The concept of thymic endocrinology describes a bidirectional effect: the thymic hormones which circulate and significantly affect the immunomodulatory function of the body and the action of the other hormones derived from the pituitary, adrenal, gonads and thyroid gland on the thymocytes, thymic epithelial cells and the thymic stromal cells. Apart from this there is also an extensive paracrine and autocrine endocrine signal network within the Intra-thymic environment involving interleukins and thymic peptides. This review attempts to delve into the understanding of this intrinsic relationship between the thymus gland and the endocrine system at large.
Keywords: Thymic endocrinology, Bidirectional effect, Immunomodulatory function.
The thymus is a small bi-lobar pyramid shaped retrosternal gland which lies in the anteri-or mediastinum. Each individual lobe of the thymus consists of many lobules separated by fibrous septa. Each lobule consists of two main compartments, the cortex (85-90%) and the medulla (10-15%). The term 'thymus' has its name because of its resemblance to the leaf of the thyme plant Thymus vulgaris. Referred to as the heart of good health the initial description of the morphology of the thymus was made by Galen (130-200AD). For many centuries thereafter it was considered only as a vestigial organ. It was much later that its role as an important part of the lymphatic system was established. It is now well understood that T cell precursors derived from the bone marrow undergo maturation by a complex set of processes in the thymus. Subsequently the positively selected thymocytes migrate to the peripheral lymphoid organs (spleen, lymph nodes, Peyer's patches and tonsils). Evidence of the role of thymus on the lymphoid system being endocrine in nature was established in the 1970s. The concept of thymic endocrinology can be structured as follows:
- Endocrine structure and function of the thymus
- Relationship of the systemic hormones with the thymus
- Paracrine and autocrine role of the thymus
Endocrine Structure and Function of The Thymus
Endocrine structure of the thymus
The thyme epithelium comprises of highly specialized cells with a high degree of anatomic, phenotypic and functional heterogeneity. There are 6 types of epithelial cells: Types 1 to 6- subcapsular/ perivascular, cortical, electrondense, deep cortical, medullary and as-sociated with Hassall's corpuscles.1 Thymic epithelial cells (TECs) secrete neuroendocrine self-peptides. These peptides are not secreted according to the classic model of neuroendocrine signalling, but by processing for presentation by, or in association with the thymic major histocompatibility complex (MHC) proteins thereby programming immunological central self-tolerance toward neuroendocrine functions. The transcription of neuroendocrine genes in TECs is under the control of the autoimmune regulator (AIRE) gene/protein.
Endocrine function of the thymus
The thymus produces several thymic hormones. Of these the most important ones are thymulin, thymosin a and thymopoietin, which have actions on both the prothymocytes and the mature T-cells in the periphery. Originally called facteur thymique serique (FTS), thymulin is a metallopeptide hormone consisting of nonapeptide (Glu- Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asp), coupled with zinc. It has a half-life of 10.3 min with a nocturnal surge. The circulating levels of thymulin reach zenith in early postnatal (around 2 pg/ml) life and gradually come down with age (around 0.4 pg/ml in adults between 21 and 65 years of age). Thymosin-A is a 28-amino acid peptidehormone which is hydrophilic and acidic in nature. It is derived from its precursor called prothymosin-A, which is a weakly immunogenic peptide. Thymosin-A has a half-life of 127 min and like thymulin also has a nocturnal surge. Levels are high in neonates and drop rapidly during early childhood. Thymopoietin is a 49-amino-acid polypeptide produced by thymic epithelial cells. THF is an octapeptide found in thymic extracts. The immunomodulatory and anti inflammatory actions of the thymic hormones are listed in Table-1.
Relationship of systemic hormones with the Thymus
Several of the systemic hormones act on the thymus and affect its growth and development as also its functional status. Thymocytes and thymic epithelial cells contain recep-tors for many hormones and peptides.
Relationship with prolactin and growth hormone:
Thymic physiology is intricately associated with both prolactin (PRL) and growth hormone (GH) by the classical endocrine, paracrine as well as autocrine circuits. PRL and GH stimulate the secretion of thymulin, by thymic epithelial cells. The effects of GH on thymulin appear to be mediated by insulin like growth factor (IGF-1). Both PRL and GH can modulate genes which play roles in distinct biological activities of the thymic epithelium like expression of high-molecular-weight cytokeratins in the medulla, expression of extracellular matrix of the thyme epithelial cells etc. Both the hormones also play positive roles in the increase in number, growth and differentiation of thymocytes. Receptors for prolactin and growth hormone have been demonstrated on the thymic cells. Administration of the dopamine receptor agonist bromocriptine has been found to be associated with a dose-dependent decrease in thymulin production.2
Relationship with thyroid hormones
Thymulin levels have been found to be higher in hyperthyroid patients than in normal subjects, whereas hypothyroid patients have lower thymulin levels than normal subjects. A significant correlation has been found between circulating thymulin and serum T4 and T3 levels.3 In vivo treatment with T3 has been associated with enhanced thymulin secretion by TEC through a direct effect on the cell .The opposite effect has been found with propiothiouracil use.4
Relationship with ACTH/ glucocorticoids
Thymulin and thymopentin enhance the levels of Adrenocorticotropic hormone (ACTH). Thymopoietin analogues can increase production of POMC-derived peptides like ACTH and beta-endorphin.5 Thymosin-A has been noted in some studies to have a downregulatory effect on ACTH6 while others have reported that thymosin-A stimulates cortisol release when injected into the cerebral ventricles. ACTH has been associated with inhibition of mitogenesis of immature and mature thymocytes.7 External glucocorticoids cause apoptosis of the thymocytes causing a profound reduction in thymic mass and volume thereby inducing a "hormonal thymectomy". The processes involved in apoptosis have been elucidated in Table-2.
The apoptotic effect of glucocorticoids is particularly marked for the immature thymocyte subpopulation. Steroid treated thymus glands have been found to have decreased germinal centers, increased fat and connective tissue and poorer corticomedullary differentiation.8
Relationship with LH, FSH and sex hormones
Thymic peptides such as thymulin stimulate the release of LH and FSH. A thymosin component peptide, thymosin b,4 appears particularly effective in stimulating the pituitary-gonadal axis by promoting GnRH from the hypothalamus and LH release at the level of the pituitary gland. In vitro studies have shown that Thymulin can cause proliferation of oogonia from fatal rat ovaries and gonocytes from foetal rat testicles.9,10 Conversely it has also been noted that physiological concentrations of estradiol, progesterone and testosterone enhance thymulin release in TEC cultures.11 Progesterone (in vivo) levels and testosterone (in vivo and vitro) can be increased by thymulin.12
Relationship with oxytocin
Production of IL-6 and LIF by primary cultures of human thymus epithelial cells have been found to be increased with addition of monoclonal antibodies to oxytocin suggesting that the secretion of these cytokines from the thymus is partially under the control of oxytocin.14
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