Low-Dose IL-2 Attenuated Depression-like Behaviors and Pathological Changes through Restoring the Balances between IL-6 and TGF-β and between Th17 and Treg in a Chronic Stress-Induced Mouse Model of Depression

Abstract

Microglia activation, increased IL-6 and decreased TGF-β were found in depressed patients or in animal models of depression. IL-6 enhances T helper 17 cell differentiation, thereby causing an imbalance between Th17 and Treg cells, which induces neuroinflammation and neuronal dysfunction. However, whether imbalances between IL-6 and TGF-β and between Th17 and Treg occur in depression and whether depression can be improved upon restoring these imbalances are unknown. Treg promoter IL-2 (1500UI/0.1 mL/day) was used to treat a mouse model of depression induced by chronic unpredictable mild stress (CUMS). The behavior and concentrations of IL-6, TGF-β, Th17, IL-17A, IL-17Rc, Treg-related factors (helios and STAT5), astrocyte A1 phenotype S100β, microglia M1 phenotype Iba-1, indoleamine-2,3-dioxygenase (IDO) enzyme, corticosterone (CORT) and neurotransmitters were evaluated. When compared to controls, CUMS reduced sucrose preference, the number of entries into and the time spent in the open arms of the elevated plus maze and the exploration in the “open field”, while it increased the immobility time in tail suspension, which was ameliorated by IL-2 treatment. RoRα, S100β, IL-17A, IL-17Rc, IL-6, Iba-1, IDO enzyme and CORT concentrations were significantly increased, and Helios, FoxP3+, STAT5 and TGF-β were significantly decreased by CUMS, which were significantly attenuated by IL-2 when compared to the CUMS group. The NE, DA and 5-HT contents and those of their metabolites were decreased by CUMS, which returned to control levels after IL-2 treatment. The study demonstrated that imbalances between IL-6 and TGF-β and between Th17and Treg occurred in the hippocampus of the depression model. IL-2 attenuated depression- and anxiety-like behaviors and normalized the neurotransmitter concentration and the activity of the IDO enzyme, astrocytes and microglia through restoring both balances, but it did not decrease the CORT concentration.