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Endocrinology Vol. 143, No. 5 1571-1574
Copyright © 2002 by The Endocrine Society

CRH-ACTH-POMC-ADRENAL

Minireview: Neuro-Immuno-Endocrine Modulation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis by gp130 Signaling Molecules

Vera Chesnokova and Shlomo Melmed

Cedars-Sinai Research Institute-University of California Los Angeles School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Academic Affairs, Room 2015 Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: . melmed{at}csmc.edu


   Abstract
Top
 Abstract
Introduction
 Development of Pituitary...
 HPA Axis Stress Response...
 Molecular Mechanisms Mediating...
 References
 
The neuroendocrine and immune systems communicate bidirectionally. The neuro-immune-endocrine interface is mediated by cytokines acting as auto/paracrine or endocrine factors regulating pituitary development, cell proliferation, hormone secretion, and feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. At birth or during neonatal ontogenesis, cytokines produce permanent alterations of HPA axis function and the stress response. Overexpressing IL-6 or leukemia inhibitory factor leads to significant changes in pituitary development and functions. Pituitary corticotroph POMC gene expression is regulated by CRH as well as several gp130 cytokines acting as neuro-immuno-endocrine modulators. Conversely, HPA axis functions modulate susceptibility or resistance to inflammatory disease. Cytokines (including IL-1, TNF, and members of the gp130 cytokine family) participate as mediators of a complex HPA axis response to stress and inflammation. Prolonged exposure to proinflammatory cytokines increases levels of the dominant negative glucocorticoid receptor isoform. Nonresponsiveness of the HPA axis to glucocorticoid negative feedback control provides a defense from destructive effects of cytokine excess. At the same time, gp130 cytokines stimulate pituitary suppressor of cytokine signaling (SOCS)-3, which represses cytokine signaling and abrogates cytokine-induced corticotroph POMC gene transcription and ACTH secretion.


   Introduction
Top
 Abstract
 Introduction
Development of Pituitary...
 HPA Axis Stress Response...
 Molecular Mechanisms Mediating...
 References
 
THE NERVOUS, ENDOCRINE, and immune systems are anatomically and functionally interconnected. These organ systems both express and respond to a large number of common regulatory molecules including steroids, neuropeptides, cytokines, and neurotransmitters, which provide the molecular basis for integrated, bidirectionally coordinated neuroendocrine-immune responses to homeostasis disturbances induced by stress, inflammation, or infection (1, 2, 3). HPA axis activation, which is under primary hypothalamic control by CRH (4), is critical for maintaining physiological homeostasis under these circumstances. Anterior pituitary hormone responses to inflammatory, psychological, and environmental stressors are complex (4, 5, 6). Specific trophic hormone responses depend upon hypothalamic humoral control, the duration and degree of stress, as well as dynamic changes in secretion and action of peripheral and central cytokines. For example, chronically depressed women have amenorrhea, lactation ceases in the face of chronic illness, and growth is stunted by psychosocial deprivation. In contrast, acute inflammatory stress may be associated with high levels of ACTH, GH, or PRL in human subjects. Thus, neuroimmune signals participate directly in regulation of pituitary genes. Stress-induced glucocorticoids, catecholamines, and CRH also mediate peripheral immune responses (4). Mechanisms for this multidirectional communication are currently being actively explored.

Immune cytokines are a large and diverse group of pleiotropic and redundant polypeptides. They are rapidly induced in response to tissue injury, infection, or inflammation. Cytokines may function as classic endocrine secretions emanating from proximal tissues, traversing the circulation and impacting a distal target (6). They also commonly behave as paracrine or autocrine cell regulators mediating adjacent cell functions. Cytokines act in the brain through one or more of the following mechanisms: 1) binding to cytokine receptors in the blood-brain barrier cerebral endothelium with subsequent triggering of PGE2 and activation of the HPA axis (IL-1ß, TNF-{alpha}, but not gp130 cytokines) (7, 8, 9, 10, 11); 2) active and specific transport mechanisms for IL-1, IL-6, leukemia inhibitory factor (LIF), INF, and TNF-{alpha} (12); 3) brain penetration through circumventricular organs (these central sites have capillaries with open junctions and abundant fenestrations) (6); 4) de novo central nervous system synthesis (1, 2, 3, 13); and 5) action on peripheral nerves that signal the brain (14). It is unclear which of these nonmutually exclusive mechanisms are involved in specific pathophysiology of the neuroimmune interface (13). Complex interactions have been described for cytokine actions, including overlapping, synergistic, and antagonistic activities. The concept of distinct groups of "proinflammatory" and "anti-inflammatory" cytokines has emerged on the basis of their peripheral action. However, this notion does not necessarily translate directly to their central nervous system actions and central regulation of the hypothalamic-pituitary-adrenal (HPA) axis (15).

Cytokines and their receptors are expressed centrally in hypothalamus as well as within anterior pituitary cells. Specifically, the gp130 cytokine family [LIF, IL-6, IL-11, ciliary neurotrophic factor (CNTF), and Oncostatin M (OSM)] participates in ACTH regulation and mediates the immuno-neuroendocrine interface (16, 17). Two POMC inducers, CRH and gp130 cytokines, act in synergy and signal through cAMP and the JAK/STAT/SOCS pathways, respectively (18). Ligands for gp130 receptor cytokine family signal via common intracellular molecules often exerting redundant functions (17). Cytokines mediate pituitary development and cell proliferation, mature ACTH hormone secretion, and negative feedback regulation of the HPA axis.


   Development of Pituitary Function
Top
 Abstract
 Introduction
 Development of Pituitary...
HPA Axis Stress Response...
 Molecular Mechanisms Mediating...
 References
 
Most experimental results, derived from pathogen-free living animals, provide little or unclear information about central cytokine functions in inflammation-free tissue. In genetically modified mice, such as cytokine-knockout animals, no significant changes are encountered in HPA axis development. However, cytokines comprise a "defense" system that is activated upon demand. The living organism is under a constant pressure of pathogenic agents, starting from intrauterine life when a pregnant mother may be exposed to infection, inflammation, or immunization. Cytokines induced under these conditions may have a pivotal role in development of subsequent endocrine functions, specifically of the HPA axis. Thus, animals undergoing neonatal exposure to endotoxin, which induces massive production of proinflammatory cytokines, as adults have decreased glucocorticoid receptor binding and decreased steroid negative-feedback efficacy when terminating corticosterone stress responses. Early treatment with endotoxin not only exerts long-term effects on endocrine and central system development but also dramatically alters predisposition to inflammatory disease (19). Administration of IL-1ß at birth induces permanent alteration of the HPA axis in adulthood (20). These results suggest an important role for immune cytokines in programming of subsequent neuroendocrine functions during early ontogenesis.

Cytokines may also directly affect pituitary development. Transgenic mice overexpressing astrocyte IL-6 demonstrate blunted ACTH, increased AVP, and increased corticosterone responses to acute immobilization stress, along with adrenal cortex and medulla hyperplasia (21). LIF, another member of the gp130 cytokine family, acts as a differentiation factor, causing a phenotypic switch of AtT20 cells from proliferative to synthetic. LIF inhibits cell cycle progression of corticotroph cells from G1 to S phase, while enhancing ACTH secretion (22). Transgenic mouse models with pituitary-directed LIF overexpression have shown LIF to be important for neuroimmune-endocrine modulation of pituitary development (23, 24). Transgenic mice overexpressing pituitary-directed LIF driven by the rat GH promoter showed striking dwarfism, undetectable serum GH, and very low IGF-1 levels (23). The impact of overexpressed LIF on earlier pituitary development, with pituitary-directed LIF driven by glycoprotein hormone {alpha}-subunit ({alpha}GSU), exhibited infertility in both sexes due to central hypogonadism, Cushingoid features, and incomplete dexamethasone suppression of elevated corticosterone. ACTH cells increased in absolute numbers accounting for 65% of anterior pituitary cells. Thus, excess pituitary LIF directs differentiation of progenitor cells away from Lim3-dependent cell lineages (FSH/LH, TSH, GH, PRL) toward the corticotroph lineage (24). Tpit-1/Tbx19, recently identified as a tissue-specific corticotroph cell factor, may be mutated in association with isolated ACTH deficiency (25, 26). Nevertheless, the ability of transcription factors to commit cells to POMC production also requires other molecules, and the proximity of early corticotrophs to dorsal mesenchyme and microvasculature could facilitate cytokine access to corticotrophs (26).


   HPA Axis Stress Response Requires Cytokines
Top
 Abstract
 Introduction
 Development of Pituitary...
 HPA Axis Stress Response...
Molecular Mechanisms Mediating...
 References
 
Cytokines, including IL-1, IL-6, and LIF, participate as mediators of the complex HPA axis response to stress or inflammation. Mice with LIF deficiency (LIFKO) mount an attenuated ACTH response to restraint and immobilization. Conversely, LIF replacement restores ACTH levels (27). During inflammatory stress, cytokines that stimulate corticotroph POMC expression and ACTH secretion are produced both peripherally as well as within the hypothalamus and pituitary (3, 4), and by stimulating the HPA axis they antagonize their own peripheral proinflammatory action. Excess HPA axis stimulation leads to immunosuppression and, therefore, increased susceptibility to infection. Inflammatory cytokines also trigger central ACTH secretagogues such as noradrenaline (28), pituitary adenylate cyclase-activating polypeptide (29), vasopressin (30), and other cytokines (31). Pituitary cytokine expression and action (17, 32, 33) and HPA regulation by cytokines (IL-1, IL-6, TNF) (2, 3) have been extensively reviewed. Pituitary corticotroph POMC gene expression is regulated by CRH as well as several gp130 cytokines acting as immuno-neuro-endocrine modulators (1, 2, 16, 32). Although CRH action is mediated by a cAMP-dependent pathway, effects of gp130 cytokines are mediated by the JAK-STAT signaling cascade. Synergistic cross-talk of different signaling cascades enables the HPA axis to respond rapidly to inflammatory and stress stimuli (34) (Fig. 1Go). gp130 receptor cytokines activate the HPA axis even in the absence of CRH (35). Both IL-6 and LIF mediate HPA responses to stress and inflammation by inducing ACTH axis in the course of the inflammatory process and are able to directly stimulate POMC expression and ACTH secretion in mouse corticotrophs (16). Experiments with CRH-deficient mice demonstrating activation of the HPA axis by IL-6 support this hypothesis (35). Moreover, IL-6 directly induces the release of adrenal corticosteroids in humans (36) and from rat adrenal cells (37). At the same time, IL-6 is important for prolonged activation of paraventricular nucleus neurons and continued CRH expression during late phases of inflammation (38). Similarly, hypothalamic LIF induced in the course of chronic inflammatory process is important for maintaining a sustained HPA axis inflammatory stress response (39). The diffusible form of murine LIF is induced in the hypothalamus and pituitary after lipopolysaccharide (40), IL-1 (41), turpentine, and complete Freund’s adjuvant injections (39), and brain IL-6 and gp130 are similarly induced after lipopolysaccharide injection (18). LIF administered before lethal septic shock has a protective effect, preventing sepsis-induced tissue damage and lowering mortality (42). LIF is also a protective factor for neurons and peripheral tissues during injury (43).



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  		Figure 1. Model for SOCS-3 as intracellular regulator of LIF-mediated gene expression. [Adapted with permission from C. Bousquet et al., J Clin Invest 104:1277–1285, 1999.]

 

   Molecular Mechanisms Mediating the Neuro-Immuno-Endocrine Interface
Top
 Abstract
 Introduction
 Development of Pituitary...
 HPA Axis Stress Response...
 Molecular Mechanisms Mediating...
References
 
Glucocorticoids are potent anti-inflammatory agents, and HPA axis functions modulate susceptibility or resistance to inflammatory disease (44). HPA feedback inhibition is mediated by glucocorticoid receptors (GR) in the hippocampus, hypothalamus, and pituitary (45). The {alpha} GR isoform binds steroid hormone, translocates to the nucleus, and activates transcription of hormone-sensitive genes (46). Proinflammatory cytokines such as TNF and IL-1 initiate a cascade of inflammatory responses by activating nuclear factor-{kappa}B (NF-{kappa}B), which in turn stimulates proinflammatory genes. Ligand-bound GR interacts with nuclear-localized NF-{kappa}B and alters its ability to promote transcription of cytokine-responsive genes (47). Glucocorticoids also increase expression of inhibitory NF-{kappa}B subunit I-{kappa}B (48). NF-{kappa}B and GR are mutually antagonistic, such that NF-{kappa}B also abolishes transactivation of glucocorticoid-responsive genes (48, 49). Thus, these two opposing regulatory systems appear inherently coupled to control the inflammatory process. Prolonged exposure to proinflammatory cytokines increases steady-state levels of the dominant negative ß-isoform of GR, blocking action of the active {alpha}-isoform, thus promoting glucocorticoid resistance (47). During prolonged continued inflammation, nonresponsiveness of the HPA axis to negative feedback control of circulating glucocorticoids provides a new level of defense from destructive effects of cytokine excess.

Concomitant with these responses, negative regulation of cytokine function is critical to prevent excessive prolonged HPA axis activation. SOCS proteins inhibit the JAK-STAT signaling cascade (50, 51). SOCS-3 is an early response gene, induced by variety of inflammatory and other stressors in hypothalamus and pituitary (52). Activation of corticotroph JAK-STAT cascade by gp130 cytokines not only induces POMC expression but also SOCS-3 expression (34). SOCS-3 subsequently inhibits corticotroph JAK-STAT signaling and renders the cell resistant to further stimulation by gp130 cytokines. At the same time, SOCS-3 appears to play a critical role in inhibiting cytokine-mediated POMC induction and ACTH secretion. SOCS-3 is potently induced by both LIF and IL-1 in the murine hypothalamus and pituitary, providing a sensitive intracellular mechanism enabling corticotroph plasticity with fast induction or suppression of ACTH secretion (52) (Fig. 1Go).


   Footnotes
 
Abbreviations: HPA, Hypothalamic-pituitary-adrenal; LIF, leukemia inhibitory factor; JAK, Janus kinase; NF-{kappa}B, nuclear factor {kappa}B; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription.

Received December 21, 2001.

Accepted for publication March 4, 2002.


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 Development of Pituitary...
 HPA Axis Stress Response...
 Molecular Mechanisms Mediating...
 References
 

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A. Kariagina, D. Romanenko, S.-G. Ren, and V. Chesnokova
Hypothalamic-Pituitary Cytokine Network
Endocrinology, January 1, 2004; 145(1): 104 - 112.
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C. J. Auernhammer, N. B. Isele, F. B. Kopp, G. Spoettl, N. Cengic, M. M. Weber, G. Senaldi, and D. Engelhardt
Novel Neurotrophin-1/B Cell-Stimulating Factor-3 (Cardiotrophin-Like Cytokine) Stimulates Corticotroph Function via a Signal Transducer and Activator of Transcription-Dependent Mechanism Negatively Regulated by Suppressor of Cytokine Signaling-3
Endocrinology, April 1, 2003; 144(4): 1202 - 1210.
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