protect wounds against viruses, bacteria, and fungi. They are summoned there by cytokines, which are released at the wound site (Dhabhar 2000). Cytokines are small proteins that are secreted most typically by immune cells and signal or activate other immune cells. Functioning somewhat as hormones do, they regulate the immune response to infection and injury.

The communication link between the HPA axis and the immune system is strong: lymphocytes and macrophages (types of white blood cells) have receptors for cortisol, and some immune-related cells in the brain have receptors for cytokines (Reiche et al. 2004) and are activated by cortisol. In response to chronic stress, a long-term increase of glucocorticoids, such as cortisol, can dysregulate and suppress immune function, as discussed later.

Allostasis

The classic fight or flight response entails activation of epinephrine and cortisol with resulting increases in immune function, energy mobilization (in the form of glucose), and enhancement of memory, which helps to avoid the threat in the future. To maintain homeostasis, the brain regulates the stress response by inducing the body to release chemical mediators—including neurotransmitters, immune-system messengers, and hormones, including cortisol and epinephrine, a process called allostasis (McEwen 1998, 2005, 2007; McEwen and Wingfield 2003). Homeostasis refers to stability in various physiologic characteristics, such as body temperature, pH, and oxygen tension, which are tightly regulated within narrow ranges that promote survival.

The chemical mediators of allostasis are released from the sympathetic and parasympathetic branches of the nervous system but are also released from the immune, cardiovascular, and metabolic systems. Their interactions occur through a nonlinear network, that is, mediators from each system regulate the production of others in a series of checks and balances.

Corresponding to multiple mediators of the stress response, there are multiple pathways by which they regulate it. In the sympathetic system, for example, greater activity of proinflammatory cytokines, signaling molecules used by the immune system, elicits greater activity of anti-inflammatory cytokines—that is, negative feedback—and negative regulation by the parasympathetic and glucocorticoid pathways. Parasympathetic activity working through the acetylcholine receptors on immune cells reduces production of proinflammatory cytokines (Tracey 2002). In other words, as the activity of proinflammatory cytokines increases, other systems can produce the opposing activity. That example shows how homeostasis can be achieved through numerous routes using a common set of interacting mediators (McEwen 2007).

Allostatic Load and Overload

Allostatic load refers to the burden of chronic stress and altered personal behaviors (“lifestyle”) that results from effects of overuse and dysregulation of the mediators of allostasis (Figure 4-2; McEwen 1998). Allostatic load is often manifested by fatigue, anger, frustration, and feeling out of control. Those feelings can lead to sleep loss (McEwen 2006, 2007), anxiety,



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