High and fluctuating glucose levels increase the expression and secretion of interleukin­18 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.