Regulation of IL-18 and IL-38 for the treatment of inflammatory pulmonary diseases

• Project/Area Number: 16K09595
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kurume University
• Principal Investigator: Hoshino Tomoaki 久留米大学, 医学部, 教授 (00261066)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IL-38 / 喘息 / 好酸球 / IL-5 / 炎症性肺疾患 / サイトカイン / IL-18 / 気管支喘息マウスモデル / 気管支喘息 / 分子細胞呼吸器学

Outline of Final Research Achievements

The role of IL-38, a new member of the IL-1 family, in airway eosinophilic inflammatory conditions such as asthma is unclear. To investigate the role of IL-38 in airway eosinophilic inflammation, an IL-38-gene deficient (KO) murine asthma model was analyzed. The IL-38 and IL-5 mRNA in WT mice was significantly higher after OVA challenge than after saline challenge (p<0.05). The number of airway eosinophils in IL-38-KO mice was significantly lower than in WT mice after OVA challenge (p<0.01). BALF analysis confirmed the lower number of airway eosinophils in IL-38-KO mice and showed that this was significantly associated with lower IL-5 protein levels (r=0.92, p<0.0001). However, the additional rm IL-38 protein did not neutralize airway eosinophilia in IL-38-KO mice.IL-38 may enhance airway eosinophilic inflammation in asthma through IL-5 induction.We also reported that IL-18 strongly involves in activation of Macrophage Activation Syndrome（MAS).

Academic Significance and Societal Importance of the Research Achievements

新規IL-1ファミリーサイトカインIL-38は抗炎症性サイトカインの可能性があることが示唆された（Biochemistry and Biophysics Reports 2015）。一方、IL-38は炎症性サイトカインの可能性を本研究で証明した。すなわち、IL-38は抗炎症性と炎症性サイトカインの二つの可能性を本研究で証明した。
申請者は抗ヒトIL-38モノクロナール抗体を樹立した。抗IL-38モノクロナール抗体H127CはBiolegend, eBioscienceから世界中で販売され,IL-38の研究に役立っている。

Research Products

• [Journal Article] Attenuated Airway Eosinophilic Inflammations in IL-38 Knockout Mouse Model (2019)
  • Author(s): MATSUOKA MASANOBU、KAWAYAMA TOMOTAKA、TOMINAGA MASAKI、KAIEDA SHINJIRO、TOKUNAGA YOSHIHISA、KAKU YOICHIRO、IMAOKA HARUKI、KINOSHITA TAKASHI、OKAMOTO MASAKI、AKIBA JUN、HOSHINO TOMOAKI
  • Journal Title: The Kurume Medical Journal Volume: 65 Pages: 37-46
  • DOI: 10.2739/kurumemedj.MS652009
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome (2018)
  • Author(s): Weiss Eric S.、Girard-Guyonvarc’h Charlotte、Holzinger Dirk、de Jesus Adriana A.、Tariq Zeshan、Picarsic Jennifer、Schiffrin Eduardo J.、Foell Dirk、Grom Alexei A.、Ammann Sandra、Ehl Stephan、Hoshino Tomoaki、Goldbach-Mansky Raphaela、Gabay Cem、Canna Scott W.
  • Journal Title: Blood Volume: 131 Pages: 1442～1455
  • DOI: 10.1182/blood-2017-12-820852
  • Peer Reviewed / Open Access
• [Journal Article] Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor (2018)
  • Author(s): Matsuo Norikazu、Azuma Koichi、Hattori Satoshi、Ohtake Junya、Kawahara Akihiko、Ishii Hidenobu、Tokito Takaaki、Yamada Kazuhiko、Shibata Yuji、Shimokawaji Tadasuke、Kondo Tetsuro、Kato Terufumi、Saito Haruhiro、Yamada Kouzo、Sasada Tetsuro、Hoshino Tomoaki
  • Journal Title: International Journal of Cancer Volume: 144 Pages: 1170～1179
  • DOI: 10.1002/ijc.31923
  • Peer Reviewed / Open Access
• [Journal Article] IL-33/ST2 contributes to severe symptoms in Plasmodium chabaudi -infected BALB/c mice (2018)
  • Author(s): Seki Takenori、Obata-Ninomiya Kazushige、Shimogawara-Furushima Rieko、Arai Toshio、Akao Nobuaki、Hoshino Tomoaki、Ohta Nobuo
  • Journal Title: Parasitology International Volume: 67 Pages: 64～69
  • DOI: 10.1016/j.parint.2017.03.008
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis (2017)
  • Author(s): Tominaga Masaki、Okamoto Masaki、Kawayama Tomotaka、Matsuoka Masanobu、Kaieda Shinjiro、Sakazaki Yuki、Kinoshita Takashi、Mori Daisuke、Inoue Akira、Hoshino Tomoaki
  • Journal Title: Respiratory Investigation Volume: 55 Pages: 293～299
  • DOI: 10.1016/j.resinv.2017.06.001
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression (2017)
  • Author(s): Takada Kazuki、Okamoto Tatsuro、Tominaga Masaki、Teraishi Koji、Akamine Takaki、Takamori Shinkichi、Katsura Masakazu、Toyokawa Gouji、Shoji Fumihiro、Okamoto Masaki、Oda Yoshinao、Hoshino Tomoaki、Maehara Yoshihiko
  • Journal Title: PLOS ONE Volume: 12 Pages: e0181598
  • DOI: 10.1371/journal.pone.0181598
  • Peer Reviewed / Open Access
• [Journal Article] Association of anti-aminoacyl-transfer rna synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease. (2017)
  • Author(s): Yoshida N, Okamoto M, Kaieda S, Fujimoto K, Ebata T, Tajiri M, Nakamura M, Tominaga M, Wakasugi D, Kawayama T, Kuwana M, Mimori T, Ida H, Hoshino T.
  • Journal Title: Respiratory investigation Volume: 55 Pages: 24-32
  • DOI: 10.1016/j.resinv.2016.08.007.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Il-33/st2 contributes to severe symptoms in plasmodium chabaudi-infected balb/c mice (2017)
  • Author(s): Seki T, Obata-Ninomiya K, Shimogawara-Furushima R, Arai T, Akao N, Hoshino T, Ohta N.
  • Journal Title: Parasitology international Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.parint.2017.03.008.
  • Peer Reviewed / Open Access
• [Journal Article] The usefulness of monomeric periostin as a biomarker for idiopathic pulmonary fibrosis (2017)
  • Author(s): Ohta S, Okamoto M, Fujimoto K, Sakamoto N, Takahashi K, Yamamoto H, Kushima H, Ishii H, Akasaka K, Ono J, Kamei A, Azuma Y, Matsumoto H, Yamaguchi Y, Aihara M, Johkoh T, Kawaguchi A, Ichiki M, Sagara H, Kadota JI, Hanaoka M, Hayashi SI, Kohno S, Hoshino T, Izuhara K
  • Journal Title: PloS one Volume: 12 Pages: e0174547
  • DOI: 10.1371/journal.pone.0174547
  • Peer Reviewed / Open Access / Acknowledgement Compliant