title: High and fluctuating glucose levels increase the expression and secretion of interleukin‑18 in mouse peritoneal macrophages.
abstract: Macrophages are involved in the progression of atherosclerosis by releasing pro-inflammatory cytokines. High levels of interleukin (IL)-18 are associated with an increased risk of developing diabetes and atherosclerosis. The present study aimed to investigate the association between IL-18, and high and fluctuating glucose levels in mouse peritoneal macrophages (MPMs), and to assess the involvement of the c-Jun N-terminal kinase (JNK) pathway in this association. The MPMs were exposed to 4, 8, 16, 24 and 32 mM glucose for 6 h, which was alternated to either 4/24 mM glucose every 1.5 h for 6 h, or to 32 mM glucose for 3, 6, 12 and 18 h. The expression and secretion levels of IL-18 were detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA, respectively. High levels of glucose increased the expression and secretion levels of IL-18 in a dose-dependent manner (P<0.05, vs. 4 mM glucose). This increase was more important in the cells exposed to fluctuating 4/24 mM glucose every 1.5 h compared with the cells exposed to stable 24 mM glucose (RT-qPCR, 0.78 ± 0.05, vs. 0.66 ± 0.07; ELISA, 188.23 ± 20.32, vs. 143.16 ± 13.07 pg/ml; P<0.05). The expression and secretion levels of IL-18 increased 8 and 12 h following exposure to high-glucose, and then decreased at 18 h (P<0.05, vs. 3 h). Furthermore, SP600125, a JNK inhibitor, decreased the high-glucose-induced gene expression of IL-18 in a dose-dependent manner. Therefore, high and fluctuating levels of glucose may be associated with inflammation and diabetic atherosclerosis by regulating the expression levels of IL-18. The present study identified the JNK signaling pathway as one of the mechanisms underlying this association. Targeting IL-18 may be a novel therapeutic approach against diabetes-associated atherosclerosis.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233020, P.R. China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233020, P.R. China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233020, P.R. China.
authors.forename: Guoxi
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Pathology, Bengbu Medical College, Bengbu, Anhui 233020, P.R. China.
authors.forename: Huaiyong
authors.initials: H
authors.lastname: Gan
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233020, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation
chemical_list: D020382:Interleukin-18; D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose