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Homeostasis, thymic hormones and aging.
Gerontology
R G Goya, F Bolognani
The thymic-pituitary axis constitutes a bidirectional circuit where the ascending feedback loop is effected by thymic factors of epithelial origin. The aim of the present article is, first, to introduce the idea of an immune-neuroendocrine homeostatic network in higher animals. Next, the relevance of the thymus in this network and the possible role of this gland in the neuroendocrine imbalances associated with aging are discussed. A number of studies are next reviewed which show that the endocrine thymus produces several bioactive molecules, generally called thymic hormones, which in addition to possessing immunoregulatory properties are also active on nervous and endocrine circuits. In particular, the reported activities of thymosin fraction five, thymosin alpha 1 and thymosin beta 4 on beta-endorphin, adrenocorticotropic hormone, glucocorticoids, luteinizing hormone-releasing hormone and luteinizing hormone secretion in different animal and cell models are reviewed. The known hypophysiotropic actions of other thymic hormones like thymulin, homeostatic thymus hormone and thymus factor are also summarized, and the impact of aging on pituitary responsiveness to thymic hormones is discussed. As a conclusion, it is proposed that in addition to its central role in the regulation of the immune function, the thymus gland may extend its influence to nonimmunologic components of the body, including the neuroendocrine system. The early onset of thymus involution might, therefore, act as a triggering event which would initiate the gradual decline in homeostatic potential that characterizes the aging process.
Pathological and biochemical consequences of acute and chronic neuroinflammation within the basal forebrain cholinergic system of rats.
Neuroscience
L B Willard, B Hauss-Wegrzyniak, G L Wenk
Inflammatory processes may play a critical role in the degeneration of basal forebrain cholinergic cells that underlies some of the cognitive impairments associated with Alzheimer's disease. In the present study, the proinflammagen lipopolysaccharide, from the cell wall of Gram-negative bacteria, was used to produce inflammation within the basal forebrain of rats. The effects of acute, high-dose injections of lipopolysaccharide (2, 20 or 40 microg) upon basal forebrain chemistry and neuronal integrity were compared with the effects of chronic, low-dose lipopolysaccharide infusions (0.18, 0.25, 1.8 or 5.0 microg/h) for either 14, 37, 74 or 112 days. Acute exposure to lipopolysaccharide decreased cortical choline acetyltransferase activity and the number of immunoreactive choline acetyltransferase-positive cells within a small region of the basal forebrain. Regional levels of five different neuropeptides were unchanged by acute, high-dose lipopolysaccharide injections. Chronic lipopolysaccharide infusions produced (i) a time-dependent, but not dose-dependent, decrease in cortical choline acetyltransferase activity that paralleled a decline in the number of choline acetyltransferase- and p75-immunoreactive cells within the basal forebrain, and (ii) a dense distribution of reactive astrocytes and microglia within the basal forebrain. Chronic neuroinflammation might underlie the genesis of some neuropathological changes associated with normal ageing or Alzheimer's disease.
Zinc, T-cell pathways, aging: role of metallothioneins.
Mech Ageing Dev
E Mocchegiani, M Muzzioli, C Cipriano +1 more
Zinc is an essential trace element for many biological functions, including immune functions. Indeed zinc is required for the biological activity of a thymic hormone, called thymulin in its zinc-bound form, important for the maturation and differentiation of T-cells. With advancing age zinc, thymic functions and peripheral immune efficiency show a progressive decline. Supplementing zinc in old age restores them. Zinc is also relevant for liver extrathymic T-cell pathway, being preeminent in old age. Since zinc is also required for metallothioneins (MTs) biological functions, binding zinc with high affinity, aim of the present article is to summarize findings from our laboratory regarding the role of zinc on T-cell pathways, investigating also the possible cause of thymic involution and impaired liver extrathymic T-cell pathway in aging. Partial hepatectomy and liver regeneration are good models for this aim because of the likeness with aging for many immune functions, including thymic functions. MTs levels are increased, other than into the liver, also into the thymus during aging and in young hepatectomized (pHx) mice as compared to young sham controls. MTs may be one of the possible causes of reduced thymic efficiency and impaired liver extrathymic T-cell pathway in old age because of their higher zinc binding affinity rather than thymulin with consequent reduction of the free quota of zinc available for normal cell-mediated immunity. Following that, MTs may contribute to thymic involution and impaired peripheral immune efficiency in aging and in young pHx mice with different roles during the whole life of an organism: protective in young-adult age which may became, at least, dangerous for immune responses in aging. In order to limit or avoid this latter MTs possible role in aging, supplementing physiological zinc may be useful to improve immune responses in old age because of no interference of endogenous zinc on already high thymus MTs levels, but with caution for competition phenomena with copper, as documented in old mice and in syndrome of accelerate aging.
The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-I.
Neuroimmunomodulation
W Burgess, Q Liu, J Zhou +6 more
Why a primary lymphoid organ such as the thymus involutes during aging remains a fundamental question in immunology. Aging is associated with a decrease in plasma growth hormone (somatotropin) and IGF-I, and this somatopause of aging suggests a connection between the neuroendocrine and immune systems. Several investigators have demonstrated that treatment with either growth hormone or IGF-I restores architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old or GH-deficient animals and humans. The proliferation, differentiation and functions of other components of the immune system, including T and B cells, macrophages and neutrophils, also demonstrate age-associated decrements that can be restored by IGF-I. Knowledge of the mechanism by which cytokines and hormones influence hematopoietic cells is critical to improving the health of aged individuals. Our laboratory has recently demonstrated that IGF-I prevents apoptosis in promyeloid cells, which subsequently permits these cells to differentiate into neutrophils. We also demonstrated that IL-4 acts much like IGF-I to promote survival of promyeloid cells and to activate the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). However, the receptors for IGF-I and IL-4 are completely different, with the intracellular beta chains of the IGF receptor possessing intrinsic tyrosine kinase activity and the alpha and gammac subunit of the heterodimeric IL-4 receptor utilizing the Janus kinase family of nonreceptor protein kinases to tyrosine phosphorylate downstream targets. Both receptors share many of the components of the PI 3-kinase signal transduction pathway, converging at the level of insulin receptor substrate-1 or insulin receptor subtrate-2 (formally known as 4PS, or IL-4 Phosphorylated Substrate). Our investigations with IGF-I and IL-4 suggest that PI 3-kinase inhibits apoptosis by maintaining high levels of the anti-apoptotic protein Bcl-2. The sharing of common activation molecules, despite vastly different protein structures of their receptors, forms a molecular explanation for the possibility of cross talk between IL-4 and IGF-I in regulating many of the events associated with hematopoietic differentiation, proliferation and survival.
The thymus-pituitary axis and its changes during aging.
Neuroimmunomodulation
R G Goya, O A Brown, F Bolognani
The pituitary-thymic axis constitutes a bidirectional circuit where the ascending feedback loop is effected by thymic factors of epithelial origin. The aim of the present article is to review the evidence demonstrating that aging brings about a progressive disruption in the integration of this network. In doing so, we briefly review the experimental evidence supporting the view that immune and neuroendocrine aging are interdependent processes. The advantages and limits of the nude mouse as a model of thymus-dependent accelerated aging is also discussed. Next, we review a number of studies which show that the endocrine thymus produces several bioactive molecules, generally called thymic hormones, which in addition to possessing immunoregulatory properties are also active on nervous and endocrine circuits. In particular, the reported activities of thymosin fraction 5 (TF5), thymosin alpha-1 and thymosin beta-4 on beta-endorphin, ACTH, glucocorticoids, LHRH and LH secretion in different animal and cell models are reviewed. The known hypophysiotropic actions of other thymic hormones like thymulin, homeostatic thymus hormone (HTH) and thymus factor are summarized. Aging has a significant impact on pituitary responsiveness to thymic hormones. Thus, it has been reported that TF5 and HTH have thyrotropin-inhibiting activity in young but not in old rats. Furthermore, intravenous administration of HTH was also able to reduce plasma GH and increase corticosterone levels in both young and old rats, although these responses were much weaker in the old animals. Further evidence on this topic is discussed. It is proposed that in addition to its central role in the regulation of the immune function, the thymus gland may extend its influence to nonimmunologic components of the body, including the neuroendocrine system. The early onset of thymus involution might therefore act as a triggering event which would initiate the gradual decline in homeostatic potential that characterizes the aging process.
Galanin inhibits performance on rodent memory tasks.
Ann N Y Acad Sci
M P McDonald, T C Gleason, J K Robinson +1 more
Central administration of galanin produces performance deficits on a variety of rodent learning and memory tasks. Galanin impairs acquisition and/or retention of the Morris water task, delayed nonmatching to position, T-maze delayed alternation, starburst radial maze, and passive avoidance in normal rats. A primary site of action is the ventral hippocampus, with an additional modulatory site in the medial septum-diagonal band. The behavioral actions of galanin at rat septohippocampal sites mediating cognitive processes are consistent with previous reports of inhibitory actions of galanin on acetylcholine release and cholinergically activated transduction at the M1 muscarinic receptor in rat hippocampus. The peptidergic galanin receptor antagonist M40 blocks the inhibitory actions of galanin on memory tasks. Treatment combinations of M40 with an M1 agonist, TZTP, improves performance on delayed nonmatching to position, in rats with 192IgG-saporin-induced cholinergic lesions of basal forebrain neurons. Nonpeptide, bioavailable, subtype-selective galanin receptor antagonists may provide tools to test the hypothesis that antagonism of endogenous galanin, which is overexpressed in the basal forebrain in Alzheimer's patients, can contribute to the alleviation of the cognitive deficits associated with Alzheimer's disease.
Growth hormone-releasing peptide-2 (GHRP-2) does not act via the human growth hormone-releasing factor receptor in GC cells.
Endocrine
C Chen, P Farnworth, S Petersenn +3 more
Effect of growth hormone-releasing peptide-2 (GHRP-2) on ovine somatotrophs is abolished by a growth hormone-releasing factor (GRF) receptor antagonist, which raises the possibility that GHRP-2 may act on GRF receptors. In the present study, we used rat pituitary GC cells with or without stable transfection of cDNA coding for the human GRF receptor (GC/R+ or GC/R-) to determine whether or not GHRP-2 acts via the GRF receptor. Northern blot analysis indicated that GRF receptor mRNA was undetectable in GC/R-cells, whereas a high level of expression occurred in GC/R+ cells that were transfected by GRF receptor cDNA. In GC/R- cells, incubation with up to 10(-7)M of either hGRF or GHRP-2 did not alter the intracellular cAMP, [Ca2+]i, or GH secretion. In GC/R+ cells, hGRF (10(-11)-10(-7)M) increased cAMP levels in a concentration-dependent manner up to 20-fold. This increase in cAMP levels was blocked by a GRF receptor antagonist, [Ac-Tyr1, D-Arg2]-GRF 1-29, but not by a Ca2+ channel blocker, NiCl2 (0.5 mM). GH secretion and [Ca2+]i were, however, not increased by hGRF. Incubation of the transfected cells with 10(-1)-10(-8)MGH RP-2 did not modify intracellular cAMP levels. This result suggests that GHRP-2 does not act through the GRF receptor.
Ipamorelin, the first selective growth hormone secretagogue.
Eur J Endocrinol
K Raun, B S Hansen, N L Johansen +4 more
The development and pharmacology of a new potent growth hormone (GH) secretagogue, ipamorelin, is described. Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2), which displays high GH releasing potency and efficacy in vitro and in vivo. As an outcome of a major chemistry programme, ipamorelin was identified within a series of compounds lacking the central dipeptide Ala-Trp of growth hormone-releasing peptide (GHRP)-1. In vitro, ipamorelin released GH from primary rat pituitary cells with a potency and efficacy similar to GHRP-6 (ECs) = 1.3+/-0.4nmol/l and Emax = 85+/-5% vs 2.2+/-0.3nmol/l and 100%). A pharmacological profiling using GHRP and growth hormone-releasing hormone (GHRH) antagonists clearly demonstrated that ipamorelin, like GHRP-6, stimulates GH release via a GHRP-like receptor. In pentobarbital anaesthetised rats, ipamorelin released GH with a potency and efficacy comparable to GHRP-6 (ED50 = 80+/-42nmol/kg and Emax = 1545+/-250ng GH/ml vs 115+/-36nmol/kg and 1167+/-120ng GH/ml). In conscious swine, ipamorelin released GH with an ED50 = 2.3+/-0.03 nmol/kg and an Emax = 65+/-0.2 ng GH/ml plasma. Again, this was very similar to GHRP-6 (ED50 = 3.9+/-1.4 nmol/kg and Emax = 74+/-7ng GH/ml plasma). GHRP-2 displayed higher potency but lower efficacy (ED50 = 0.6 nmol/kg and Emax = 56+/-6 ng GH/ml plasma). The specificity for GH release was studied in swine. None of the GH secretagogues tested affected FSH, LH, PRL or TSH plasma levels. Administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol. Very surprisingly, ipamorelin did not release ACTH or cortisol in levels significantly different from those observed following GHRH stimulation. This lack of effect on ACTH and cortisol plasma levels was evident even at doses more than 200-fold higher than the ED50 for GH release. In conclusion, ipamorelin is the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH. The specificity of ipamorelin makes this compound a very interesting candidate for future clinical development.
Zinc and immune function: the biological basis of altered resistance to infection.
Am J Clin Nutr
A H Shankar, A S Prasad
Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation.
Zinc, thymic endocrine activity and mitogen responsiveness (PHA) in piglets exposed to maternal aflatoxicosis B1 and G1.
Vet Immunol Immunopathol
E Mocchegiani, A Corradi, L Santarelli +6 more
Growth retardation, thymic involution and impaired peripheral immune efficiency are constant events in piglets exposed to maternal aflatoxicosis. Zinc may play a key role because of its requirement for good immune responses, including thymic endocrine activity. Zinc is required to activate a thymic hormone, i.e. thymulin (ZnFTS), which is responsible for cell-mediated immunity. Zinc deficiency and decreased thymic endocrine activity are present in piglets fed from sows exposed to aflatoxins (AF) B1 and G1 as compared with healthy control piglets. In particular, active ZnFTS is decreased while concentrations of inactive thymulin (FTS) are high. The in vitro addition of zinc up to the plasma samples induces a reduction of inactive thymulin. The lymphocytes mitogen responsiveness (PHA) is decreased and a thymic cortical lymphocyte depletion is also present. These data suggest that the thymic defect, followed by impaired peripheral immune efficiency, may largely depend by the low peripheral zinc bioavailability to saturate all thymulin molecules produced.
Thymic endocrinology.
Ann N Y Acad Sci
J W Hadden
The thymus involutes relatively early in life; cellular immune deficiencies of aging correspond to decline in function of the hypothalamic-pituitary-endocrine axis. Recent studies point to important roles for the pituitary, the pineal, and the autonomic nervous system as well as the thyroid, gonads and adrenals in the thymus integrity and function. Thymic function at the local level requires complex cellular interactions among thymic stromal cells and developing thymocytes involving paracrine and autocrine mediators including interleukins (ILs) 1, 2, 6, 7, 8, colony-stimulating factors (CSFs), interferon-gamma, thymosin alpha 1, and zinc-thymulin. An important endocrine function of the thymus is to package zinc in zinc-thymulin for delivery to the periphery. Thymic involution has been treated with interleukins, thymic hormones, growth hormone, prolactin, melatonin, zinc, and others. Our work to reverse thymic involution in hydrocortisone-treated, aged mice with interleukins, thymosin alpha 1, and zinc will be reviewed. Recent efforts to treat successfully immune deficiency in aged and cancer-bearing humans will be presented.
Coadministration of galanin antagonist M40 with a muscarinic M1 agonist improves delayed nonmatching to position choice accuracy in rats with cholinergic lesions.
J Neurosci
M P McDonald, L B Willard, G L Wenk +1 more
The neuropeptide galanin is overexpressed in the basal forebrain in Alzheimer's disease (AD). In rats, galanin inhibits evoked hippocampal acetylcholine release and impairs performance on several memory tasks, including delayed nonmatching to position (DNMTP). Galanin(1-13)-Pro2-(Ala-Leu)2-Ala-NH2 (M40), a peptidergic galanin receptor ligand, has been shown to block galanin-induced impairment on DNMTP in rats. M40 injected alone, however, does not improve DNMTP choice accuracy deficits in rats with selective cholinergic immunotoxic lesions of the basal forebrain. The present experiments used a strategy of combining M40 with an M1 cholinergic agonist in rats lesioned with the cholinergic immunotoxin 192IgG-saporin. Coadministration of intraventricular M40 with intraperitoneal 3-(3-S-n-pentyl-1,2,5-thiadiazol-4-yl)-1,2,5, 6-tetrahydro-1-methylpyridine (TZTP), an M1 agonist, improved choice accuracy significantly more than a threshold dose of TZTP alone. These results suggest that a galanin antagonist may enhance the efficacy of cholinergic treatments for the cognitive deficits of AD.
New analogs of human growth hormone-releasing hormone (1-29) with high and prolonged antagonistic activity.
J Pept Res
K Toth, M Kovacs, M Zarandi +5 more
Based on our previous results, in conjunction with various structural considerations, 19 new analogs of the GHRH antagonist [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Abu15,Nle27,Agm29]++ +hGHRH(1-29) (MZ-5-156) were synthesized by the solid-phase method. These compounds were designed to develop further analogs of this class with increased receptor-binding affinity. All analogs had Abu15 and Nle27 modifications and were acylated with phenylacetic acid at the N-terminus. Most of the analogs had D-Arg2 and Phe(pCl)6 substituents and Agm29 or Arg29-NH2 at the C-terminus. Additional single substitutions consisted of the incorporation of D- or L-Tic1, D-Tic2, Tic6 or Phe(pNO2)6 and Arg29-NH2. The Arg29-NH2 analog of MZ-5-156 (KT-48) was further modified by single substitutions using Pal1; D-Tpi2; D- or L-Phe4; Phe(pX)6 X = F, Cl, I; Tyr7; Aib8; Tyr(Me)10 or Phe(pCl)10. Four peptides had multiple substitutions. All the analogs were evaluated for their ability to inhibit GH release induced by hGHRH(1-29)NH2 in vitro and some were also tested in vivo. Peptides [PhAc-Tyr1,D-Arg2,Phe(pI)6,Abu15,Nle27]hGHRH(1-2 9)NH2 (KT-30), [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Aib8,Abu15,Nle27] hGHRH(1-29)NH2 (KT-50) and [PhAc-Tyr1,D-Arg2,Phe(pCl)6,Tyr(Me)10,Abu15,Nle27]h GHRH(1-29)NH2 (KT-40) with Phe(pI)6, Aib8 or Tyr(Me)10 modifications, respectively, showed high and prolonged inhibitory effect in superfused rat pituitary system. Analog KT-50 also exhibited a strong and long-term inhibitory activity in vivo in rats. Most of the new analogs showed high binding affinities to rat pituitary GHRH receptors.
Galanin-acetylcholine interactions in rodent memory tasks and Alzheimer's disease.
J Psychiatry Neurosci
M P McDonald, J N Crawley
Galanin is a 29-amino-acid neuropeptide that is widely distributed in the mammalian central nervous system. Galanin-immunoreactive cell bodies, fibres and terminals, and galanin binding sites, are located in the basal forebrain of rats, monkeys and humans. Galanin fibres hyperinnervate the surviving cholinergic cell bodies in patients with Alzheimer's disease (AD). In rats, galanin inhibits acetylcholine release and produces deficits in learning and memory. These findings suggest that overexpressed galanin may contribute to the cognitive impairments exhibited by patients with AD. This paper reviews the literature on galanin distribution and function in light of its putative role in the mnemonic deficits in patients with AD, the effects of galanin on tests of learning and memory, and preliminary experiments with galanin antagonists in animal models of AD.
The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-L-prolylglycine.
Eur J Drug Metab Pharmacokinet
T A Gudasheva, S S Boyko, R U Ostrovskaya +7 more
The metabolism of a new piracetam analogue, the dipeptide cognitive enhancer N-phenylacetyl-L-prolylglycine ethyl ester (GVS-111) was studied in vivo. GVS-111 itself was not found in rat brain 1 h after 5 mg/kg i.p. administration up to limit of detection (LOD) under high performance liquid chromatography (HPLC) conditions. Three substances corresponding to the three possible GVS-111 metabolites, namely phenylacetic acid, prolylglycine and cyclo-prolylglycine, were found in experimental rat brain samples as well as in controls using HPLC, gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) methods. Only cyclo-prolylglycine concentration increased (2.5-fold) 1 h after GVS-111 administration. Cyclo-prolylglycine formation from GVS-111 in the presence of plasma and brain enzymes was shown in vitro. These data could be considered as evidence that GVS-111 is prodrug which converts in the body to cyclo-prolylglycine, and which is identical to the endogenous cyclopeptide that produces the nootropic activity.
Effect of neuropeptides on cognitive function.
Exp Gerontol
G W Bennett, T M Ballard, C D Watson +1 more
Recent evidence indicates that, in addition to the involvement of cholinergic and other neurotransmitter systems, various neuropeptides that occur in cortical and subcortical brain regions have a role in cognitive behavior. This evidence results largely from behavioral studies in rodents and other animals, following peptide administration and only in a very few cases from similar studies in human subjects. Several neuropeptides studied appear to enhance or produce changes conducive to improvement in cognitive performance and these include vasopressin, corticotrophin-releasing hormone (CRH), somatostatin, substance P, neuropeptide Y, and thyrotrophin-releasing hormone (TRH), while one peptide, galanin, has been reported to inhibit cognitive processes. Of those neuropeptides that improve performance, only TRH has been shown recently to attenuate the memory impairment of human subjects and Alzheimer patients treated with an anticholinergic drug, and this review describes a series of complimentary studies in adult and aged rodents that contribute to our understanding of the possible mechanisms involved in the role of TRH in cognition.
Zinc and metallothioneins on cellular immune effectiveness during liver regeneration in young and old mice.
Life Sci
E Mocchegiani, D Verbanac, L Santarelli +4 more
Partial hepatectomy in young mice (pHx) induces thymic atrophy, disregulation of thymocytes subsets and a strong accumulation of zinc in thymic tissue after 1-2 days of liver regeneration. Zinc is relevant for good immune functioning. Restoration of zinc into both the thymus and thymocytes subsets in the late period of liver regeneration is observed in young pHx mice. These findings have suggested a link between the thymus and the liver influencing T-cell functions and involving zinc. This kind of link could be relevant in aging because thymic involution, negative crude zinc balance and crippled immune functions are constant events. The preminence of a liver extrathymic T-cell pathway after pHx or during aging has been suggested. Thus the study of pHx in young and old mice may offer a good model to better understand the role played both by thymic involution and by liver extrathymic T-cell pathway and the role of zinc in these physiological processes during aging. Young pHx mice after 1-2 days of liver regeneration show: reduced thymic endocrine activity, increment of double negative (DN) thymocytes subsets, impairment of peripheral immune efficiency (PHA, NK activity and IL-2) and negative crude zinc balance, which are all restored in the late period of liver regeneration. By contrast the thymic and peripheral immune defects and the negative crude zinc balance, already present in old sham mice, are not modified during liver regeneration in old pHx mice. Circulating leukocytes and lymphocytes are not significantly modified both in young and old pHx mice as compared to respective sham controls. Zinc may also be crucial for extrathymic T-cells pathway, being preminent in aging, rather than in young age, due to its metallothioneins (MT) binding capacity. MT are significantly increased in young pHx and in aging inducing a low zinc-free quota for thymic and peripheral immune efficiency in young pHx mice, and for extrathymic T-cell pathway, in old age. Thus low zinc bioavailability, due to MT, may play a pivotal role, not only for thymocytes but also for liver extrathymic T-cell pathway.
Zinc-controlled Th1/Th2 switch significantly determines development of diseases.
Med Hypotheses
J E Sprietsma
Functional, excessive-possibly temporary-deficiencies of the trace element zinc can change immune functions prematurely from predominantly cellular Th1 responses to humoral Th2 responses. T helper (Th1) cells produce cytokines such as interleukin-2 (IL-2) and interferon gamma, thereby controlling viral infections and other intracellular pathogens more effectively than Th2 responses through cytokines such as IL-4, IL-5, IL-6 and IL-10. The accelerated shift from the production of extra Th1 cells during these cellular immune activities to more Th2 cells with their predominantly humoral immune functions, caused by such a zinc deficiency, adversely influences the course of diseases such as leprosy, schistosomiasis, leishmaniasis and AIDS, and can result in allergies. It is noteworthy that AIDS viruses (HIVs) do not replicate in Th1 cells, which probably contain more zinc, but preferentially in the Th0 and Th2 cells; all the more so, because zinc and copper ions are known to inhibit intracellular HIV replication. Considering the above Th1/Th2 switch, real prospects seem to be offered of vaccination against such parasites as Leishmania and against HIVs.
The somatotropic axis in neonatal calves can be modulated by nutrition, growth hormone, and Long-R3-IGF-I.
Am J Physiol
H Hammon, J W Blum
Effects on the somatotropic axis [plasma levels of insulin-like growth factors (IGFs) I and II, IGF-binding proteins (IGFBPs), and growth hormone (GH)] of feeding different amounts of colostrum or milk replacer, of Long-R3-IGF-I (administered subcutaneously or orally; 50 micrograms.kg body wt-1.day-1 for 7 days), and of subcutaneously injected recombinant bovine GH (rbGH; 1 mg.kg body wt-1.day-1 for 7 days) were evaluated in calves during the 1st wk of life. Plasma Long-R3-IGF-I increased after subcutaneous application but not with the oral dose. Endogenous IGF-I was higher in calves fed colostrum six times compared with those fed only milk replacer. Native IGF-I was highest in rbGH-injected calves but was lowered by the subcutaneous injection of Long-R3-IGF-I. IGF-II concentrations were not modified by any of the treatments. IGFBP-2 increased in calves fed only milk replacer and those receiving subcutaneous Long-R3-IGF-I. GH was not modulated by differences in nutrition but increased after rbGH administration and similarly in all groups after intravenous injection of GH-releasing factor analog GRF-(1-29). Parenteral administration of Long-R3-IGF-I decreased GH concentration but did not affect the secretory pattern. The data demonstrate that the somatotrophic axis is basically functioning in neonatal calves and is influenced by nutrition, GH, and Long-R3-IGF-I.
Altered thymic endocrine activity along with impairments of peripheral zinc metabolism and T-lymphocyte populations are associated with myasthenia gravis: a follow-up study.
J Neuroimmunol
F Licastro, E Mocchegiani, N Fabris +6 more
Thymic endocrine activity was assessed by a bioassay to determine the basal activity of thymulin (TH), a zinc dependent hormone, and its in vitro reactivation in two different age groups of patients with myasthenia gravis (MG). Before thymectomy, basal TH plasma levels were increased in patients over the age of 50 years. Plasma zinc levels were increased in all patients, this increment being very high in old patients. One year after thymectomy both TH and zinc plasma levels decreased. While zinc plasma levels were within the normal ranges for their respective ages, TH levels were lower in young and higher in old patients than in age comparable controls. Young patients with MG showed increased CD3,DR positive peripheral T-cells as well as lymphocytes with the CD16,CD56 phenotype. An increment of CD3 positive cells along with CD4 and CD16,CD56 positive cells were found in older patients. Thymectomy partially affected blood lymphocyte representation only in young patients, since CD3,DR T-cells decreased one year after surgery. No significant variations in T-cell representation were found in old patients after thymectomy. Immunosuppression in thymectomized patients did not significantly affected TH and zinc plasma levels. Very high levels of TH and the presence of additional alterations in T-lymphocyte subsets in old patients suggested that differential age related pathogenetic immunological mechanisms might be associated with the disease.