Immunoneuroendocrine Connectivity: The Paradigm of the Thymus-Hypothalamus/Pituitary Axis

Abstract

It is now largely established that the immune and neuroendocrine systems cross-talk by using similar ligands and receptors. In this context, the thymus-hypothalamus/pituitary axis can be regarded as a paradigm of connectivity in both normal and pathological conditions. For example, cytokines and thymic hormones modulate hypothalamic-pituitary functions: (a) interleukin (IL)-1 seems to upregulate the production of corticotropin-releasing factor and by adrenocorticotropin by hypothalamic neurons and pituitary cells, respectively; (b) thymulin enhances LH secretion. Conversely, a great deal of data strongly indicate that the hypothalamic-pituitary axis plays a role in the control of thymus physiology. Growth hormone (GH) for example, enhances thymulin secretion by thymic epithelial cells (TEC), both in vivo and in vitro, also increasing extracellular matrix-mediated TEC/thymocyte interactions. Additionally, gap junction-mediated cell coupling among TEC is upregulated by ACTH. In a second vein, it was shown that GH injections in aging mice increased total thymocyte numbers and the percentage of CD3-bearing cells, as well concanavalin-A mitogenic response and IL-6 production. In addition to mutual effects, thymus-pituitary similarities for cytokine and hormone production have been demonstrated. Cytokines such as IL-1, IL-2, IL-6, interferon-γ, transforming growth factor-β and others can be produced by hypothalamic and/or pituitary cells. Conversely, hormones including GH, PRL, LH, oxytocin, vasopressin and somatostatin can be produced intrathymically. Moreover, receptors for various cytokines and hormones are expressed in both the thymus and the hypothalamus/pituitary axis. Lastly, it is noteworthy that a thymus-pituitary connectivity can also be seen under pathological situations. In this regard, an altered HPA axis has been reported in AIDS, human falciparum malaria and murine rabies, that also show a severe thymic atrophy.

Lethal Silver-Haired Bat Rabies Virus Infection Can Be Prevented by Opening the Blood-Brain Barrier

“…It is known that pathogenic strains of RV infect the hypothalamus and alter HPA activity (24,29), resulting in the elevated production of steroid hormones and the reduced production of growth hormones (29). These changes may be responsible for the lymphoid organ atrophy and altered immune function (29,31) seen during the late stages of rabies.…”

The Immunoendocrine Thymus as a Pacemaker of Lifespan

“…Thymosin fraction 5 advanced vaginal opening and elevated oestrogen level in female mouse [28]. Thymic hormones can regulate the release of hormones from the pituitary gland [29] and thymic deprivation causes dysgenesis of pituitary anterior lobe [30], and thymic peptides influence hormone production of pituitary and gonads, e.g., thymulin enhances LH secretion and neonatal thymulin gene therapy prevents the reduction of circulating gonadotropin levels in athymic mice [31][32][33]. The proper functioning of the hypothalamo-pituitary-gonadal axis is dependent on thymic endocrine influences [34].…”

Age-Dependent Changes in 24-Hour Rhythms of Thymic and Circulating Growth Hormone and Adrenocorticotropin in Rats Injected with Freund’s Adjuvant

“…The influence of GH on thymic epithelium is pleiotropic: GH enhances in vivo the expression of cytokeratins, stimulates in vitro proliferation and enhances extracellular matrix-mediated thymic epithelial cells/thymocyte interactions [10]. Receptors for GH are detectable on both thymocytes and thymic epithelial cells [51] and several studies indicate that both thymocytes and thymic epithelial cells produce GH [10]. Indeed, the results strongly indicate that the thymus is physiologically under control of both intra-and extramural GH [4].…”

“…GH stimulates the secretion of thymulin and conversely, low levels of circulating thymulin parallel hypopituitary states [for references, see 10]. The influence of GH on thymic epithelium is pleiotropic: GH enhances in vivo the expression of cytokeratins, stimulates in vitro proliferation and enhances extracellular matrix-mediated thymic epithelial cells/thymocyte interactions [10]. Receptors for GH are detectable on both thymocytes and thymic epithelial cells [51] and several studies indicate that both thymocytes and thymic epithelial cells produce GH [10].…”

“…Besides, a possible thymic production of pituitary hormones has been documented, as revealed by the detection of immunoreactivity for GH, ACTH, prolactin, thyrotropin (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), oxytocin and vasopressin, and the specific messenger RNAs for some of these hormones, in thymic cells [1,[5][6][7][8][9][10].…”