The novel therapeutic strategy for pulmonary hypertension targeting inflammation amplification loop mediated by IL-6

• Project/Area Number: 25670386
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: NAKAOKA YOSHIKAZU 大阪大学, 医学(系)研究科(研究院), 助教 (90393214)
• Co-Investigator(Renkei-kenkyūsha): SHIRAI Mikiyasu 独立行政法人国立循環器病研究センター, 部長 (70162758) ; MURAKAMI Masaaki 北海道大学, 遺伝子病制御研究所, 教授 (00250514) ; KOMURO Issei 東京大学, 医学系研究科, 教授 (30260483)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺高血圧症 / 炎症 / interleukin-6 / Th17細胞 / interleukin-21 / M2マクロファージ / サイトカイン / interleukin-6受容体抗体 / インターロイキン６ / インターロイキン６受容体抗体

Outline of Final Research Achievements

The molecular mechanisms of interleukin-6(IL-6)-mediated pathogenesis of PAH have been elusive. Here, we identified IL-21 as a novel downstream target of IL-6-signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly upregulated after hypoxia exposure in the lungs of mice treated with control antibody, but not in those treated with MR16-1. Whereas IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. These findings suggest that IL-6/IL-21-signaling is critical in the pathogenesis of pulmonary arterial hypertension.

Research Products

• [Journal Article] Cytokine storm after cessation of tocilizumab in a patient with refractory Takayasu arteritis. (2015)
  • Author(s): Arita Y, Nakaoka Y, Otsuki M, Higuchi K, Hashimoto-Kataoka T, Yasui T, Masaki T, Ohtani T, Kishimoto T, Yamauchi-Takihara K, Komuro I, Sakata Y.
  • Journal Title: International Journal of Cardiology Volume: 187 Pages: 319-321
  • DOI: 10.1016/j.ijcard.2015.03.399
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice. (2015)
  • Author(s): Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Takemura T, Ezaki H, Kamada Y, Nishida K, Nakaoka Y, Kiso S, Takehara T.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 308 Issue: 7 Pages: 613-624
  • DOI: 10.1152/ajpgi.00289.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart (2014)
  • Author(s): Arita Y, Nakaoka Y, Matsunaga T, Kidoya H, Yamamizu K, Arima Y, Kataoka-Hashimoto T, Ikeoka K, Yasui T, Masaki T, Yamamoto K, Higuchi K, Park JS, Shirai M, Nishiyama K, Yamagishi H, Otsu K, Kurihara H, Minami T, Yamauchi-Takihara K, Koh GY, Mochizuki N, Takakura N, Sakata Y, Yamashita JK, Komuro I
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 4452-4452
  • DOI: 10.1038/ncomms5552
  • Peer Reviewed / Open Access
• [Journal Article] Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity. (2014)
  • Author(s): Park DY, Lee J, Park I, Choi D, Lee S, Song S, Hwang Y, Hong KY, Nakaoka Y, Makinen T, Kim P, Alitalo K, Hong YK, Koh GY.
  • Journal Title: Journal of Clinical Investigation Volume: 24 Issue: 9 Pages: 3960-74
  • DOI: 10.1172/jci75392
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Neureguiln-1/ErbBシグナルの心血管系における生理機能 (2014)
  • Author(s): 中岡良和
  • Journal Title: 医学のあゆみ Volume: 250 Pages: 200-206
• [Journal Article] 大型血管炎の標準治療 (2014)
  • Author(s): 中岡良和
  • Journal Title: Modern Physician～臨床医のための血管炎の知識up-to-date Volume: 34 Pages: 1034-1039
• [Journal Article] 野本論文に対するEditorial Comment-難治性高安動脈炎に対する抗ＩＬ-6レセプター抗体Tocilizumabの有効性について (2014)
  • Author(s): 中岡良和
  • Journal Title: 心臓 Volume: 46 Pages: 1592-1593
  • NAID: 130005113470
• [Journal Article] Angiopoietin-1 Suppresses Choroidal Neovascularization and Vascular Leakage. (2013)
  • Author(s): Lee J, Park DY, Park DY, Park I, Chang W, Nakaoka Y, Komuro I, Yoo OJ, Koh GY.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: in press Issue: 4 Pages: 2191-2199
  • DOI: 10.1167/iovs.14-13897
  • Peer Reviewed
• [Journal Article] Tocilizumab for the treatment of patients with refractory takayasu arteritis. (2013)
  • Author(s): Nakaoka Y, Higuchi K, Arita Y, Otsuki M, Yamamoto K, Hashimoto-Kataoka T, Yasui T, Ikeoka K, Ohtani T, Sakata Y, Shima Y, Kumanogoh A, Yamauchi-Takihara K, Tanaka T, Kishimoto T, Komuro I.
  • Journal Title: Int Heart J. Volume: 54 Pages: 405-411
  • NAID: 130003383361
  • Peer Reviewed
• [Journal Article] Angiopoietin-1 guides directional angiogenesis through integrin αvβ5 signaling for recovery of ischemic retinopathy. (2013)
  • Author(s): Lee J, Kim KE, Choi DK, Jang JY, Jung JJ, Kiyonari H, Shioi G, Chang W, Suda T, Mochizuki N, Nakaoka Y, Komuro I, Yoo OJ, Koh GY.
  • Journal Title: Sci Transl Med. Volume: 5 Issue: 203
  • DOI: 10.1126/scitranslmed.3006666
  • Peer Reviewed
• [Journal Article] 高安動脈炎の診断と治療 -生物学的製剤による治療の現状に焦点を当てて (2013)
  • Author(s): 中岡良和
  • Journal Title: 医学のあゆみ Volume: 246 Pages: 5-11
• [Journal Article] Interleukin-6 シグナル制御による肺動脈性肺高血圧症の治療の可能性 (2013)
  • Author(s): 中岡良和
  • Journal Title: 日本循環器学会専門医誌 循環器専門医 Volume: 21 Pages: 271-276
• [Journal Article] 影山論文に対するEditorial Comment - 冠動脈・大動脈疾患を合併する巨細胞性動脈炎では厳密な慢性炎症のコントロールに留意する必要がある (2013)
  • Author(s): 中岡良和
  • Journal Title: 心臓 Volume: 45 Pages: 1293-1294
  • NAID: 130004716912
• [Presentation] IL-6はTh17反応とＭ2極性化を介して (2014)
  • Author(s): 片岡崇弘
  • Organizer: 第2回肺高血圧学会、第3回肺循環学会
  • Place of Presentation: 大手町サンケイプラザ
  • Year and Date: 2014-10-04
• [Presentation] 難治性高安動脈炎に対するトシリズマブによるinterleukin-6阻害療法による治療の試み (2014)
  • Author(s): 中岡良和
  • Organizer: 日本心臓病学会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2014-09-26
• [Presentation] Angiopoietin-1 derived from myocardium has a criticall role for coronary vein formation in the developing heart (2014)
  • Author(s): Yoh Arita
  • Organizer: 8th International Kloster Seeon Meeting
  • Place of Presentation: Kloster Seeon(ドイツ・バイエルン州）
  • Year and Date: 2014-09-20 – 2014-09-23
• [Presentation] Interleukin-6 promotes hypoxia-induced pulmonary arterial hypertension through Th17 response and alternative activation of macrophages (2014)
  • Author(s): Yoshikazu Nakaoka
  • Organizer: 8th International Kloster Seeon Meeting
  • Place of Presentation: Kloster Seeon(ドイツ・バイエルン州）
  • Year and Date: 2014-09-20 – 2014-09-23
• [Presentation] The role of angiopoietin-1 in coronary vessel formation in the developing heart (2014)
  • Author(s): Yoshikazu Nakaoka
  • Organizer: 第18回国際血管生物学会（ＩＶＢＭ2014）
  • Place of Presentation: 京都みやこめっせ
  • Year and Date: 2014-04-14
  • Invited
• [Presentation] 難治性高安動脈炎に対するトシリズマブの安全性と有効性の検討 (2014)
  • Author(s): 中岡良和
  • Organizer: 第111回 日本内科学会総会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2014-04-09
• [Presentation] Blockade of interleukin-6 signaling prevents hypoxia induced pulmonary hypertension in mice (2013)
  • Author(s): Takahiro Hashimoto-Kataoka, Yoshikazu Nakaoka, Takashi Sonobe, Kaori Higuchi, Yoh Arita, Taku Yasui, Kuniyasu Ikeoka, Takeshi Masaki, Keiko Yamauchi-Takihara, Mikiyasu Shirai, Issei Komuro
  • Organizer: American Heart Association Scientific Sessions 2013
  • Place of Presentation: Dallas Convention Center (Dallas, TX, USA)
• [Presentation] 低酸素誘発性肺高血圧モデルでIL-6/Th17細胞シグナルは肺血管リモデリングに必須である (2013)
  • Author(s): 片岡 崇弘、中岡 良和、曽野部 崇、保仙 直毅、稲垣 薫克、樋口 香織、有田 陽、安居 琢、池岡 邦泰、正木 豪、瀧原 圭子、白井 幹康、小室 一成
  • Organizer: 第4回Molecular Cardiovascular ConferenceII
  • Place of Presentation: キロロリゾートホテルピアノ(北海道余市郡赤井川村)
• [Presentation] 低酸素誘発性肺高血圧モデルでIL-6/Th17細胞シグナルは肺血管リモデリングに必須である (2013)
  • Author(s): 片岡 崇弘、中岡 良和、曽野部 崇、保仙 直毅、稲垣 薫克、樋口 香織、有田 陽、安居 琢、池岡 邦泰、正木 豪、瀧原 圭子、白井 幹康、小室 一成
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 千里阪急ホテル(大阪府豊中市)
• [Presentation] Blockade of interleukin-6 signaling might be a promising therapeutic option for pulmonary arterial hypertension via regulating Th17 cell differentiation
  • Author(s): Takahiro Hashimoto-Kataoka, Yoshikazu Nakaoka, Takashi Sonobe, Naoki Hosen, Yoh Arita, Taku Yasui, Kuniyasu Ikeoka, Takeshi Masaki, Tadakatsu Inagaki, Keiko Yamauchi-Takihara, Mikiyasu Shirai, Issei Komuro
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
• [Presentation] 抗Interleukin-6(IL-6)受容体抗体によるIL-6阻害療法は低酸素誘発性肺高血圧の病態形成を抑制する
  • Author(s): 中岡良和、橋本崇弘、曽野部崇、瀧原圭子、白井幹康、小室一成
  • Organizer: 第2回日本肺循環学会学術集会
  • Place of Presentation: 東京ステーションコンファレンス(東京都千代田区)
  • Invited
• [Presentation] Tocilizumab Ameliorates Vascular Inflammation and Clinical Symptoms in the Patients with Takayasu Arteritis Refractory to Glucocorticoids
  • Author(s): Yoshikazu Nakaoka, Yoh Arita, Kaori Higuchi, Takahiro Hashimoto-Kataoka, Taku Yasui, Yasushi Sakata, Keiko Yamauchi-Takihara, Tadamitsu Kishimoto, Issei Komuro
  • Organizer: 第30回国際心臓研究学会（ISHR）日本部会総会
  • Place of Presentation: La Valencia Hotel, San Diego, USA
• [Presentation] Angiopoietin-1 is essential for coronary venogenesis in the developing heart
  • Author(s): 中岡 良和
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Invited
• [Presentation] 冠静脈形成の分子機構
  • Author(s): 中岡良和、有田陽、松永太一、山下潤、小室一成
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 千里阪急ホテル(大阪府豊中市)
• [Presentation] 心筋由来のAngiopoietin-1は静脈洞内皮細胞の遊走と静脈分化の促進を通して冠静脈
  • Author(s): 中岡良和、有田陽、小室一成
  • Organizer: 第36回日本分子生物学会
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Invited
• [Presentation] Tocilizumab Ameliorates Vascular Inflammation and Clinical Symptoms in the Patients with Takayasu Arteritis Refractory to Glucocorticoids
  • Author(s): Yoshikazu Nakaoka, Kaori Higuchi, Yoh Arita, Taku Yasui, Kuniyasu Ikeoka, Takeshi Masaki,Tomohito Ohtani, Keiko Yamauchi-Takihara, Yasushi Sakata, Issei Komuro
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京国際フォーラム(東京都千代田区)
• [Presentation] 心臓における冠血管発生
  • Author(s): 中岡 良和
  • Organizer: 第13回日本再生医療学会総会
  • Place of Presentation: 国立京都国際会館(京都府京都市)
  • Invited
• [Remarks] 大阪大学大学院医学系研究科循環器内科学・心血管サイトカインGroup
  • URL: http://www.cardiology.med.osaka-u.ac.jp/?page_id=66
• [Remarks] 大阪大学大学院医学系研究科循環器内科学心血管サイトカイン研究グループ
  • URL: http://www.med.osaka-u.ac.jp/pub/cardiology/27research/2751res.html
• [Patent(Industrial Property Rights)] 肺高血圧治療薬およびそのスクリーニング法 (2014)
  • Inventor(s): 中岡良和、片岡崇弘
  • Industrial Property Rights Holder: 中岡良和、片岡崇弘
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-09-08