Prolonged Restraint Stress Increases IL-6, Reduces IL-10, and Causes Persistent Depressive-Like Behavior That Is Reversed by Recombinant IL-10

Abstract

Altered inflammatory cytokine profiles are often observed in individuals suffering from major depression. Recent clinical work reports on elevated IL-6 and decreased IL-10 in depression. Elevated IL-6 has served as a consistent biomarker of depression and IL-10 is proposed to influence depressive behavior through its ability to counterbalance pro-inflammatory cytokine expression. Clinical and animal studies suggest a role for IL-10 in modifying depressive behavior. Murine restraint stress (RST) is regularly employed in the study of behavioral and biological symptoms associated with depressive disorders. While responses to acute RST exposure have been widely characterized, few studies have examined the ongoing and longitudinal effects of extended RST and fewer still have examined the lasting impact during the post-stress period. Consistent with clinical data, we report that a protocol of prolonged murine RST produced altered cytokine profiles similar to those observed in major depressive disorder. Parallel to these changes in circulating cytokines, IL-10 mRNA expression was diminished in the cortex and hippocampus throughout the stress period and following cessation of RST. Moreover, chronic RST promoted depressive-like behavior throughout the 28-day stress period and these depressive-like complications were maintained weeks after cessation of RST. Because of the correlation between IL-10 suppression and depressive behavior and because many successful antidepressant therapies yield increases in IL-10, we examined the effects of IL-10 treatment on RST-induced behavioral changes. Behavioral deficits induced by RST were reversed by exogenous administration of recombinant IL-10. This work provides one of the first reports describing the biological and behavioral impact following prolonged RST and, taken together, this study provides details on the correlation between responses to chronic RST and those seen in depressive disorders.

Repeated social defeat stress induces neuroinflammation and impairs hippocampal neurogenesis that differentially regulate mood and cognition

“…Previous work from our lab and others has shown increased social avoidance (a behavior associated with affect and mood) following social defeat in mice [41,42]. Here, we have shown that RSD-induced enhancement in social avoidance is maintained even 28 days after stress, and that this maintenance temporally corresponds with reduced number of neurons in the caudal hippocampus.…”

Ketamine Alleviates Depressive-Like Behaviors <i>via</i> Down-Regulating Inflammatory Cytokines Induced by Chronic Restraint Stress in Mice

“…Moreover, several lines of evidence indicate that both acute and chronic stress lead to increase in serum pro-inflammatory cytokine levels in animal studies with unclear mechanisms. 24,25) Interestingly, Voorhees et al also found that IL-10 has been decreased following a stress paradigm, indicating that stress may not only alter the pro-inflammatory cytokines but also the antiinflammatory cytokines. It should be mentioned that pro-inflammatory cytokines may activate the HPA axis directly to augment the stress response.…”

Salvianolic acid B ameliorates depressive-like behaviors in chronic mild stress-treated mice: involvement of the neuroinflammatory pathway

“…Our previous research indicated that the dysregulation of pro-and anti-inflammatory cytokines have a crucial role in the pathophysiology of depression [38] . Pro-inflammatory cytokines (TNF-α, IL-1β) or lipopolysaccharide-induced depressive-like behavior and neuroinflammatory reaction can be reversed by anti-inflammatory cytokines, such as TGF-β and IL-10 [39,40] . Conversely, anti-inflammatory agents have therapeutic benefits for mood disorders [41,42] .…”