenterol 44

      Pages: 1097-1108

    • Related Report
      2010 Final Research Report
  • [Journal Article] MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent alphavbeta3 integrin signaling.2009

    • Author(s)
      Aziz MM, Ishihara S, Mishima Y, Oshima N, Moriyama I, Yuki T, Kadowaki Y, Rumi MA, Amano Y, Kinoshita Y.
    • Journal Title

      J Immunol 182

      Pages: 7222-7232

    • Related Report
      2010 Final Research Report
  • [Journal Article] Alterations of peripheral blood CD5(+) B cells in inflammatory bowel disease.2009

    • Author(s)
      Mishima Y, Ishihara S, Amano Y, Oshima N, Kadota C, Otani A, Moriyama I, Li YY, Aziz M, Kinoshita Y
    • Journal Title

      Scandinavia Journal of Gastroenterology 44

      Pages: 172-179

    • Related Report
      2010 Final Research Report
  • [Journal Article] Irritable bowel syndrome and inflammatory bowel disease : infectious gastroenteritis-related disorders?2009

    • Author(s)
      Ishihara S, Aziz M, Oshima N, Mishima Y, Imaoka H, Moriyama I, Kinoshita Y
    • Journal Title

      Clin J Gastroenterol 2

      Pages: 9-16

    • Related Report
      2010 Final Research Report
  • [Journal Article] Inflammatory bowel disease : review from the aspect of genetics.2009

    • Author(s)
      Ishihara S, et al
    • Journal Title

      J Gastroenterol. 44(11)

      Pages: 1098-1108

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent α_vβ_3-integrin signaling2009

    • Author(s)
      Aziz MM, et al
    • Journal Title

      J Immunol. 182(11)

      Pages: 7222-7232

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alterations of peripheral blood CD5(+) B cells in inflammatory bowel disease.2009

    • Author(s)
      Mishima Y, et al
    • Journal Title

      Scandinavia Journal of Gastroenterology 1

      Pages: 1-8

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prolactin induces MFG-E8 production in macrophages via transcription factor C/EBPβ-dependent pathway.2008

    • Author(s)
      Aziz MM, Ishihara S, Rumi MA, Mishima Yo, Oshima N, Kadota C, Moriyama I, Li YY, Rahman FB, Otani A, Oka A, Ishimura N, Kadowaki Y, Amano Y, Kinoshita Y
    • Journal Title

      Apoptosis 13

      Pages: 609-620

    • Related Report
      2010 Final Research Report
  • [Journal Article] Decoy oligodeoxynucleotide targeting activator protein-1(AP-1) attenuates intestinal inflammation in murine experimental colitis.2008

    • Author(s)
      Moriyama I, Ishihara S, Rumi MA, Aziz MD, Mishima Yo, Oshima N, Kadota C, Kadowaki Y, Amano Y, Kinoshita Y
    • Journal Title

      Labolatory investigation 88

      Pages: 652-663

    • Related Report
      2010 Final Research Report
  • [Journal Article] Abnormal liver function in Crohn's disease related to location of disease lesions.2008

    • Author(s)
      Fruta K, Sato S, Miyake T, Okamoto E, Ishine J, Ishihara S, Amano Y, Adachi K, Kinoshita Y.
    • Journal Title

      Inflamm Bowel Dis 14

      Pages: 138-139

    • Related Report
      2010 Final Research Report
  • [Journal Article] Prolactin induces MFG-E8 production in macrophages via transcription factor C/EBPβ-dependent pathway2008

    • Author(s)
      Aziz MM, Ishihara S, et al
    • Journal Title

      Apoptosis 13

      Pages: 609-620

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Decoy oligodeoxynucleotide targeting activator protein-1(AP-1) attenuates intestinal inflammation in murine experimental colitis.2008

    • Author(s)
      Moriyama I, Ishihara S, et al
    • Journal Title

      Labolatory investigation

      Pages: 652-663

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alterations of peripheral blood CD5(+) B cells in inflammatory bowel disease.2008

    • Author(s)
      Mishima Y, Ishihcira S, et al
    • Journal Title

      Scandinavia Journal of Oastroenterolocv 1

      Pages: 1-8

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent a_vβ_3-integrin signaling.

    • Author(s)
      Aziz MM, Ishihara S, et al
    • Journal Title

      J Immunol (in press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] ノックアウトマウスを用いたMFG-E8の腸管炎症制御の機能解析と治療への応用2011

    • Author(s)
      楠龍策, 石原俊治, 他
    • Organizer
      第7回消化管学会総会学術集会
    • Place of Presentation
      福岡
    • Year and Date
      2011-02-18
    • Related Report
      2010 Annual Research Report
  • [Presentation] ノックアウトマウスを用いたMFG-E8の腸管炎症制御の機能解析と治療への応用2011

    • Author(s)
      楠龍策, 石原俊治, 結城崇史, 木下芳一
    • Organizer
      第7回消化管学会総会学術集会
    • Related Report
      2010 Final Research Report
  • [Presentation] 炎症性腸疾患の腸管粘膜局所におけるMFG-E8の発現に関する検討2010

    • Author(s)
      多田育賢, 石原俊治, 楠龍策, 大谷文, 三島義之, 大嶋直樹, 森山一郎, 結城崇史, 天野祐二, 木下芳一
    • Organizer
      第52回日本消化器病学会大会
    • Place of Presentation
      横浜
    • Year and Date
      2010-10-13
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Chron病モデルマウスの病態における腸管B細胞の機能異常に関する検討2010

    • Author(s)
      岡明彦, 石原俊治, 三島義之, 多田育賢, 楠龍策, 大谷文, 森山一郎, 結城崇史, 天野祐二, 木下芳一
    • Organizer
      第52回日本消化器病学会大会
    • Place of Presentation
      横浜
    • Year and Date
      2010-10-13
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Decreased production of IL-10 in TLR9-activated peripheral blood B cells in inflammatory bowel disease.2010

    • Author(s)
      Oka A, Ishihara S, Mishima Y, Oshima N, Kusunoki R, Tada Y, Moriyama I, Yuki T, Kinoshita Y
    • Organizer
      Digestive Disease Week.
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Intestinal inflammation down-regulates SIGIRR/TIR8 expression in epithelial cells by inhibiting SP1-mediated pathway.2010

    • Author(s)
      Kadota C, Ishihara S, Mishima Y, Oshima N, Oka A, Kusunoki R, Tada Y, Moriyama I, Yuki T, Kinoshita Y
    • Organizer
      Digestive Disease Week.
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Crosstalk between TLR5 and Notch1 signaling in epithelial cells during intestinal inflammation.2010

    • Author(s)
      Yuki T, Ishihara S, Aziz MM, Mishima Y, Oshima N, Otani A, Oka A, Kusunoki R, Tada Y, Moriyama I, Yoshikazu K
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] 炎症性腸疾患患者の末梢血B細胞におけるIL-10産生能に関する検討2010

    • Author(s)
      岡明彦, 石原俊治, 三島義之, 多田育賢, 楠龍策, 大谷文, 森山一郎, 結城崇史, 天野祐二, 木下芳一
    • Organizer
      第96回日本消化器病学会総会
    • Place of Presentation
      新潟
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] 腸管炎症におけるNotch-1とTLR5シグナルの相互作用に関する検討。2010

    • Author(s)
      結城崇史, 石原俊治, 多田育賢, 楠龍策, 大谷文, 三島義之, 天野祐二, 木下芳一
    • Organizer
      第96回日本消化器病学会総会
    • Place of Presentation
      新潟
    • Related Report
      2010 Final Research Report
  • [Presentation] Decreased production of IL-10 in TLR9-activated peripheral blood B cells in inflammatory bowel disease2010

    • Author(s)
      Oka A, Ishihara S, et al
    • Organizer
      Digestive Disease Week
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2010 Annual Research Report
  • [Presentation] Intestinal inflammation down-regulates SIGIRR/TIR8 expression in epithelial cells by inhibiting SP1-mediated pathway2010

    • Author(s)
      Kadota C, Ishihara S, et al
    • Organizer
      Digestive Disease Week
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2010 Annual Research Report
  • [Presentation] Crosstalk between TLR5 and Notch1 signaling in epithelial cells during intestinal inflammation2010

    • Author(s)
      Yuki T, Ishihara S, et al
    • Organizer
      Digestive Disease Week
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2010 Annual Research Report
  • [Presentation] 腸管炎症におけるNotch-1とTLR5シグナルの相互作用に関する検討2010

    • Author(s)
      結城崇史, 石原俊治, 他
    • Organizer
      第96回日本消化器病学会総会
    • Place of Presentation
      新潟
    • Related Report
      2010 Annual Research Report
  • [Presentation] クローン病モデルマウスにおけるIL-10産生腸管制御性B細胞に関する検討2009

    • Author(s)
      三島義之, 石原俊治, 木下芳一
    • Organizer
      第51回日本消化器病学会大会
    • Place of Presentation
      京都
    • Related Report
      2010 Final Research Report
  • [Presentation] Decreased production of IL-10 and TGF-β in TLR-activated intestinal B cells in SAMP1/Yit mice.2009

    • Author(s)
      Mishima Y, Ishihara S, Aziz M, Oshima N, Otani A, Oka A, Kusunoki R, Moriyama I, Amano Y, Kinoshita Y
    • Organizer
      Digestive Disease Week 2009
    • Place of Presentation
      Chicago, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Intrarectal administration of MFG-E8 protein ameliorates murine experimental colitis by inhibiting NF-κB activation in intestinal epithelial cells.2009

    • Author(s)
      Oshima N, Ishihara S, Kadota C, Oka A, Kusunoki R, Moriyama I, AmanoY, Kinoshita Y
    • Organizer
      Digestive Disease Week 2009
    • Place of Presentation
      Chicago, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Crosstalk between Notch and toll signaling in murine colitis.2009

    • Author(s)
      Ishihara S, Aziz M, Mishima Y, Oshima N, Otani A, Oka A, Kusunoki R, Moriyama I, Ishimura M, Li YY, Amano Y, Kinoshita Y
    • Organizer
      Digestive Disease Week 2009
    • Place of Presentation
      Chicago, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] クローン病モデルマウスにおけるIL-10産生B細胞に関する検討2009

    • Author(s)
      三島義之, 石原俊治, 楠龍策、岡明彦, 大谷文, 大嶋直樹, 森山一郎, 天野祐二, 木下芳一
    • Organizer
      第95回日本消化器病学会総会
    • Place of Presentation
      札幌
    • Related Report
      2010 Final Research Report
  • [Presentation] 精製MFG-E8蛋白の経肛門的投与による実験腸炎抑制の試み2009

    • Author(s)
      大谷文、石原俊治, 大嶋直樹、三島義之、岡明彦、楠龍策、森山一郎、天野祐二、木下芳一
    • Organizer
      第95回日本消化器病学会総会
    • Place of Presentation
      札幌
    • Related Report
      2010 Final Research Report
  • [Presentation] 炎症性腸疾患の末梢血CD5陽性B細胞の解析2009

    • Author(s)
      三島義之, 石原俊治, 大谷文, 天野祐二, 木下芳一
    • Organizer
      第5回日本消化管学会
    • Place of Presentation
      東京
    • Related Report
      2010 Final Research Report
  • [Presentation] 消化管粘膜におけるIL-10、TGF-beta産生B細胞に関する検討2008

    • Author(s)
      三島義之, 石原俊治, 岡明彦, 大谷文, 大嶋直樹, 角田力, 森山一郎, 天野祐二, 木下芳一
    • Organizer
      第50回日本消化器病学会大会
    • Place of Presentation
      東京
    • Related Report
      2010 Final Research Report
  • [Presentation] 下部消化管の炎症と機能相関をめぐって消化管上皮の自然免疫応答におけるA20発現の意義2008

    • Author(s)
      大嶋直樹, 石原俊治, 木下芳一, パネルディスカッション
    • Organizer
      第50回日本消化器病学会大会
    • Place of Presentation
      東京
    • Related Report
      2010 Final Research Report
  • [Presentation] Milk fat globule EGF-8 attenuates intestinal inflammation in murine experimental colitis via inhibition of NF-κB activation.2008

    • Author(s)
      Ishihara S, Aziz M, Rumi MA, Oshima N, Mishima Y, Kadota C, Otani A, Oka A, Norihisa I, Moriyama I, Kadowaki Y, Amano Y, Kinoshita Y
    • Organizer
      Digestive Disease Week 2008
    • Place of Presentation
      San Diego, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] A20 is an early responsive negative regulator of Toll-like receptor signaling in intestinal epithelial cells during inflammation.2008

    • Author(s)
      Oshima N, Ishihara S, Rumi MAK, Aziz MM, Mishima Yo, Kadota C, Moriyama I, Ohtani A, Oka A, Li YY, Kadowaki Y, AmanoY, Kinoshita Y
    • Organizer
      Digestive Disease Week 2008
    • Place of Presentation
      San Diego, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] Intestinal CD5^+ B cells produce IL-10 and TGF-β via Toll-like receptor-mediated signaling.2008

    • Author(s)
      Mishima Y, Ishihara S, Aziz MM, Rumi MAK, Oshima N, Kadota C, Moriyama I, Li YY, Ohtani A, Oka A, Kadowaki Y, Amano Y, Kinoshita Y
    • Organizer
      Digestive Disease Week 2008
    • Place of Presentation
      San Diego, USA
    • Related Report
      2010 Final Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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