Neuroendocrine Hormone Influence on the Immune System

The immune system, in addition to autonomic nervous activity, is influenced by hormones released by the neuroendocrine system (Table 1.3; see also Brooks (1990), Carr (1992), Clevenger, Sillman, and Prystowsky (1990), Clevenger, Sillman, Hanley-Hyde, and Prystowsky (1992), Foster, Mandak, Kromer, and Rot (1992),

Jain et al. (1991), Johnson, Farrar, and Torres (1982a), Johnson, Smith, Torres, and Blalock (1982b), Johnson, Torres, Smith, Dion, and Blalock (1984), Kelley (1989), Kruger, Smith, Harbour, and Blalock (1989), Matera, Cesano, Bellone, and Oberholtzer (1992), Mathew, Cook, Blum, Metwali, Felman, and Weinstock (1992), McGillis, Humphreys, and Reid (1991), Ottaway, Bernaerts, Chang, and Greenberg (1983), Pascual, Xu-Amano, Kiyono, McGhee, and Bost (1991), Provinciali, Di Stefano, and Fabris (1992), Rouabhia, Chakir, and Deschaux (1991), Smith, Hughes, Hashemi, and Stefano (1992), Stanisz, Befus, and Bienenstock (1986), and Zelazowski, Dohler, Stepien, and Pawlikowski (1989)). A great deal of evidence exists to support both the presence of receptors for neuroendocrine hormones on cells of the immune system as well as the ability of these hormones to modulate specific functions of the various immune cell types (Tables 1.2 and 1.3; see also Weigent and Blalock (1995)).

Table 1.3. Modulation of immune responses by neuropeptides.





Antibody synthesis

Johnson et al. 1982a, 1982b

IFN-y production

Johnson et al. 1984

B-lymphocyte growth

Brooks 1990


Antibody synthesis

Johnson et al. 1982a, 1982b


Carr 1992

NK activity


Antibody synthesis

Johnson et al. 1992; Kruger et al. 1989

Comitogenic with ConA

Provinciali et al. 1992


Cytotoxic T cells

Kelley 1989


LH and FSH


Provinciali et al. 1992


Rouabhia et al. 1991


Comitogenic with ConA

Clevenger et al. 1990, 1992;

Induces IL2 receptors

Matera et al. 1992


IL1 production

Jain et al. 1991;

Enhance NK

Smith et al. 1992



Antibody synthesis

Harbour et al. 1990; Kruger et al. 1989


Stimulate chemotaxis

Guarcello et al. 1991;

Inhibit NK activity

Zelazowski et al. 1989

Inhibit chemotactic response

Substance P

Stimulate chemotaxis

Stanisz et al. 1986;

Stimulate proliferation

Pascual et al. 1991

Modulate cytokine levels


Inhibit proliferation

Ottaway et al. 1983; Mathew et al. 1992


T cell helper

Johnson et al. 1982a, 1982b

Functions for IFN-y production


Inhibit proliferation

Stanisz et al. 1986

Reduces IFN-y production


B cell differentiation

Foster et al. 1992

T cell chemotaxis

The receptors for corticotropin (ACTH) and endorphins have been identified on cells of the immune system as well as the ability of these hormones to modulate many aspects of immune reactivity. The binding of ACTH initiates a signal transduction pathway that involves both cAMP and mobilization of Ca2+ (Clarke and Bost 1989). Analysis of the effects of ACTH by patch-clamp methods suggests that this hormone can modulate macrophage functions through the activation of Ca2+-dependent K+ channels (Fukushima, Ichinose, Shingai, and Sawada 2001). ACTH has been shown to suppress major histocompatibility complex (MHC) class II expression, stimulate NK cell activity, suppress interferon-gamma (IFN) production, modulate IL-2 production, and function as a late-acting B cell growth factor (Brooks 1990; Johnson et al. 1982a, 1982b). The production of opioid peptides in immune cells (Smith 2003), and lymphocyte receptors for the opioid peptides share many of the features, including size, sequence, immunogenicity, and intracellular signaling as those described on neuronal tissue. Many aspects of immunity are modulated by the opiate peptides including (1) enhancement of the natural cytotoxicity of lymphocytes and macrophages toward tumor cells, (2) enhancement or inhibition of T cell mitogenesis, (3) enhancement of T cell rosetting, (4) stimulation of human peripheral blood mononuclear cells, and (5) inhibition of major histocompatibility class II antigen expression (Carr 1992; Johnson et al. 1982b).

The anti-inflammatory influences of a-melanocyte-stimulating hormone (a-MSH) and other melanocortins are primarily exerted through inhibition of inflammatory mediator production and cell migration (Luger, Scholzen, Brzoska, and Bohm 2003). These effects occur through binding of melanocortins to melanocortin receptors on cells of the immune system (Lipton and Catania 2003). The in vitro and in vivo inhibitory effects of a-MSH influence adhesion, production of cytokines and other mediators of inflammation, including IL-1, IL-6, IL-10, tumor necrosis factor (TNF)-a, chemokines, and nitric oxide (Luger et al. 2003). The effects of a-MSH, on inflammatory mediator production is thought to occur through the participation of G-proteins, the JAK kinase signal transducer activator of transcription (JAK/STAT) pathway, and inhibition of the activation of the nuclear factor NF-kB (Lipton and Catania 2003).

It has also been shown that cells of the immune system contain receptors for growth hormone (GH) and prolactin (PRL) and that these hormones are potent modulators of the immune response (Gala 1991). A systematic survey of PRL receptor expression by flow cytometry showed that PRL receptors are universally expressed in normal hematopoietic tissues with some differences in density, which could be increased by concanavalin (Con)A treatment. GH receptors from a number of species have been sequenced and GH binding and cellular processing of the GH receptor have been studied in a cell line of immune origin. In the IM-9 cell line, it has been shown that GH stimulates proliferation and that the GH receptor can be down-regulated by phorbol esters (Suzuki, Suzuki, Saito, Ikebuchi, and Terao 1990). A role for GH in immunoregulation has been demonstrated in vitro for numerous immune functions, including stimulation of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis in the spleen and thymus. GH also affects hematopoiesis by stimulating neutrophil differentiation, augmenting erythropoiesis, increasing proliferation of bone marrow cells, and influences thymic development (Gala 1991). GH affects the functional activity of cytolytic cells, including T lymphocytes and NK cells (Kelley 1989). GH has also been shown to stimulate the production of superoxide anion formation from macrophages (Edwards, Ghiasuddin, Schepper, Yunger, and Kelley 1988). It is not clear whether GH directly influences intrathymic or extrathymic development or acts indirectly by augmenting the synthesis of thymulin or insulin-like growth factor-1 (IGF-I). There is a vast literature on the ability of IGF-1 to exert immunomodulatory effects (Kooijman, Hooghe-Peters, and Hooghe 1996). Although most reports suggest IGF-1 is proinflammatory (Renier, Clement, Desfaits, and Lambert 1996), it also may exert anti-inflammatory actions via stimulation of IL-10 production in activated T cells (Kooijman and Coppens 2004). The observations suggest that GH may stimulate local production of IGF-I, which acts to promote tissue growth and action in a paracrine fashion. Likewise, PRL can have modulating effects on the immune system (Gala 1991). PRL is involved in the activation of many immunological responses, including stimulating the activity of Th1 and Th2 lymphocytes that alter antitumor cytotoxicity and autoimmunity (DeBellis, Bizzaro, Pivonello, Lombardi, and Bellastella 2005). PRL stimulated the release of IL-1 by macrophages and abolished the stress-induced inhibition of proliferation of peripheral blood lymphocytes (Fomicheva, Nemirovich-Danchenko, and Korneva 2004). Data show that suppression of PRL secretion in mice with bromocriptine increases the lethality of a Listeria challenge and abrogates T cell-dependent activation of macrophages (Bernton, Bryant, Holaday, and Dave 1991). Antibodies to the PRL receptor have been shown to abolish PRL-induced proliferation of Nb2 cells (Clevenger et al. 1992). Other studies suggest that PRL may promote survival of certain lymphocyte subsets, modulate the naive B cell repertoire, and promote antigen-presenting functions (Matera, Mori, and Galetto 2001).

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