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

2014 Fiscal Year Final Research Report

• 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
• Keywords: 肺高血圧症 / 炎症 / interleukin-6 / Th17細胞 / interleukin-21 / M2マクロファージ

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.

Free Research Field

循環器内科学、血管生物学、血管病学