Analysis of IL-6-mediated drug-resistance of hepatitis C virus infection

• Project/Area Number: 24590958
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAKAGAWA Mina 東京医科歯科大学, 医歯学融合教育支援センター, 准教授 (30401342)
• Co-Investigator(Kenkyū-buntansha): ASAHINA Yasuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692) ; WATANABE Mamoru 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
• Co-Investigator(Renkei-kenkyūsha): SAKAMOTO Naoya 北海道大学, 医学研究科, 教授 (10334418)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 治療抵抗性機序 / C型慢性肝炎 / インターロイキン6 / 治療抵抗性 / 肝発癌 / インターロイキン６ / コア変異株 / コア変異 / DAA製剤 / 小胞体ストレス

Outline of Final Research Achievements

Our previous study described the association of serum IL-6 levels and ER stress and drug-resistance using JFH1 genotype 2a cell culture system. Based on the pTPF1-M170T (LC011929), we constructed full-length 1b clones that expressed core mutant viruses which were clinically resistant to IFN. Although TPF1-M170T clones are not currently allowed in drug-screening tests, perhaps this unique character can assist in establishing the molecular mechanism of HCV replication. We conducted a cohort study to investigate whether serum IL-6 levels influenced treatment outcomes of TVR/PEG-IFN/RBV triple therapy. Our results suggest that baseline low levels of IL-6, as well as their transient increase and decline during early stage of treatment, are correlated to good response to treatment, whereas sustained high levels of serum IL-6 are correlated to treatment resistance in most cases. Taken together, serum IL-6 levels correlate with resistance to treatment also with DAA combination therapy.

Research Products

• [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C. (2015)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
  • Journal Title: J Gastroenterol Hepatol Volume: 印刷中 Issue: 6 Pages: 1075-84
  • DOI: 10.1111/jgh.12902
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. (2015)
  • Author(s): Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H et al.
  • Journal Title: Hum Genet Volume: 134 Issue: 3 Pages: 279-289
  • DOI: 10.1007/s00439-014-1520-7
  • Peer Reviewed / Open Access
• [Journal Article] Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions. (2015)
  • Author(s): Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kudo M, Chuganji Y, Tsukuda Y, Tsunematsu S, Sato F, Terasita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Fujita Y, Abe R, Taniguchi M, Nakagawa M, Asahina Y, Sakamoto N
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 8 Pages: 837-45
  • DOI: 10.1111/hepr.12421
  • NAID: 120005820706
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] α-fetoprotein levels afterinterferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C (2013)
  • Author(s): Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nakagawa M, Kakinuma S, Watanabe M,Izumi N
  • Journal Title: Hepatology Volume: (in press) Issue: 4 Pages: 1253-1262
  • DOI: 10.1002/hep.26442
  • Peer Reviewed
• [Journal Article] Wnt5a Signaling Mediates Biliary Differentiation of Fetal Hepatic Stem/Progenitor Cells (2013)
  • Author(s): Kakinuma S, Kiyohashi K, Kamiya A, Sakamoto N, Nitta S, Yamanaka H, YoshinoK, Fujiki J, Murakawa M, Kusano-Kitazume A, Shimizu H, Okamoto R, Azuma S, Nakagawa M, Asahina Y, Tanimizu N, Kikuchi A, Nakauchi H, and *WatanabeM
  • Journal Title: Hepatology Volume: (in press) Issue: 6 Pages: 2502-2513
  • DOI: 10.1002/hep.26293
  • Peer Reviewed
• [Journal Article] Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity (2013)
  • Author(s): Nitta S, Sakamoto N, Nakagawa M, Kakinuma S, Mishima K, Kusano-kitazume A, Kiyohashi K, Murakawa M, Nishimura-Sakurai Y, Azuma S, Tasaka-Fujita M, asahina Y, Yoneyama M, Fujita T, Watanabe M
  • Journal Title: Hepatology Volume: 57 Issue: 1 Pages: 46-58
  • DOI: 10.1002/hep.26017
  • Peer Reviewed
• [Journal Article] Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C. (2013)
  • Author(s): Nakagawa M, Sakamoto N, Watanabe T, Nishimura-Sakurai Y, Onozuka I, Azuma S, Kakinuma S, Nitta S, Kiyohashi K,Kusano-Kitazume A, Murakawa M, Yoshino K, Itsui Y, Tanaka Y, Mizokami M,Watanabe M, Ochanomizu Liver Conference Study Group
  • Journal Title: Hepatol Int Volume: 7(1) Issue: 1 Pages: 153-161
  • DOI: 10.1007/s12072-012-9363-6
  • Peer Reviewed
• [Journal Article] Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C (2012)
  • Author(s): Kurosaki M, Sakamoto N, Nakagawa M, et al.
  • Journal Title: J Hepatol Volume: 56(3) Issue: 3 Pages: 602-608
  • DOI: 10.1016/j.jhep.2011.09.011
  • Peer Reviewed
• [Presentation] 難治性C型慢性肝炎に対するプロテアーゼ３剤併用療法の治療効果とDAA耐性変異の検討 (2015)
  • Author(s): 中川美奈、朝比奈靖浩, 渡辺守
  • Organizer: 第40回日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-11-27
• [Presentation] C型慢性肝炎に対するDAAs併用療法の治療効果と耐性変異の検討 (2015)
  • Author(s): 中川美奈、朝比奈靖浩, 渡辺守
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2015-04-23
• [Presentation] Impact of host and therapeutic factors and resistant associated variants on response to interferon based- direct acting antiviral treatment in difficult-to-treat chronic hepatitis C patients. (2014)
  • Author(s): Mina Nakagawa, Yasuhiro Asahina, Miki Taniguchi, Takako Watanabe, Yuki Nishimura-Sakurai, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Yujiro Tanaka, Mamoru Watanabe
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-09 – 2014-11-11
• [Presentation] Gene alterations in β-catenin and p53/ cell cycle control pathway are closely associated with development and prognosis of hepatocellular carcinoma: Comprehensive analyses by next generation sequencing technology. (2014)
  • Author(s): Fukiko Kawai-Kitahata, Yasuhiro Asahina, Syun Kaneko, Hiroko Nagata, Fumio Goto, Satoshi Otani, Miki Taniguchi, Miyako Murakawa, Sayuri Nitta, Takako Watanabe, Megumi Tasaka-Fujita, Yasuhiro Itsui, Mina Nakagawa, Sei Kakinuma, Nobuyuki Enomoto, Mamoru Watanabe
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-09 – 2014-11-11
• [Presentation] C型慢性肝炎に対するインターフェロンをベーストしたプロテアーゼ3剤併用療法の治療効果とDAA耐性変異の検討 (2014)
  • Author(s): 中川美奈、朝比奈靖浩, 渡辺守
  • Organizer: 第18回日本肝臓学会大会
  • Place of Presentation: ポートピアホテル（神戸）
  • Year and Date: 2014-10-23
• [Presentation] NS3およびNS5A阻害剤耐性変異とシメプレビルおよびテラプレビル3剤併用療法の治療効果 (2014)
  • Author(s): 朝比奈靖浩, 中川美奈、渡辺守
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京）
  • Year and Date: 2014-05-29
• [Presentation] インターフェロン治療後の線維化マーカーの推移と発癌リスクの検討 (2014)
  • Author(s): 中川美奈、朝比奈靖浩, 渡辺守
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ（東京）
  • Year and Date: 2014-05-29
• [Presentation] 次世代プロテアーゼ阻害剤併用3剤治療の適応症例の検討 (2014)
  • Author(s): 中川美奈、朝比奈靖浩, 渡辺守
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム（東京)
  • Year and Date: 2014-04-24
• [Presentation] 慢性肝疾患における肝細胞癌とIL-6の関連
  • Author(s): 谷口未樹、中川美奈
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 難治性C型慢性肝炎におけるテラプレビル3剤併用療法の効果と安全性の検討
  • Author(s): 朝比奈靖浩, 中川美奈、渡辺守
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島
• [Presentation] 難治性C型慢性肝炎におけるテラプレビル3剤併用療法の有用性の検討
  • Author(s): 朝比奈靖浩, 中川美奈、渡辺守
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 難治性C型慢性肝炎におけるIFN応答性に関与する要因とテラプレビル3剤併用療法の効果
  • Author(s): 中川美奈、坂本直哉、朝比奈靖浩
  • Organizer: 第16回日本肝臓学会大会
  • Place of Presentation: 神戸
• [Presentation] C型肝疾患コホートにおける宿主遺伝子多型およびHCV遺伝子構造と予後との関連
  • Author(s): 中川美奈、坂本直哉、朝比奈靖浩
  • Organizer: 第16回日本肝臓学会大会
  • Place of Presentation: 神戸
• [Presentation] 宿主遺伝子情報に基づいたC型慢性肝炎の最適な治療法の選択
  • Author(s): 中川美奈、坂本直哉、渡辺守
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] 慢性肝疾患における肝細胞癌とIL-6の関連
  • Author(s): 中川美奈、坂本直哉、渡辺守
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] 宿主遺伝子情報に基づいたC型慢性肝炎治療の効果・安全性の最適化
  • Author(s): 中川美奈、坂本直哉、渡辺守
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京