Downregulation of interleukin-1 beta via Jmjd3 inhibition improves post-myocardial infarction depression

Abstract

Patients with myocardial infarction (MI) comorbid with the depressive disorder may have increased serum cytokine concentrations, notably, of interleukin-1 beta (IL-1β). The histone H3 lysine-27 (H3K27) demethylase Jmjd3 is crucial in cytokine regulation, and administering an H3K27 demethylase-selective inhibitor (GSK J4) might ameliorate inflammatory symptoms. We hypothesized that Jmjd3 might regulate IL-1β concentrations, thus affecting the development of post-MI depression (PMD). In this study, a mouse model was created to examine the connection between IL-1β and PMD and determine the regulatory function of cytokine in controlling inflammation and depressive symptoms. MI was induced in 30 5-week-old male C57BL/6N mice via a left coronary ligation, and MI onset was confirmed by electrocardiogram (ECG). After treatment with dimethylsulfoxide (DMSO) or GSK J4 for 14 days, the mice were subjected to tail-suspension tests (TSTs) and forced swimming tests (FSTs) before being sacrificed for tissue harvest. In the TSTs, the GSK J4-treated MI mice displayed a significantly shorter immobility time than did the DMSO-treated MI mice (P<0.001). In the FSTs, the DMSO-treated MI mice showed a significantly longer immobility time than did the DMSO-treated sham-operated mice (P<0.001). The GSK J4-treated MI mice had a significantly reduced immobility time compared to the DMSO-treated MI mice (P<0.001). IL-1β expression in the myocardium, hippocampus, prefrontal cortex (PFC), and hypothalamus increased after MI onset (P=0.003, 0.015, 0.0003, and 0.013, respectively) but decreased after treatment with GSK J4 (P<0.001, P=0.005, P<0.001, P=0.018, respectively). In the myocardium and hypothalamus, Jmjd3 expression levels were lower in mice that received GSK J4 treatment than in those that received DMSO treatment (P<0.05). GSK J4 inhibited the cardiac expression of IL-1β and Jmjd3, and alleviated PMD in MI mice. Therefore, IL-1β and Jmjd3 may be critical in the pathogenesis of PMD, and Jmjd3 may potentially serve as a target for PMD treatment.