Interleukin-1 targeting therapy using low molecular weight compounds in inflammatory disorder

2017 Fiscal Year Final Research Report

• Project/Area Number: 26461481
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Fukushima Medical University (2016-2017); Department of Clinical Research, National Hospital Organization Nagasaki Medical Center (2014-2015)
• Principal Investigator: Migita Kiyoshi 福島県立医科大学, 医学部, 教授 (60264214)
• Co-Investigator(Kenkyū-buntansha): 増本 純也 愛媛大学, プロテオサイエンスセンター, 教授 (20334914) ; 川上 純 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90325639)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: IL-1 / インフラマソーム / 好中球 / TNF-α / カスパーゼ1 / NOD様受容体 / サイトカインネットワーク

Outline of Final Research Achievements

We investigated the proinflammatory effects of SAA in vitro in relation to the NLRP3 inflammasome in neutrophils. SAA stimulation induced pro-IL-1β mRNA expression in neutrophils. Furthermore, SAA engaged the caspase-1-activating inflammasome, resulting in the production of active IL-1β. SAA-induced pro-IL-1β expression was marginally suppressed by the Syk specific inhibitor, R406, and SAA-induced pro-IL-1β processing in neutrophils was prevented by R406. Furthermore, SAA-induced NLRP3 mRNA expression was completely blocked by R406. Analysis of intracellular signaling revealed that SAA stimulation activated the tyrosine kinase Syk and mitogen-activated protein kinase (MAPK). These results demonstrate that the innate neutrophil immune response against SAA involves a two-step activation process: an initial signal promoting expression of pro-IL-1β and a second signal involving Syk-dependent activation of the NLRP3 inflammasome, allowing processing of pro-IL-1β.

Free Research Field

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