Social Stress Immunity and Glucocorticoid Resistance in Mice

Animal studies investigating the effects of social stress on immune function have tended to use male rodents exposed to social conflict. Several models of social conflict have been developed that involve disruption of a preexisting social hierarchy and social defeat. The social disruption (SDR) model is one example in which an aggressive male intruder is introduced into the residence of a group of younger male mice. The introduction of the dominant intruder elicits observable aggressive confrontations (e.g., posturing, fighting, and wounding) and defeat of the younger resident mice.

Chronic social stress has profound effects on endocrine and immune function in mice (Padgett et al., 1998; Avitsur et al., 2001; Quan et al., 2001; Johnson et al., 2004a). For instance, SDR produces significant increases in circulating levels of corticosterone and glucocorticoid (GC) resistance (Avitsur et al., 2001). GC resistance refers to a decrease in the immune system's capacity to respond to the inhibitory effects of corticosterone in terminating inflammatory responses. When mice are exposed to social stress, their splenocytes become less sensitive to corticosterone when stimulated with lipopolysaccharide (LPS), showing increased proliferation and viability relative to control splenocytes (Avitsur et al., 2001). In addition, these mice exhibit splenomegaly, an increased number of CD11b+ mono-cytes, and elevated levels of the proinflammatory cytokines TNF-a, IL-6, and IL-1ß (Quan et al., 2001; Avitsur et al., 2002, 2003b; Stark et al., 2002). SDR has also been shown to increase susceptibility to endotoxic shock after an LPS in vivo challenge. Compared with controls, SDR mice subjected to LPS challenge show pronounced inflammatory organ damage and exaggerated proinflammatory cytokine responses in lung, spleen, liver, and brain compared with controls (Quan et al., 2001). Together, these results suggest that GC resistance and elevated cytokine expression mediate the increase in susceptibility to endotoxic shock observed after social stress.

Humans exposed to chronic stress also exhibit alterations in hypothala-mic pituitary adrenal axis function (McEwen, 1998) and the development of GC resistance (Lowy et al., 1984; Stratakis et al., 1994; Miller et al., 2002). For instance, the parents of children undergoing treatment for cancer report higher levels of psychological distress, flatter diurnal cortisol rhythms, and GC resistance relative to the parents of healthy children (Miller et al., 2002). To assess GC resistance, these investigators examined whether the parents' immune responses showed decreased sensitivity to the anti-inflammatory effects of dexamethasone, a synthetic GC. Compared with parents of healthy children, the ability of a dexamethasone to inhibit the in vitro production of the proinflammatory cytokine IL-6 was suppressed among the parents of cancer patients.

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