[Studies on endocrine regulation of hemopoiesis; effect of thyroid, parathyroid, and thymus hormones].
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Increased level of serum thymic activity and normal serum concentration of alpha-1-thymosin were revealed in inhabitants of region polluted by radionuclides after Chernobyl accident (settlement Vyshkov, Bryansk region). In the same population the serum level of autoantibodies, reacting with thymic epithelial cell line was elevated. Similar but less prominent alterations were found in population of radiologically pure region (settlement Potchep). Revealed autoantibodies had mainly IgM isotype. The negative correlation exists between levels of autoantibodies and serum thymic activity. Sera of persons from the control group and one half of Vyshkov inhabitants reacted with thymic epithelial cells of both human and mouse origin; in other half of Vyshkov inhabitants species-specific autoantibodies were revealed. We propose that correlated increase of antithymic autoantibody level and decrease of serum thymic activity are the consequence and indicators of unfavorable ecological conditions; however the contribution of radiation factor to their induction can not be estimated on the basis of presented data.
In animals with a deficit of thymus hormones there are detected activation of lipid peroxidation processes, changes in activity of key enzymes of energy-supplying tracts of anaerobic and pentose cycles along with antioxidative protection and ionic content of erythrocytes. Apparently thymus removal, causing its hormones' deficit and disturbances in the system of neurohormonal regulation, modified the synthesis and activity of key metabolic enzymes. The character of biochemical shifts in erythrocytes of the animals with a deficit of thymus hormones during their adaptation to physical load demonstrated functional stress of protective mechanisms and disorders of adaptative blood reactions.
The influence of thymus hormone preparations on NK cell activity was studied. The following preparations were used: crude extract from calf thymus (TFX), its fraction V (TFX V) and synthetic pentapeptide (TP-5) fragment of native hemopoietin. It was shown that all preparations under study activate NK cells in vitro. The weakest effect was observed in the case of TFX, while both TFX V and TP-5 showed equally good stimulatory properties. The obtained results are discussed. The weak effect of the crude TFX is probably caused by the fact that it contains only 15% of fraction V which is responsible for affinity to the immune system.
The two major constituents in preparations of the homeostatic thymus hormone (HTH) were purified. Amino acid sequence analysis showed that the components (HTH alpha and HTH beta) are identical to histones H2A and H2B, suggesting the possibility that histones might have hitherto unrecognized occurrence and functions. If the HTH activities are not ascribed to the two histones in the preparation, they could only be derived from minor constituents present in minimal amounts. Therefore, the histone structures were scrutinized for properties of relevance in relation to hormone activities and for similarities with thymic hormones. Similarities between COOH-terminal regions of histones H2A, H2B, and H3 were noticed, as well as some similarities between NH2-terminal regions of histones and parts of recognized thymus hormones and related proteins. Potential signals, resembling cleavage sites in prohormones, are present in the histone structures, and further correlations with recently discovered ubiquitin functions may explain molecular mechanisms for actions of the HTH preparations. None of the observations is significant by itself, but the combined results suggest the hypothesis of different relationships and functions, including hormone-like activities, for some histones.
There is increasing evidence that the neuroendocrine system is responsive to hormonal signals generated by the immune system. Thus, interleukin-1, hepatocyte stimulating factor and thymosin have been shown to stimulate adrenocorticotropin, beta-endorphin and luteinizing hormone secretion. We report here that homeostatic thymus hormone (HTH), a well-characterized thymic preparation, reduces plasma thyrotropin (TSH) and growth hormone (GH) in young (3 months) Sprague-Dawley male rats, but fails to do so (TSH) or has a significantly weaker effect (GH) in old (26 months) animals. Young and old conscious, free-moving rats carrying an indwelling atrial cannula received the substances to be tested via the cannulas. Plasma samples were taken every 30 min for 5 h and hormones were measured by RIA. In the young rats, HTH (8 mg/kg body wt) induced a marked reduction in plasma TSH which was significantly greater than the normal circadian decline observed in saline-injected young controls. The old rats displayed high basal levels of TSH which showed no circadian rhythmicity and did not respond to HTH. Plasma thyroxine (T4) showed a significant age-related reduction but was not affected by HTH. The above dose of HTH significantly reduced plasma GH in young and old rats, but the effect was greater in the young animals. Mean basal levels of plasma GH were significantly lower in old than in young rats. The present results suggest that HTH, whose production by the thymus is known to be stimulated by TSH and GH, is involved in an inhibitory feedback loop regulating plasma TSH and GH in young rats. Our data also suggest an age-related desensitization of the TSH and GH systems to thymic influence in this species.
A variety of thymus hormone preparations, as well as drugs known to perturb cell differentiation, were tested for their ability to induce nonfunctional cortical thymocytes to become functional precursor cells. Murine cortical thymocytes, defined as the high peanut agglutinin (PNA) binding or as the low H-2K, major [86%] thymocyte subpopulation, were isolated by fluorescence-activated cell sorting. Their function was assessed in a high cloning efficiency, growth factor saturated, concanavalin A-stimulated limit-dilution culture system, determining the number of precursors of extended clones (PTL-p), or determining with a lectin-mediated tumor-lysis readout the number of precursors of cytolytic clones (CTL-p). The hormone preparations tested were crude or partially purified culture supernatants from thymus "epithelial" monolayers (TES), soluble extracts of thymic nonlymphoid tissue (STF), semipure thymus humoral factor (THF), and the pure peptides thymopoietin 32-36 (TP5) and "facteur thymique sérique" (FTS). These preparations were either added directly to the limit dilution cultures, or were first preincubated with the cells, which were then subjected to limit-dilution culture. In no case did the hormone preparations cause any increase in the level of PTL-p or CTL-p in the PNA+ or low H-2K thymocyte population, even though a conversion of only a few percent to functional cells could have been detected. Two possible explanations are considered. One is that the main function of these materials is to control post-thymic peripheral T cells, rather than to induce intrathymic differentiation. Another is that the typical cortical thymocyte is beyond the stage at which thymocytes can be induced by hormones, a view that is strengthened by the failure of either 5-azacytidine or the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate to activate these cells. In this latter explanation the true intrathymic target of hormone action may be an earlier, and very minor, thymus subpopulation.
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There is increasing evidence that the neuroendocrine system is responsive to hormonal signals generated by the immune systems. In particular, interleukin-1 and thymosin have been shown to stimulate the pituitary-adrenal axis in young animals. We report here that homeostatic thymus hormone (HTH), a well-characterized thymic preparation, increases plasma levels of corticosterone but not prolactin (PRL) in a dose- and age-dependent manner in male Sprague-Dawley rats. Young (3 months) and old (26 months) conscious, free-moving animals carrying an indwelling atrial cannula received the substances to be tested via the cannulas. Plasma samples were taken every 30 min for 5 h and hormones were measured by radioimmunoassay. HTH doses of 1 and 8 mg/kg body weight injected into young rats elicited a 7.8- and 12.8-fold increase in plasma corticosterone, respectively, as compared to saline-injected controls. The HTH-induced peak corticosterone levels were reached within 1.5 and 2.5 h after HTH injection. Plasma PRL was not affected by HTH in either age group. A single dose of 8 mg HTH/kg body weight induced a smaller corticosterone response in old than in young rats, although the time course of the response was similar in both age groups. The present results further suggest the existence of a lymphoid-neuroendocrine axis in young animals. The data also suggest that a disruption in immune-endocrine integration occurs during aging in rats.
The primary structures of the 2 polypeptide chains (HTH alpha and HTH beta) of the homeostatic thymus hormone (HTH) were determined. The entire structures were found to be identical to those of histones H2A and H2B, respectively, without evidence for sub-types, proteolytic processings, or other peptide fragments. The results show that suggestions for new extranuclear and hormone-like histone functions apply to HTH preparations with intact protein chains of the H2 histones.
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