INTRODUCTION

Maintenance of homeostasis during immune challenge involves activation of the immune system, resolution of the challenge, and protection of the host against potentially toxic inflammatory processes. Examples of immune challenges include infection with viruses, bacteria, fungi, or parasites; tissue damage and destruction; and inappropriate responses to auto-antigens that may result in the development of autoimmune disease. Upon immune challenge, the immune system is activated to release numerous protein hormones called “cytokines.” One functional group of cytokines is that which mediates the innate immune response, including the proinflammatory cytokines tumor necrosis factor–alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), and the type I interferons (IFN-α/β). These cytokines are released in the early stages of an immune response from a variety of cell types, including activated immune cells, such as macrophages (and their CNS counterparts microglia), vascular endothelial cells, fibroblasts, and neurons. Adrenocorticotropin Hormone and the Immune System Essay. Another group of cytokines is that which mediates later, adaptive immunity, such as the T cell cytokines IL-2 and IFN-γ (type II interferons), which are especially important in mediating anti-viral defenses. In addition to contributing to the progression of the immune response against viral infection, cytokines released as part of the innate or adaptive immune response can activate the HPA axis, resulting in the release of adrenal glucocorticoids (37,57,120,178,258,290) (Fig. 1). In turn, glucocorticoids negatively feedback onto immune cells to suppress the further synthesis and release of cytokines, thereby protecting the host from the detrimental consequences of an overactive immune response (e.g., tissue damage, autoimmunity, septic shock). In addition, glucocorticoids play an important role in shaping immunity by influencing immune cell trafficking to sites of inflammation and altering downstream, adaptive immune responses by causing a shift from cellular (Th1/inflammatory) to humoral (Th2/anti-inflammatory) type immune responses (72). Therefore, in contrast to the traditional view of glucocorticoids as immunosuppressant hormones, they are more accurately conceptualized as immunomodulatory hormones, that can stimulate as well as suppress immune function, depending on the type of immune response, the immune compartment, and the cell type involved. Adrenocorticotropin Hormone and the Immune System Essay.

FIG. 1

Bidirectional communication between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis (human brain). The immune system, via early innate proinflammatory cytokines (TNFα, IL-1, and IL-6) and interferons, and late acquired T cell cytokines (IL-2 and INF-γ), stimulates glucocorticoid release by acting at all three levels of the HPA axis. In turn, glucocorticoids negatively feedback on the immune system to suppress the further synthesis and release of proinflammatory cytokines (red dotted line). In addition, glucocorticoids play an important role in shaping downtream acquired immune responses, by causing a shift from cellular (Th1/inflammatory) to humoral (Th2/anti-inflammatory) type immune responses. By doing so, glucocorticoids protect an organism from the detrimental consequences of overactive inflammatory immune responses. ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing factor; hipp, hippocampus; IFN, interferon: IL, interleukin; ME, median eminence; PVN, paraventricular nucleus of the hypothalamus; TNF, tumor necrosis factor. Reprinted with modifications by permission from Silverman et al. (274).

Although hypothalamic corticotropin-releasing hormone (CRH) is considered a primary mechanism by which cytokines stimulate glucocorticoid release, increasing evidence supports a direct action of cytokines at the level of the pituitary and adrenal glands, as well. Cytokine receptors have been detected at all HPA axis levels, and therefore, each level can serve as an integration point for immune and neuroendocrine signals. In addition, cytokines are synthesized in the brain, the anterior pituitary, and the adrenal gland. The production of local cytokines in these tissues may function in a paracrine manner to amplify and maintain elevated HPA activity during chronic inflammation. Adrenocorticotropin Hormone and the Immune System Essay. Once glucocorticoids are released, maintenance of appropriate glucocorticoid activity is accomplished by local tissue regulation of glucocorticoid availability and action by factors such as corticosterone binding globulin (CBG), 11β-hydroxysteroid dehydrogenase (11β-HSD), the multidrug resistance transporter (MDR), and ultimately, the glucocorticoid receptor (GR) (274).

The kinetics and magnitude of HPA axis stimulation, and hence glucocorticoid release, induced by viral infection may be specific to the virus, the kinetics of the immune response to the virus, and the extent of virus/immune-induced pathology. Viruses that induce early, innate NK cell-mediated anti-viral defenses, characterized by early proinflammatory cytokine production, cellular infiltration, and inflammation, tend to produce early glucocorticoid responses, thereby protecting the host from proinflammatory cytokine-mediated pathology. On the other hand, viruses that induce later, adaptive T cell–mediated anti-viral defenses, characterized by late Th1/CTL cytokine production, cellular infiltration, and inflammation, tend to produce late glucocorticoid responses, thereby protecting the host from T cell–mediated pathology. Viruses that elicit both strong early proinflammatory and later T cell responses may exhibit a biphasic glucocorticoid response, whereas those that induce little or no inflammation, may not stimulate significant glucocorticoid release. Examples of these different responses are presented in this review, as we describe what is currently known about HPA axis activation during infections with Newcastle disease virus (NDV), murine cytomegalovirus (MCMV), lymphocytic choriomeningitis virus (LCMV), influenza, herpes simples virus type-1, (HSV-1), and human immunodeficiency virus (HIV).

Given the critical role of the HPA axis and glucocorticoid responses in maintaining a balance between the beneficial and detrimental effects of proinflammatory cytokines, as well as shaping downstream immune responses, it has become increasingly apparent that cytokine–HPA axis interactions are fundamental to immune regulation during viral infection. Moreover, redundant pathways of glucocorticoid induction, incorporating all three levels of the HPA axis, exist to ensure the survival of the host during immune challenge. Indeed, the essential role of glucocorticoids in protecting the host against a lethal overactivation of inflammatory responses has been demonstrated in a number of animal model systems, including viral infection (148,243,254,268). . Adrenocorticotropin Hormone and the Immune System Essay

THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS

In considering HPA axis activity during viral infection, it is important to review the functional anatomy and physiology of the HPA axis. Activation of the HPA axis is well known to subserve the body’s response to a stressor, which can be defined as any physical or psychological stimulus that disrupts an organism’s homeostatic balance. Viral infections, in general, are physiologically stressful, as indicated by the concomitant activation of the HPA axis (89). Along with catecholamines (the end-product of sympathetic nervous system activation), glucocorticoids orchestrate the “fight or flight” response, which consists of the rapid mobilization of energy (glucose, amino acids, and fatty acids) from storage sites to critical muscles and the brain, concomitant with increased heart rate, blood pressure, and breathing rate to facilitate the rapid transport of nutrients and oxygen to relevant tissues. During such emergency situations, activation of the HPA axis also assists the body in shunting metabolic resources from growth, digestion, reproduction, and certain aspects of immunity to the more immediate challenge at hand. Particularly pertinent to infection as a stressor, according to Munck (196), “the physiological function of stress–induced increases in glucocorticoid levels is to protect not against the source of stress itself, but against the normal defense reactions (e.g., immune response/inflammation) that are activated by stress; glucocorticoids accomplish this function by turning off those defense reactions, thus preventing them from overshooting and themselves threatening homeostasis. Adrenocorticotropin Hormone and the Immune System Essay. ” Therefore, some glucocorticoid actions may help mediate the recovery from the stress response, rather than mediate the stress response itself.

Activation of the HPA axis begins with the release of corticotropin-releasing hormone (CRH). CRH neurons originate in the parvocellular division of the paraventricular nucleus (PVN) of the hypothalamus and terminate in the external layer of the median eminence (ME), releasing CRH into the hypophysial-portal circulation (Fig. 2). CRH, in turn, acts on CRH-R1 receptors on anterior pituitary corticotrophs to stimulate the rapid release of adrenocorticotropic hormone (ACTH) from cellular stores, and, after a delay, the synthesis of the ACTH precursor peptide proopiomelanocortin (POMC) to replenish ACTH stores. ACTH then is released into the peripheral circulation and stimulates the release of glucocorticoids (cortisol in humans and non-human primates; corticosterone in rodents) from the adrenal cortex by acting on the MC2-R (type 2 melanocortin receptor) (for review, see (127)). Whereas both CRH-R1 and MC2-R are membrane bound, G-protein coupled receptors (linked to the adenylate cyclase–cAMP–PKA pathway), glucocorticoid receptors (GR’s) are cytosolic steroid receptors, that when activated by binding of its ligand (glucocorticoids), translocate into the nucleus to interact with other relevant transcription factors (e.g., NFκB or AP-1) or to directly alter the transcription of glucocorticoid-sensitive genes (by binding to a glucocorticoid response element [GRE] in their promoter region). Every nucleated cell in the body expresses glucocorticoid receptors; hence the widespread effects of glucocorticoids on practically every system of the body (e.g., metabolic, endocrine, nervous, cardiovascular, immune).

FIG. 2

The hypothalamo-pituitary unit. CRH and CRH/AVP neurons originating from the parvocellular division of the PVN of the hypothalamus terminate in the external layer of the median eminence (ME), releasing CRH and or CRH/AVP into the hypophysial-portal circulation, which then act on corticotrophs in the AP to release ACTH into the general circulation. In addition, AVP neurons originating from the magnocellular division of the PVN pass through the internal layer of the ME and terminate on capillaries in the PP to release AVP into the general circulation. ACTH, adrenocorticotropic hormone; AP, anterior pituitary; AVP, arginine vasopressin; CRH, corticotropin-releasing factor; OC, optic chiasm; PP, posterior pituitary; PVN, paraventricular nucleus of the hypothalamus; Adrenocorticotropin Hormone and the Immune System Essay.

CRH neurons of the PVN serve as a final common stress pathway by receiving converging inputs from multiple areas of the brain, allowing CRH to coordinate the behavioral, neuroendocrine, and autonomic responses to stress (264). These afferent pathways include projections from (a) ascending brainstem noradrenergic pathways (from the ventrolateral medulla [VLM] and the nucleus of the solitary tract [NTS]) that relay visceral sensory information, (b) descending cortical and limbic pathways (from the septum, amygdala, and hippocampus) via the bed nucleus of the stria terminalis [BNST] that relay cognitive and emotional information, (c) intrahypothalmic connections receiving innervation from brainstem and limbic structures, and (d) circumventricular organs [CVO’s] (e.g., organum vascularis of the lamina terminalis [OVLT], subfornical organ [SFO]) that relay blood-borne chemosensory signals. Therefore, hypothalamic CRH neurons are strategically situated to intercept and disperse signals from and to the body about the internal and external environment.

In response to prolonged stress, the expression of hypothalamic CRH mRNA and pituitary POMC mRNA increase, along with hypersecretion of CRH and ACTH. However, upon continued exposure to CRH, pituitary CRH-R1 receptors downregulate, desensitizing the pituitary corticotroph to CRH signals and hence reducing ACTH release to the primary stressor (127). Although parvocellular PVN expression of arginine vasopressin (AVP) (co-expressed in CRH neurons) is low at baseline, it increases substantially in response to chronic stress. In the presence of CRH (although not alone), AVP acts synergistically to potentiate ACTH release via the vasopressin V1b receptor (linked to the PLC–Ca²⁺/DAG–PKC pathway) (without affecting POMC transcription) (127,163). Therefore, AVP action on pituitary corticotrophs is able to maintain corticotroph responsiveness, and hence ACTH release, to novel stressors following repeated activation of the HPA axis, despite concomitant CRH-R1 desensitization.

HPA axis activity itself also needs to be kept in check, therefore, glucocorticoids exert negative feedback at the hypothalamus and pituitary to inhibit the synthesis and secretion of CRH and POMC/ACTH, respectively (154). Moreover, glucocorticoid negative feedback causes a reduction in corticotroph CRH-R1 mRNA expression and an increase in CRH-R1 downregulation, leading to a decrease in CRH-R1 number, and hence, the desensitization of the corticotroph to the stimulatory effects of CRH on ACTH release. In addition, the hippocampus, which displays a high density of GR, exerts a negative influence on the PVN, and hence HPA axis activity, as well (129). According to Paul Plotsky (240), “One may speculate that attenuation of the ACTH secretory-response by glucocorticoid feedback conserves the response capacity of the HPA axis to subsequent stressors, and acts to limit the duration of total tissue glucocorticoid exposure, thus minimizing catabolic, anti-reproductive, and immunosuppressive effects, and counter-balancing the tendency of central circuitry to over-respond to a repeated stressor.” Adrenocorticotropin Hormone and the Immune System Essay.

BIDIRECTIONAL COMMUNICATION BETWEEN NEUROENDOCRINE AND IMMUNE SYSTEMS: HISTORICAL PERSPECTIVE

That substances released from the adrenal gland could affect immune function was one of the initial indications that there are meaningful interactions between the neuroendocrine and immune systems. Indeed, as early as the 1850s, Thomas Addison described a patient with adrenal insufficiency who exhibited an excess of circulating lymphocytes, thus providing some of the first evidence of a reciprocal relationship between adrenal hormones and immunologic parameters. In the 1920s, H. Jaffe demonstrated that adrenalectomized rats exhibited hypertrophy of the thymus, and conversely, in the 1930s, Hans Selye reported that animals exposed to a variety of stressors exhibited enlarged adrenal glands coupled with thymic involution. In the 1940s, Philip Hench discovered that patients with autoimmune disorders, such as rheumatoid arthritis, produced an endogenous substance under “stressful” conditions that had anti-inflammatory/immunosuppressive properties and hence, ameliorated the symptoms of the autoimmune disease. Isolation and characterization of this endogenous compound by Kendall led to the discovery of the adrenal steroid, cortisone, which along with other glucocorticoids, have become a mainstay in the treatment of autoimmune and inflammatory diseases. Of note, Hench and Kendall shared the Nobel prize in Medicine for their discovery in 1950.

Although the immunomodulatory effects of glucocorticoids initially were believed to be mediated by pharmacological rather than physiological concentrations of steroid, seminal work by Besedovsky and colleagues in the 1970s and 1980s substantiated a physiological role for glucocorticoids in regulating immune responses. For example, physiologic concentrations of glucocorticoids were found to facilitate antigenic specificity (40) and reduce splenic weight and cellularity (83). Adrenocorticotropin Hormone and the Immune System Essay. Besedovsky was also one of the first to demonstrate that immune system activity could influence the release of glucocorticoids. Indeed, his work demonstrated that circulating glucocorticoids increase in the rat during the immune response to foreign antigens (i.e., sheep red blood cells [SRBCs]) (37). Furthermore, rats injected with culture supernatants from peripheral blood or spleen cells stimulated with mitogens in vitro produce increases in plasma glucocorticoid levels similar in magnitude to those reached at the peak of the immune response after antigen exposure (41). Besedovsky and colleagues concluded that lymphoid cells produce a glucocorticoid increasing factors (GIF) (41,43), that completes an immunoregulatory feedback circuit, in which immune cells secrete “hormones” that stimulate the release of adrenal glucocorticoids, that in turn negatively feedback on immune cells to prevent overactivity and preserve specificity of immune responses.

The concept of bi-directional communication between immune and neuroendocrine systems became firmly established with the work of Blalock and colleagues in the 1980s. These investigators demonstrated the synthesis/expression of common ligands and receptors in immune and neuroendocrine systems, for example, neuropeptides in immune cells and cytokines in endocrine glands (48,327). In addition, they proposed the concept of a “lymphoid-adrenal axis,” in which ACTH produced by virus (Newcastle disease virus [NDV])–stimulated lymphocytes was able to directly stimulate corticosterone release in the absence of pituitary-derived ACTH (in hypophysectomized mice) (275,277). Of note, subsequent studies failed to replicate Blalock’s findings and reported that extra-pituitary sources of ACTH were not sufficient to stimulate NDV-induced adrenal steroidogenesis (38,88,91,220). Complementary to these latter studies, Besedovsky et al. (43) showed that rats injected with culture supernatants from mitogen-stimulated peripheral blood or spleen cells produced an increase in plasma ACTH concentrations (along with increased glucocorticoid levels—like NDV-infected animals); however, when the rats were hypophysectomized, the glucocorticoid response was abolished. These studies suggested that immune-induced glucocorticoid release is dependent on a functioning pituitary gland, and that “GIFs” do not directly stimulate the adrenals in the absence of pituitary-derived ACTH. Adrenocorticotropin Hormone and the Immune System Essay. Furthermore, Besedovsky et al. observed changes in hypothalamic electrical activity (36) and norepinephrine turnover (42) in SRBC-injected rats, concomitant with peak immune and corticosterone responses, suggesting that the brain is involved in immune-neuroendocrine regulation.

In the mid-1980s, a series of papers in the journal Science demonstrated that the monocyte-derived, proinflammatory cytokine IL-1 fulfilled the requirement of a GIF. These studies showed that administration of IL-1 to rats and mice increased plasma ACTH and corticosterone levels (32,35,262) and did so by acting at multiple levels of the HPA axis. Although none of these early studies provided evidence for a direct action of IL-1 on glucocorticoid release from the adrenal gland (262,333), some demonstrated a direct IL-1 effect on ACTH release from pituitary cells (34,333) and some did not (32,262). These latter studies confirmed a role for hypothalamic CRH in the IL-1–induced ACTH and glucococorticoid responses (32,262). In addition, IL-1 was shown to be a critical mediator of the HPA response during viral (NDV) infection (35). Subsequent to this early landmark work, a plethora of studies have examined the direct impact of various cytokines (e.g., IL-1, IL-6, TNFα, IFN’s, IL-2) alone or in combination, on HPA axis function. Interestingly, more recent data from both in vivo and in vitro studies indicate that cytokines may have the capacity to stimulate the adrenal gland directly, and therefore may activate glucocorticoid release independent of central nervous system (CNS) neuroendocrine pathways (see section on cytokine effects on the adrenal gland).

THE IMMUNE RESPONSE TO VIRUSES

Prior to considering the pathways by which cytokines activate the HPA axis, it is important to review some general features of the immune response to viral infection, including the role of relevant cytokines.

Immune responses to viral infections share certain characteristics that are distinct from bacterial and parasitic infections (1,136) (Fig. 3). The presence of a virus in infected cells is recognized by the detection of double-stranded RNA, generated during viral replication. This signal leads to the transcription and secretion of type I interferons (IFN-α and IFN-β), which protect neighboring cells not yet infected by making them resistant to viral replication, and hence, inducing an anti-viral state. In addition to inhibiting viral replication, type I IFN’s activate natural killer (NK) cell cytotoxicity and increase MHC class I expression, allowing for more effective antigen presentation to CD8⁺ cytolytic T cells (CTLs). NK cells are one of the principal mechanisms of innate immunity against viruses early in the course of infection, before late, specific immune responses have developed. Adrenocorticotropin Hormone and the Immune System Essay. In addition to their lytic functions, NK cells can be stimulated by IL-12 (released by macrophages and dendritic cells; acts in synergy with TNFα) to release IFN-γ (type II interferon), which is crucial in controlling infections before T cells have been activated to produce more IFN-γ. In the presence of IL-12 and IFN-γ, CD4⁺ T cells are encouraged to develop into inflammatory T cells (Th1), which promote cellular immunity through the activation of macrophages (via IFN-γ release) and CD8⁺ T cells (via IL-2 release). IL-2 is a crucial cytokine for T cell proliferation and differentiation. The principle mechanism of specific immunity against established viral infections, especially with non-cytopathic viruses, is the CD8⁺ CTL. During the early, innate immune response to viral infections (as well as other types of infections), the proinlfammatory cytokines, TNFα, IL-1, and IL-6, also are induced to aid in the progression of anti-viral immunity.

FIG. 3

Cellular and cytokine responses to viral infection and potential immunomodulatory effects of glucocorticoids. Ab, antibody; CTL, cytotoxic T lymphocyte; IFN, interferon; IL, interleukin; NK, natural killer; TNF, tumor necrosis factor; TGF, transforming growth factor. Reprinted by permission from Miller et al. (188).

When considering the HPA axis effects of cytokines, it is important to keep in mind that (a) cytokines are pleiotropic (one cytokine can exert many actions), (b) they are redundant (different cytokines can exert the same action), (c) they often influence the synthesis of other cytokines (e.g., TNF → IL-1 → IL-6, while IL-6 inhibits TNF and IL-1 synthesis), and (d) they often influence the action of other cytokines (e.g., TNF, IL-1, and IL-6 can act synergistically). The importance of synergistic actions of cytokines in HPA axis stimulation has been demonstrated by several studies. For example, in an in vitro preparation of isolated rat hypothalami, Buckingham et al. (59) showed that the release of CRH by conditioned media from lipopolysaccharide (LPS)–stimulated peritoneal macrophages (containing multiple cytokines) was much greater than that observed in response to TNFα, IL-1, or IL-6 alone. In addition, there is in vivo evidence that supports the role of synergistic actions of these proinflammatory cytokines in stimulating a complete, LPS-induced ACTH response (236) and in stimulating greater HPA axis activity together compared to their individual effect (310). Adrenocorticotropin Hormone and the Immune System Essay.

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CYTOKINE–HPA AXIS INTERACTIONS: POTENTIAL MECHANISMS

Given the importance of the glucocorticoid response in restraining potentially detrimental immune responses, redundant or complementary pathways of glucocorticoid induction are activated by cytokines at all three levels of the HPA axis, including the hypothalamus, pituitary, and adrenal gland. Although hypothalamic CRH is considered a primary mechanism by which cytokines stimulate glucocorticoid release, increasing evidence supports a direct action of cytokines at the level of the pituitary and adrenal glands as well. Cytokine receptors have been detected at all HPA axis levels and therefore, each level can serve as an integration point for immune and neuroendocrine signals. In addition to circulating cytokines being able to act upon all three levels of the HPA axis, cytokines are synthesized in the brain, the anterior pituitary, and the adrenal gland. The production of local cytokines may function in a paracrine manner to amplify and maintain elevated HPA activity during chronic inflammation. Therefore, each level of the HPA axis contains a local cytokine network, which can be stimulated by a variety of circulating cytokines. In examining the effects of cytokines on HPA axis function, the innate proinflammatory cytokines—IL-1, IL-6, and TNFα—have been the most studied. However, other cytokines (e.g., IFN’s and IL-2) also have been shown to influence HPA axis activity. Adrenocorticotropin Hormone and the Immune System Essay.