Thymic hormones and factors

Several polypeptides have been extracted, mainly from the thymus glands of young calves, and some of them have been successfully isolated and prepared synthetically (Table 1). A variety of these compounds exhibit immunobiological activity, although the precise role of many of the factors purported to have intrathymic effects is still unknown. They include thymulin, thymopoietin, thymic humoral factor (THF) and thymosins. So far, only thymulin is recognized as a hormone in accordance with the classical endocrine and physiological criteria, i.e. it is thymus restricted and regulated in its secretion. Thymectomy does not remove the presence of the other thymic factors from serum, and their genes are expressed in other nonthymic tissues. It must be remembered, however, that these criteria are under revision and, for example, in the same way, it is now realized that the lymphocytes produce serotonin and other neural peptides that once were thought to be confined to the nervous system. Other peptides may act as components of the extracellular matrix.

Another central question remaining about these

Table 1 Thymic peptides

Name

Chemical properties

Thymopoietin

Thymopentin (TP5) Thymic humoral factor (THF)

THF-y2

Thymulin (Zn-FTS)

Polypeptide of 28 residues.

3.1 kDa; pi 4.2. Sequence determined

Polypeptide of 109-111 amino acids, exhibiting Tu1 at N-terminal position. 13 kDa; pi 3.5. Sequence determined Polypeptide of 49 residues. 5-6 kDa; pi 5.5. Sequence determined Pentapeptide fragment of thymopoietin residues 32-36 Polypeptide of 31 residues.

3.2 kDa; pi 5.7. Sequence determined

Octapeptide. 918 Da. Sequence determined Nonapeptide. 857 Da; pi 7.5. Sequence determined factors is whether they only possess intrathymic activities or whether they are secreted to act on distal sites.

Thymulin

Initially called 'facteur thymique serique', thymulin was originally purified from porcine and human serum and from calf thymus. An important characteristic of thymulin is that it is biologically active only when coupled in an equimolar ratio with zinc; patients with Crohn's disease or acute lymphoblastic leukemia are zinc deficient and have a reduction in thymulin activity. The presence of an altered zinc status is also found in the elderly.

Thymulin appears to be synthesized and released by a subpopulation of TECs. It helps regulate the differentiation of an immature thymocyte subpopulation and also the function of mature T and natural killer (NK) cells by binding to a membrane receptor with high affinity. The production of thymulin is under pleiotropic control, involving the levels of thymulin itself and of other hormones such as prolactin, growth hormone (GH) through insulin-like growth factor I (IGF-I) secretion, adrenocorticotropin (ACTH), thyroxine (T4), the opioids ^-endorphin and leu-enkephalin, and cytokines II-la and 3.

Behavioral results support these physiological im-munoneuroendocrine connections. The serum levels of this peptide decrease with age, coincidental with thymic atrophy. However, aged thymus retains the capacity to increase thymulin secretion in response to GH and T4.

Thymic humoral factor

Trainin and colleagues isolated a crude extract of calf thymus, THF, and, by various chromatographic systems, subsequently the octapeptide THFy2. Both enhance lymphocyte proliferation and IL-2 production by spleen cells from neonatally thymecto-mized mice or from immunocompromised patient's lymphocytes.

However, THFy2 was not detected in TECs grown in culture, and its serum levels are not reduced by thymic involution or thymectomy.

Thymopoietin

G Goldstein and coworkers isolated thymopoietin from calf thymus by its neuromuscular effect. Later it was found that thymopoietin binds cell membrane receptors present on prothymocytes and on mature T cells and certain T cell lines, involving, respectively, stimulation of adenylate or guanylate cyclase.

Although immunoreactive material was detected in human TEC cultures, thymopoietin mRNA is present in primary and secondary lymphatic tissues as well as other sites, such as striated muscle, heart, small intestine and cerebellum, and is particularly abundant in isolated thymocytes. Moreover, serum levels of thymopoietin are not reduced by thymic involution or thymectomy, and it is localized in the cells intracellularly and no secretagogue has been reported, thus indicating a nonendocrine role.

Three distinct human thymopoietin mRNAs have been described with distinct structural domains and functional motifs, which suggests that the proteins have unique functions and may be directed to distinct subcellular localizations. A nuclear role has been suggested.

Thymopoietin from calf thymus enhances early T ccll differentiation and the expression of specific alloantigens in vitro, perhaps by the same mechanism as the pentapeptide composed of residues 32-36, called thymopentin (TP5), which also has distinct biological properties.

Thymosins

Thymosins are a group of low molecular weight acidic peptides isolated from the original factor thymosin fraction 5 (TF5) extracted from the bovine thymus by AL Goldstein and colleagues. At least 30 different peptides can be identified by isoelectric focusing of TF5, including thymosin al (Tali. £4 (T|34) and MB35. TF5 displays potent stimulatory effects on T cell-mediated immunity, and may he involved in maintaining the size of the thymus and of thymocyte subpopulations. Tal induces the expression of the T cell differentiation antigens Thy-1, CD5 and CDS and increases murine lymphocyte mitogenic responses, antibody and cytokine production. T(34, as Tal, increases terminal deoxvnucle-otidyltransferase (TdT) expression. In addition, multiple effects of these preparations on neuroendocrine function have been identified. For instance, T(34 is able to stimulate luteinizing hormone (LH) secretion from pituitary and LH-releasing hormone from the hypothalamus, MB35 stimulates the production of prolactin and GH, and Tal downregulates thyroid-stimulating hormone (TSH), ACTH and prolactin secretion, at least partially, through hypothalamic pathways.

A full-length cDNA of 1200 bp for Tal has been cloned and studied by Eschenfeldt and colleagues. This cDNA encodes a highly acidic protein of ! I 1 amino acids called prothymosin a (ProTa), which contains Tal in positions 1-28. ProTa has no N-terminal signal peptide, and its mRNA is exclusively located on free polysomes. The ProTa gene belongs to a family of six members, one of which gives rise to two mRNAs. Sequence homologies with other mammalian species are high; it is found in multiple tissues and has a nuclear targeting sequence. Ta I has been localized intracellularly in dense vacuoles within the cytoplasm of TECs but not in the endoplasmic reticulum or Golgi apparatus. These findings suggest a nuclear function for ProTa (which is most likely the active compound) in the regulation of cell proliferation, and Tal is probably a decay product, because a small constitutive production has been observed, although no secretagogue has been identified.

Tal has sequence homologies with the vasoactive intestinal peptide (VIP) family and it is able to function as a VIP receptor antagonist with weak intrinsic activity. Recently, cell surface receptors for ProTa were found and, while not yet fully characterized, they appear to be different to those for Ta I. ProTa also has immunopotentiating activities.

Tp4 is identical to Fx, an actin-sequcstering peptide which is present in many different cell types. The sequence of MB35 is identical to a portion of histone H2A, a component of nuclear protein A24.

Thymic peptides

Mature T cell Macrophage

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