The Protective Role of the Hypothalamic‐Pituitary‐Adrenal Axis against Lethality Produced by Immune, Infectious, and Inflammatory Stress

Abstract

We have shown that ADX and HYPOX rats exhibit a markedly increased sensitivity to the lethal effects of IL-1-beta and LPS compared to sham controls with an intact HPAA. These results indicated that the reports of lethal effects of cytokines and LPS which generates cytokines in mice with a compromised HPAA were not idiosyncratic or specific to mice but represented a general response that would have been expected in any organism with a compromised HPAA. We further demonstrated that protection against lethal effects due to IL-1-beta or LPS could be produced by treating ADX rats with glucocorticoid in a quantity estimated to be equivalent to corticosterone secretion provoked during stress. In contrast, we found that acutely stalk-sectioned rats with pituitaries disconnected from hypothalamic regulation did not show a markedly increased susceptibility to lethal effects of LPS as did ADX or HYPOX rats. Although a minority of stalk-sectioned rats were killed by LPS, the majority of rats were protected from lethal actions of LPS. This response suggested that an intact pituitary-adrenal axis without the normal hypothalamic control could still provide significant protection presumably due to generation of cytokines which stimulated the pituitary over several hours. The results from our lethality studies clearly underscore the importance of activating the stress axis and increasing glucocorticoid secretion to protect against potentially lethal effects of cytokines that can be induced by immune, infectious, or inflammatory stimuli. Cytokine-stimulated effects can initially result in beneficial actions to the host by promoting immune/inflammatory responses that are protective in nature and help defend against a variety of invading stimuli (infectious, immune, inflammatory, traumatic, neoplastic). Normally the HPAA responds to cytokine stimulation by ultimately increasing glucocorticoid secretion in order to counterregulate cytokine actions, modulate the host response, and protect the host from excessively catabolic effects of unregulated cytokine generation and actions. For many years, clinicians have recognized that patients with deficient glucocorticoid secretion (e.g., Addison's disease or pituitary ACTH deficiency) require increased glucocorticoid replacement during episodes of fever, infection, or inflammatory stress. However, the reasons why stress-equivalent glucocorticoid replacement were required were not entirely clear. Now, we understand that glucocorticoids are critically important for protecting the host against its own defense mechanisms so that the stimulation of cytokines can facilitate a protective response against an invading insult without also killing the host.

Endogenous glucocorticoids protect against TNF-alpha-induced increases in anxiety-like behavior in virally infected mice

“…12,15 Of note, although not examined in this study, replacement of glucocorticoids in glucocorticoid-deficient animals has been shown to reverse the detrimental consequences of these effects. 13,15 Consistent with the observed changes in the behavior of MCMV-infected mice, a number of studies have found alterations in locomotor and exploratory activity in immune-challenged animals. For example, rats or mice peripherally injected with LPS (i.p.…”

“…[4][5][6][7][8][9][10][11][12] Previous work by our group and others has demonstrated that removal of glucocorticoids (via adrenalectomy (ADX)) during viral infection is associated with elevations in plasma and tissue concentrations of proinflammatory cytokines and renders animals more susceptible to septic shock and death. [13][14][15] In addition, in the case of infection with murine cytomegalovirus (MCMV), a cytopathic virus that induces an early natural killer cell-mediated, anti-viral defense accompanied by elevations in plasma TNF-alpha, IL-1 and IL-6, 15 the increased death rate in adrenalectomized, MCMV-infected, animals can be reversed by glucocorticoid replacement. 15 Previous studies also have shown that the MCMV-induced corticosterone response, which parallels peak plasma cytokine concentrations and occurs around 36 h after infection, is dependent on IL-6.…”

Winter day lengths enhance T lymphocyte phenotypes, inhibit cytokine responses, and attenuate behavioral symptoms of infection in laboratory rats

“…It was beyond the scope of the present study to determine whether short-day increases in corticosterone are maintained throughout the circadian cycle; however, in hamsters short-day increases in cortisol are evident at several phases of the circadian cycle (including shortly before lights-off, as described here) and amplified (SD≫LD) following LPS treatments (Bilbo et al, 2003). Endogenous glucocorticoids have potent inhibitory effects on sickness behaviors (Goujon, et al, 1997), attenuating proinflammatory cytokine production in the periphery (Kapcala et al, 1995;Pezeshki et al, 1996;Goujon et al, 1996), and suppressing expression of proinflammatory cytokines in the CNS (Wisse et al, 2004). In rats, exogenous glucocorticoids also inhibit behavioral and thermoregulatory responses to LPS and IL-1β (McClellan et al, 1994;Morrow et al, 1996;Propes & Johnson, 1997).…”

Differential effects of dexamethasone treatment on lipopolysaccharide-induced testicular inflammation and reproductive hormone inhibition in adult rats

“…Glucocorticoids exert a negative feedback effect on the inflammatory response by reducing the production, secretion and actions of the principal inflammatory mediators, such as IL-1 , and are widely used clinically as anti-inflammatory agents (Kapcala et al 1995). However, glucocorticoids also inhibit testicular steroidogenesis by actions at the hypothalamus and pituitary (Bambino & Hsueh 1981), and by direct inhibition of P450scc, 3 -hydroxysteroid dehydrogenase and P450c17 levels (Sapolsky 1985, Hales & Payne 1989, Monder et al 1994, Gao et al 1996, acting through specific receptors on the Leydig cells (Stalker et al 1989).…”