Cytokine Production by Spleen Cells after Social Defeat in Mice: Activation of T Cells and Reduced Inhibition by Glucocorticoids

Abstract

Social disruption (SDR) is an effective model of social stress associated with an enhanced inflammatory reactivity of the immune system. The aim of the present study was to further describe SDR effects on cytokine production by spleen cells, testing selectively monocyte and T cell functions as a result of this stressor. For this purpose, splenocytes from control mice (C) and mice socially stressed for 7 days (SDR) were cultured in the presence of lipopolysaccharide (LPS) or concanavalin A (Con A). Splenocyte proliferation, cytokine production and sensitivity of spleen cells to corticosterone were assessed in vitro. The humoral response to keyhole limpet hemocyanin (KLH) immunization was assessed. SDR induced splenomegaly and enhanced splenocyte basal proliferation. The pro-inflammatory influence of SDR was confirmed by an increased release of interleukin-6 (IL-6) by LPS-stimulated cultures and by a reduced sensitivity of spleen cells to the anti-inflammatory effect of corticosterone. The mechanism increasing cytokine production in response to LPS was cytokine specific, since among inflammatory cytokines, IL-6 but not interferon-gamma (IFN-gamma) was enhanced by stress. In stressed mice, the increase in IL-6 and IFN-gamma and the decrease in IL-10 release in Con A-stimulated cultures indicate that SDR did not modify the Th1/Th2 cytokine balance but globally activated T cells. Plasma anti-KLH antibody levels were similar in both groups. Wounded and non-wounded mice presented similar responses to stress. This study shows that social disruption stress enhances the reactivity of cells from both the acquired and innate immune systems.

Altered Immunomodulation by Glucocorticoids in Neonatal Pigs Exposed to a Psychosocial Stressor

“…We found that social isolation had no effect on lymphocyte proliferation in response to ConA, whereas in vitro LPS-induced cell proliferation was increased in isolated piglets. Our results support previous findings in which mice exposed to social disruption demonstrated enhanced proliferation of LPSstimulated splenocytes (8,10,28). In addition, our data suggest that short-term social stress promotes humoral immune responses.…”

“…However, most previous work using socially defeated mice has shown decreased GC sensitivity of spleen cells, which was more pronounced in animals with higher number of injuries because of fighting (8,9). In particular, a study from Merlot et al (10) reported that wounded and nonwounded mice presented similar responses to social stress. In general, development of GC resistance after repeated or chronic stress is viewed as maladaptive if the resistant individual has a predisposition to an autoimmune disease or is exposed to an infectious challenge but it may be also adaptive for healing wounds and protection against bacterial contamination (8,28,31).…”

Early childhood poverty, immune-mediated disease processes, and adult productivity

“…diminished job productivity associated with age-related chronic diseases (33). Animal models show that occupying subordinate social positions is associated with proinflammatory shifts in cytokine signaling pathways (40), and other recent evidence suggests that exposures to early low SES environments are linkable to similar immune changes in human children (36,41,42). Low childhood SES is associated with higher blood levels of the acutephase reactant C-reactive protein, cytokine IL-6, and TNF-α (43), and low SES children are more likely to develop a proinflammatory phenotype, placing them at risk for inflammatory diseases such as atherosclerosis, autoimmune disorders, and cancer (44).…”

Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen

“…Previous studies have demonstrated that repeated social stress in mice is associated with decreased GC sensitivity of immune cells and excessive inflammation Engler et al, 2005;Johnson et al, 2004;Merlot et al, 2004;Sonoda et al, 2005;Stark et al, 2001). For example, lipopolysaccharide (LPS)-stimulated splenocytes from mice that repeatedly experienced acute encounters with an aggressive conspecific exhibited considerably higher cell survival in the presence of corticosterone (CORT) and showed greatly enhanced production of pro-inflammatory cytokines compared to splenocyte cultures from non-stressed controls (Avitsur et al, 2005Merlot et al, 2004;Stark et al, 2001). The decrease in splenic GC responsiveness was only observed after stimulation with LPS whereas unstimulated cells did not differ in their ex vivo response to CORT.…”