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

Guanqiao Wang; Rui Liang; Tengli Liu; Le Wang; Jiaqi Zou; Na Liu; Yan Liu; Xiangheng Cai; Yaojuan Liu; Xuejie Ding; Boya Zhang; Zhiping Wang; Shusen Wang; Zhongyang Shen

doi:10.1507/endocrj.EJ19-0015

ORIGINAL

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

Guanqiao Wang, Rui Liang, Tengli Liu, Le Wang, Jiaqi Zou, Na Liu, Yan Liu, Xiangheng Cai, Yaojuan Liu, Xuejie Ding, Boya Zhang, Zhiping Wang, Shusen Wang, Zhongyang Shen

Author information

Guanqiao Wang
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
Rui Liang
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
Tengli Liu
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
Le Wang
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
Jiaqi Zou
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
Na Liu
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
Yan Liu
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
Xiangheng Cai
Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
Tianjin Medical University, Tianjin 300070, China
Yaojuan Liu
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
Xuejie Ding
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
Boya Zhang
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
Zhiping Wang
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
Shusen Wang
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
Zhongyang Shen
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

Keywords: Type 2 diabetes mellitus, Inflammation, COX-2, IL-1β, Islet dysfunction

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Supplementary material

2019 Volume 66 Issue 8 Pages 691-699

DOI https://doi.org/10.1507/endocrj.EJ19-0015

Browse “Advance online publication” version

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Abstract

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.

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