Named Series: Twenty Years of Brain, Behavior, and Immunity
Protein hormones and immunity

https://doi.org/10.1016/j.bbi.2006.11.010Get rights and content

Abstract

A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The best known pathway for transmission of information from the immune system to the neuroendocrine system is humoral in the form of cytokines, although neural transmission via the afferent vagus is well documented also. In the other direction, efferent signals from the nervous system to the immune system are conveyed by both the neuroendocrine and autonomic nervous systems. Communication is possible because the nervous and immune systems share a common biochemical language involving shared ligands and receptors, including neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines. This means that the brain functions as an immune-regulating organ participating in immune responses. A great deal of evidence has accumulated and confirmed that hormones secreted by the neuroendocrine system play an important role in communication and regulation of the cells of the immune system. Among protein hormones, this has been most clearly documented for prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-I), but significant influences on immunity by thyroid-stimulating hormone (TSH) have also been demonstrated. Here we review evidence obtained during the past 20 years to clearly demonstrate that neuroendocrine protein hormones influence immunity and that immune processes affect the neuroendocrine system. New findings highlight a previously undiscovered route of communication between the immune and endocrine systems that is now known to occur at the cellular level. This communication system is activated when inflammatory processes induced by proinflammatory cytokines antagonize the function of a variety of hormones, which then causes endocrine resistance in both the periphery and brain. Homeostasis during inflammation is achieved by a balance between cytokines and endocrine hormones.

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.

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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).

    1

    These authors contributed equally to the preparation of this manuscript.

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