Lightman, 1992), CRH is the major stimulator of ACTH release. Stimulated ACTH secretion subsequently stimulates adrenocorticosteroid (CS, particularly glucocorticoid) secretion. Glucocorticoids in turn modulate and inhibit HPAA activation via negative feedback effects at suprahypothalamic, hypothalamic, and pituitary levels (Harbuz and Lightman, 1992).

Why does the HPAA become activated during various immune, inflammatory, and infectious insults? According to a hypothesis proposed by Munck and colleagues (1984) several years ago, such activation of the HPAA occurs so that glucocorticoids can suppress immune and inflammatory responses initiated by cytokines and thereby can modulate and dampen immune system activation. This dampening of immune system activation prevents more severe and excessive catabolic effects, including the ultimate deleterious effect, death. Consequently, immune system activation of the HPAA appears to occur to modulate excessive, deleterious effects of cytokines after they have produced their initial, beneficial effects (Urbaschek and Urbaschek, 1987; Vogel and Hogan, 1990) in facilitating an inflammatory response. A fine balance occurs relative to the level of cytokine activity. In general, relatively low levels of specific cytokines promote beneficial protective effects in helping the host respond to a perturbing immune, inflammatory, or infectious challenge. In contrast, uncontrolled production of specific cytokines resulting in relatively high circulating levels often results in severe pathological consequences, such as hypotension and lethal shock. Although responses to specific inflammatory, immune, or infectious insults are not necessarily identical, they provoke a similar central neuroendocrine response via the generation of similar cytokines and thus can all be viewed as "inflammatory stress." For purposes of discussion, these environmental perturbations can be viewed similarly not only because they induce a similar counterregulatory response (i.e., HPAA activation) but also because the consequences of this response expose the organism to similar immunosuppressive and anti-inflammatory actions following the initial induction of immune potentiating and inflammatory effects (Besedovsky and del Ray, 1996). These actions are aimed at controlling the disruption of homeostasis produced by the offending agent or stimulus.

IL-1, TNF-α, and IL-6 are the most important cytokines for stimulating the HPAA (Chrousos, 1995; Gaillard, 1994; Reichlin, 1993). Because IL-1 is the most potent (on a molar basis) cytokine that activates the HPAA, and the most frequently studied relative to the HPAA, stimulation of the HPAA by IL-1 is often viewed as a prototypical model for immune activation of the HPAA. Additional complexity is added by the fact that IL-1 exists in two forms (α, which is primarily membrane-associated, and β, which is primarily secreted); that there are at least two IL-1 receptors; and that IL-1 actions can be counterregulated by an endogenous receptor antagonist (IL-1ra) (Dinarello,