of environmental effects on gene expression in offspring have important implications for depression.

Limited but increasing evidence draws links between early adversity, abnormalities of the HPA, CRH, and LC-NE systems, and depression. For example, Essex et al. (2002) assessed cortisol levels in 4.5-year-olds and found that children who had been exposed to maternal stress both in infancy and concurrently had significantly higher levels of cortisol than nonstressed children or those exposed to either but not both periods of maternal stress. Moreover, the children with elevated cortisol had higher rates of behavioral and emotional symptoms (especially internalizing symptoms) approximately 2 years later. Although not specifically about depression, the results are consistent with the idea that early stress exposure predicts elevated cortisol when stress occurs later in life, and the pattern is predictive of later symptomatology (see also Heim et al., 2000, on early abuse experiences, depression, and adult HPA axis functioning). Preventing adverse environmental factors in children warrants further attention.

Immune System Processes and Depression

Spurred in part by the evidence of the strong association between depression and coronary heart disease, researchers have begun to examine the potential role of the immune system, and particularly proinflammatory cytokines, in the link between stress and depression (e.g., Danese et al., 2008; Miller and Blackwell, 2006). Recent models have proposed that chronic stress activates the immune system in a way that leads to inflammation, and that chronic inflammation in turn leads to symptoms of depression as well as pathological processes underlying heart disease (Miller and Blackwell, 2006). Cytokines are signaling molecules that coordinate inflammation in response to pathogens and include interleukin-1β, interleukin-6 (IL-6), and tumor necrosis factor-α. Among other functions, they direct white blood cells toward infections, signaling them to divide and activating their killing mechanisms. Downstream products of this process, including C-reactive protein (CRP), a molecule produced by the liver in response to IL-6, are used as an index of the inflammatory response.

Although the directions of these effects are yet to be disentangled, evidence indicates that chronic stress is associated with increased levels of both CRP and depression. Levels of IL-6 and CRP are elevated in individuals exposed to chronic stress (Segerstrom and Miller, 2004). Chronic stressors may prime the immune system to make a heightened response to stress. Alternatively, chronic stress may interfere with the capacity of the immune system to return to baseline after termination of a stressor, perhaps due to dysregulation of the HPA response and the production of glucocorticoids in response to stress (Miller and Blackwell, 2006). The inflammatory re-



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