Opposing effects of IL-1β/COX-2/PGE2 pathway loop on islets in type 2 diabetes mellitus

  • Wang Guanqiao
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Liang Rui
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Liu Tengli
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Wang Le
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Zou Jiaqi
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Liu Na
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Liu Yan
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Cai Xiangheng
    Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China Tianjin Medical University, Tianjin 300070, China
  • Liu Yaojuan
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
  • Ding Xuejie
    Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
  • Zhang Boya
    Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
  • Wang Zhiping
    Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
  • Wang Shusen
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China Tianjin Clinical Research Center for Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, China
  • Shen Zhongyang
    NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300384, China Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China Tianjin Clinical Research Center for Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, China

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<p>The cyclooxygenase2 (COX-2) enzyme catalyzes the first step of prostanoid biosynthesis, and is known for its crucial role in the pathogenesis of several inflammatory diseases including type 2 diabetes mellitus (T2DM). Although a variety of studies revealed that COX-2 played a role in the IL-1β induced β cell dysfunction, the molecular mechanism remains unclear. Here, using a cDNA microarray and in silico analysis, we demonstrated that inflammatory responses were upregulated in human T2DM islets compared with non-diabetic (ND) islets. COX-2 expression was significantly enhanced in human T2DM islets, correlated with the high inflammation level. PGE2, the catalytic product of COX-2, downregulated the functional gene expression of PDX1, NKX6.1, and MAFA and blunted the glucose induced insulin secretion of human islets. Conversely, inhibition of COX-2 activity by a pharmaceutical inhibitor prevented the β-cell dysfunction induced by IL-1β. COX-2 inhibitor also abrogated the IL-1β autostimulation in β cells, which further resulted in reduced COX-2 expression in β cells. Together, our results revealed that COX-2/PGE2 signaling was involved in the regulation of IL-1β autostimulation, thus forming an IL-1β/COX-2/PGE2 pathway loop, which may result in the high inflammation level in human T2DM islets and the inflammatory impairment of β cells. Breaking this IL-1β/COX-2/PGE2 pathway loop provides a potential therapeutic strategy to improve β cell function in the treatment of T2DM patients.</p>

収録刊行物

  • Endocrine Journal

    Endocrine Journal 66 (8), 691-699, 2019

    一般社団法人 日本内分泌学会

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