Hypothalamic PituitaryAdrenal Axis

In concert with the ANS, the HPA axis serves as a central component of the mammalian stress response system. Although glucocorticoids, which represent the final product of HPA axis activation, have long been viewed as immunosuppressive because of their well-documented ability to suppress inflammation (largely through protein-protein interactions between the glucocorticoid receptor and NF kB) (Rhen et al. 2005), it is increasingly recognized that HPA axis effects on immunity are complex (Dhabhar et al. 1995). This complexity arises from the fact that HPA axis effects on the immune system depend on numerous factors, including the immune compartment that is assessed, the element of the HPA axis being evaluated (i.e., CRH vs. Cortisol), and the duration and timing relative to the immune response and stressor application. Thus, for example, glucocorticoids are known to acutely diminish CD4 cell counts in the blood; however, at the same time, glucocorticoids enhance CD4-mediated DTH reactions in the skin, through their effects on lymphocyte trafficking (Dhabhar 1998). Moreover, different HPA axis elements demonstrate divergent immune system effects. For example, the end result of CRH-induced HPA axis activation is proinflammatory cytokine suppression, and yet studies demonstrate that the direct effect of CRH on proinflammatory cytokine production may be stimulatory (Labeur et al. 1995; Paez Pereda et al. 1995).

Finally, the effect of glucocorticoids on naturalistic measures of immunity, such as DTH, depends on both the concentration and the duration of glucocorticoids within the immune compartment under consideration. Thus, low doses of glucocorticoids applied for brief periods have been shown in rodents to stimulate DTH, whereas higher (or more protracted) glucocorticoid exposure suppresses DTH (Dhabhar and McEwen 1999).

CRH applied within the CNS suppresses several measures of immunity, including splenic NKCA, mitogen-stimulated lymphocyte proliferation, and in vivo and in vitro antibody formation, as well as T-cell responses to T-cell receptor antibody (Caroleo et al. 1993; Irwin et al. 1988; Labeur et al. 1995; Rassnick et al. 1994). CRH-overproducing mice demonstrate a profound decrease in the number of B cells and severely diminished primary and memory antibody responses (Stenzel-Poore et al. 1994). These immunosuppressive effects appear to be mediated by stress response outflow pathways activated by CRH, given that blockade of the SNS abolishes CRH effects on NKCA and adrenalectomy obviates CRH effects on lymphocyte proliferation (Irwin et al. 1988; Labeur et al. 1995). In addition, the B-cell decreases in CRH-overproducing mice are consistent with the marked reduction in rodent B cells observed after chronic glucocorticoid exposure (Miller et al. 1994).

In contradistinction to its immunosuppressive properties, CRH has also been shown to enhance proinflammatory cytokine production in animals and humans when administered peripherally or within the CNS. Chronic intracerebroventricular administration of CRH to rats leads to induction of IL-lß messenger RNA (mRNA) in splenocytes, and acute intravenous administration in humans has been reported to cause a fourfold increase in the induction of IL-let (Labeur et al. 1995; Schulte et al. 1994). Similarly, the addition of CRH to in vitro mononuclear cell preparations induces the release of IL-1 and IL-6 (Leu and Singh 1992; Paez Pereda et al. 1995). Both chronic and acute CRH infusion have also been reported to increase production of the immunoregulatory cytokine IL-2 in humans and animals (Labeur et al. 1995; Schulte et al. 1994). In addition to potential proinflammatory activities of CRH within the CNS, peripheral production of CRH has been demonstrated in inflammatory diseases, such as ulcerative colitis and arthritis, in which it appears to act as a local proinflammatory agent (Karalis et al. 1997; Nishioka et al. 1996).

Of all neurotransmitters or hormones known to modulate immune functioning, the actions of glucocorticoids, although complicated, are probably best understood (Raison et al. 2002). Identified effects of glucocorticoids on the immune (and inflammatory) system include

■ Modulation of immune cell trafficking throughout the body (Dhabhar et al. 1995)

■ Modulation of cell death pathways (i.e., apoptosis) (McEwen et al. 1997)

■ Inhibition of arachidonic acid pathway products (e.g., prostaglandins) that mediate inflammation and sickness symptoms (e.g., fever) (Goldstein et al. 1992)

■ Modulation of Th1/Th2 cellular immune response patterns in a manner that inhibits Th1 (cell-mediated) responses and promotes Th2 (antibody) responses (Elenkov and Chrousos 1999)

■ Inhibition of T-cell- and NK-cell-mediated cytotoxicity (Raison et al. 2002)

■ Inhibition of cytokine production and function through interaction of glucocorticoid receptors with transcription factors (NF-kB, in particular), which, in turn, regulate cytokine gene expression and/or the expression of cytokine-inducible genes (McKay and Cidlowski 1999)

Although, as discussed below, glucocorticoids may actually enhance certain aspects of naturalistic immune functioning when produced for brief periods at low to moderate doses in the context of acute and/or mild stress, glucocorticoids, in general, play a primary role in restraining excessive or prolonged inflammatory activation (Munck 1989). This property has long been exploited by modern medicine for the treatment of autoimmune and other chronic inflammatory conditions, with the result that glucocorticoids remain a cornerstone of our anti-inflammatory armamentarium. Consistent with their pharmacological uses, glucocorticoids have been shown to be essential for inflammatory regulation in response to immune system activation. For example, neutralization of endogenous glucocorticoid function results in enhanced pathology and mortality in animals exposed to lipopolysaccharide, as well as other inflammatory stimulators, such as streptococcal cell wall antigen or myelin basic protein (Bertini et al. 1988; Sternberg et al. 1989). Similarly, rodents that have been rendered glucocorticoid deficient by adrenalectomy have markedly increased death rates following infection with murine cytomegalovirus, an effect that arises from unrestrained activity of the proinflammatory cytokine TNF-a (Ruzek et al. 1999).

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