IL‐4 Inhibits IL‐1β‐Induced Depressive‐Like Behavior and Central Neurotransmitter Alterations

Abstract

It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1β-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1β-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1β-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1β-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1β-induced depressive behavior by inhibiting IL-1β-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1β-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1β-induced depressive behavior and neuroinflammation which warrants further study.

Tauroursodeoxycholic acid produces antidepressant‐like effects in a chronic unpredictable stress model of depression via attenuation of neuroinflammation, oxido‐nitrosative stress, and endoplasmic reticulum stress

“…The IL‐1β is a core cytokine mediating the formation and/or development of depression, and the increased IL‐1β may contribute to the production of TNF‐α and IL‐6 in chronic stress‐stimulated brains . As all these reactions mainly occur in microglia, we investigated the activation status of microglia via evaluating the protein expression levels of Iba‐1, a classical marker for microglial activation, in mice hippocampus and prefrontal cortex.…”

“…Traditional antidepressants and electroconvulsive therapy are reported to modulate microglial structures and functions, thereby preventing depression formation . Other studies show that direct administration of mice with tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) or interleukin‐β (IL‐1β) also induces typical depression‐like behaviors . Recently, an IL‐1β‐producing structure, inflammasome, has been confirmed a sensor for depression‐inducing stress .…”

“…Other studies show that direct administration of mice with tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) or interleukin-b (IL-1b) also induces typical depression-like behaviors [9][10][11]. Recently, an IL-1bproducing structure, inflammasome, has been confirmed a sensor for depression-inducing stress [12].…”

Cytokine secretion and the risk of depression development in patients with connective tissue diseases

“…As depression has been associated with a predominant Th1 immune response, the reduced level of IL‐4 in depressed subjects is of particular interest. In animal models, IL‐4 is involved in regulating the hormonal and neurotransmitter mechanisms connected to depressive responses induced by IL‐1β . Infusion of IL‐4 led to a decrease in IL‐1β‐induced anhedonic behavior and caused an increased in social activity level.…”

“…Infusion of IL‐4 led to a decrease in IL‐1β‐induced anhedonic behavior and caused an increased in social activity level. IL‐4 administration may be directly involved in the mediation of noradrenergic and 5‐HT neurotransmission and may impair IL‐1β‐induced behavioral and immunological changes . The effect of IL‐4 on cognition is shown to be beneficial in animal models, in contrast to pro‐inflammatory cytokines (such as IL‐1β and TNF‐α), which have been extensively shown to exert a negative effect on cognitive behavior characterized by sickness, depression, and stress …”