Named Series: Twenty Years of Brain, Behavior, and ImmunityProtein hormones and immunity☆
Introduction
The brain has the potential to orchestrate responses from leukocytes through the autonomic nervous system as well as through the endocrine system. Neuroendocrine interactions predominantly occur at the level of the hypothalamic–pituitary axis, so pituitary-derived hormones can clearly mediate effects of the central nervous system on immune responses. However, pituitary hormones may also affect the immune system independently of the central nervous system. This occurs through autocrine or paracrine interactions within the immune system and as a result of regulation of pituitary hormones by cytokines that act directly at the pituitary level. A clear example is the abundant expression of IL-1 type I and II receptors specifically on GH-secreting cells in the murine anterior pituitary gland (French et al., 1996).
Prolactin (PRL) is a member of a class of related protein hormones that includes PRL and placental lactogens (PL). It is a pleiotropic hormone that is mainly produced in the pituitary. PRL secretion in the pituitary is under negative control by dopamine but can also be stimulated by thyrotropin-releasing hormone. Although the main functions of PRL are mammary gland development and initiation and maintenance of lactation, PRL receptors (PRLR) are widely distributed throughout many different tissues. The fact that PRL subserves many different functions is in accordance with the expression of PRL in extrapituitary tissues, the existence of several molecular variants of PRL with different activities and the tissue-specific regulation of PRL.
The PRLR belongs to a large, heterogeneous family of cytokine-hematopoietic receptors known as the class I cytokine receptor family. There is a strong homology between the growth hormone receptor (GHR) and the PRLR. The primary structural homology between the GHR or PRLR and other members of this family is restricted to two extracellular domains of 100 amino acids and intracellular motifs known as boxes. Rodents express three isoforms of the PRLR, whereas humans express four. One of these isoforms is unable to signal, suggesting that it might act as a decoy receptor. The PRLR is only known to bind PRL, placental lactogens and high concentrations of primate GH. Indeed, the priming actions of GH on human neutrophils are mediated not by the GHR but rather by the PRLR (Fu et al., 1992). PRLR homodimerization via two different sites on PRL leads to subsequent activation of associated kinases that phosphorylate downstream targets. Most signaling studies have focussed on the JAK-STAT signaling pathway, which is used by all hematopoietic-cytokine receptors. Binding of PRL to its receptor predominantly evokes the activation of JAK-2 which leads to tyrosine phosphorylation of the PRLR, allowing recruitment of latent cytoplasmic transcription factors (STAT). JAK-2 activation by PRL mainly activates STAT-5 and to a lesser extent STAT-1 and -3. Common use of the JAK-STAT pathway by PRL, GH and other cytokines likely leads to redundancy in their actions.
GH is expressed primarily in the pituitary, but also by cells of the immune system, and is positively regulated by growth hormone-releasing hormone (GHRH) and is negatively regulated by somatostatin in the pituitary. The main effect of GH is to promote postnatal longitudinal growth through interaction with the GHR, which is also a member of the class I cytokine receptor family. GH binding to the GHR causes receptor dimerization and activation of JAK2 and STAT proteins. GH is most well known for its regulation of carbohydrate, lipid, nitrogen and mineral metabolism. Many of the actions of GH are mediated by the induction of insulin-like growth factor-I (IGF-I) expression at local sites, but the primary source of circulating IGF-I is the liver. An evolving theme over the past 20 years is the idea that GH and IGF-I also play a role in the development, maintenance and function of the immune system. An overview of IGF-I receptor (IGF-1R) activation has recently appeared (McCusker et al., 2006).
Thyroid-stimulating hormone (TSH) is a peptide hormone acting through a typical serpentine G-protein coupled receptor to stimulate the production of thyroxin (T4) by the thyroid gland. T4 is a prohormone to T3 that regulates oxygen consumption, lipid metabolism and carbohydrate metabolism, and is required for normal growth and maturation. T3 enters the cell and binds to a nuclear receptor which then acts as a transcription factor by binding to thyroxin response elements in the promoter region of target genes, including TSH and GH.
Section snippets
Prior to 1987
The first indication that pituitary hormones play a role in lymphopoiesis and effector functions of leukocytes came from experiments using pituitary-deficient rodents such as hypophysectomized rats and Snell-Bagg dwarf mice. Hypophysectomy leads to a combined deficiency in all pituitary hormones including the anterior pituitary hormones (TSH, GH, PRL, follicle-stimulating hormone, luteinizing hormone, and POMC-derived peptides such as adrenocorticopic hormone (ACTH) and α-melanocyte-stimulating
1987–1997
During this decade, further in vitro evidence for a role of PRL in the immune system was provided (Matera et al., 1992). Above all, it became clear that the immune system in rodents as well as in humans produces PRL, GH and IGF-I (Kooijman et al., 1996). Using antibodies against human and rodent PRL, it was shown that leukocyte-derived PRL is functional as these antibodies inhibit lymphocyte proliferation (Berczi, 1992). Although several immunoreactive PRL variants were detected in cells from
1997–2007
Prior to the turn of the century, it was considered that physiological concentrations of IGF-I did not have any major adverse consequences in the body. However, it has become increasingly clear that the concentration of circulating IGF-I is inversely related to life span and is positively correlated to progression of the development of several different types of tumors. We have shown that IGF-I acts in cycling cells via insulin receptor substrate-1, phosphatidylinositol 3′-kinase (PI3-K), AKT
2007 and beyond
The idea that GH, PRL and IGF-I interact with immunosuppressive hormones strongly suggests that there is a “two way street” in hormone-hormone interactions, as well as with hormone-immune system interactions. That is, not only should these protein hormones counteract the catabolic effects of glucocorticoids, but glucocorticoids are likely to impair the actions of GH, PRL and IGF-I. For example, IGF-I-induced activation of ERK 1,2 is significantly impaired by dexamethasone, which may be due to
Acknowledgment
We apologize to colleagues whose work, often primary relevant papers, could not be cited due to space limitations.
References (59)
- et al.
A regulatory role of prolactin, growth hormone, and corticosteroids for human T-cell production of cytokines
Brain Behav. Immun.
(2004) - et al.
Expression of insulin-like growth factor-2 receptors on EL4 cells overexpressing growth hormone
Brain Behav. Immun.
(2007) - et al.
Modulation of prolactin expression in human T lymphocytes by cytokines
J. Neuroimmunol.
(2005) Receptor regulation in neuro–endocrine–immune communication: current knowledge and future perspectives
Brain Behav. Immun.
(2007)Growth hormone, lymphocytes and macrophages
Biochem. Pharmacol.
(1989)From hormones to immunity: the physiology of immunology
Brain Behav. Immun.
(2004)- et al.
Growth hormone, prolactin, and insulin-like growth factors: new jobs for old players
Brain Behav. Immun.
(1992) The plasticity of aging: insights from long-lived mutants
Cell
(2005)- et al.
Modulatory effect of prolactin on the resting and mitogen-induced activity of T, B, and NK lymphocytes
Brain Behav. Immun.
(1992) - et al.
Prolactin receptors on large granular lymphocytes: dual regulation by cyclosporin A
Brain Behav. Immun.
(1988)
Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression
Brain Behav. Immun.
Prolactin as a modulator of B cell function: implications for SLE
Biomed. Pharmacother.
Tumor necrosis factor α inhibits cyclin A expression and retinoblastoma hyperphosphorylation triggered by insulin-like growth factor-I induction of new E2F-1 synthesis
J. Biol. Chem.
Immunoregulatory properties of growth hormone and prolactin
J. Pharmacol. Therapeut
Mechanism of signaling by growth hormone receptor
Physiol. Rev.
Murine macrophages express abundant insulin-like growth factor-I class I Ea and Eb transcripts
Endocrinology
The central role of SOCS-3 in integrating the neuro-immunoendocrine interface
J. Clin. Invest.
The immunology of prolactin
Semin. Reprod. Endocrinol.
Characterization of an up-stream promoter directing extrapituitary expression of the human prolactin gene
Mol. Endocrinol.
Stress-induced alterations in delayed-type hypersensitivity to SRBC and contact sensitivity to DNFB in mice
Proc. Soc. Exp. Biol. Med.
Adrenal involvement in the expression of delayed-type hypersensitivity to SRBC and contact sensitivity to DNFB in stressed mice
Proc. Soc. Exp. Biol. Med.
Immune system development and funciton in prolactin receptor-deficient mice
J. Immunol.
Circulating insulin-like growth factor I mediates the protective effects of exercise against brain insults of different etiology and anatomy
J. Neurosci.
Impaired quality of life in hypopituitary adults with growth hormone deficiency: can somatotropin replacement therapy help?
Treat. Endocrinol.
Growth hormone restores glucocorticoid-induced T cell suppression
FASEB J.
The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency
Endocr. Rev.
Anterior pituitary hormones, stress, and immune system homeostasis
Bioessays
Effects of prolactin deficiency on myelopoiesis and splenic T lymphocyte proliferation in thermally injured mice
Endocrinology
Role of interferon-gamma in counteracting the suppressive effects of transforming growth factor-beta 2 and glucocorticoids on the production of tumor necrosis factor-alpha
J. Leukoc. Biol.
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This research was supported by grants from the National Institutes of Health to K.W.K. (MH51569 and AI50442) and D.A.W. (AI41651).
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These authors contributed equally to the preparation of this manuscript.