Possible underlying mechanisms of sexual dimorphism in the immune response, fact and hypothesis

It is a confirmed fact that in females both the humoral and cell mediated immune response is more active than in males. A large amount of information supports the view that hormones of the endocrine system are intimately involved in this immunological dimorphism. Such hormones include the gonadal steroids, the adrenal glucocorticoids, growth hormone (GH) and prolactin (Prl) from the pituitary, thymic hormones, and substances generated by activated lymphocytes. It is suggested that a complex medley of these hormonal interactions effect both developing lymphocytes within the microenvironment and regulate adult effector cells. The most important of these hormonal interactions leading to immunological dimorphism are the effects elicited by estrogen (E) elaborated at elevated levels from the female ovary after puberty. Elevated E leads to basal GH secretion, increased Prl, and increased thymosin release, all of which are hypothesized to effect lymphocyte development and stimulate adult T- and B-cell function in females. Interactions of hormonal regulatory axes involving the hypothalamus, pituitary, gonads, adrenals, and thymus are also thought to be involved. Factors elaborated by activated immune cells including IL-1 and IL-2 may also play a role in down regulation of these responses. Finally, genetic components are also considered pertinent especially under conditions of pathological disequilibrium leading to autoimmune disease. While the benefits provided by immunological dimorphism are still not entirely clarified, since sex hormones are intimately involved in immunological regulation it is quite possible that the increased immune response in females allows them to compensate for the increased physiological stress which accompanies reproduction. The final outcome would thus be the assurance of reproductive success of the species.     

Distribution of ACTH-like immunoreactivity in rat brain and gastrointestinal tract

Summary Immunocytochemistry reveals ACTH-like immunoreactivity to reside not only in the pituitary but also in central nerves and in antral gastrin cells. In all probability, the central nerves store a peptide identical with or closely resembling true ACTH. Their pattern of distribution is, in some regions, similar to that of enkephalin-immunoreactive nerves. The antiserum demonstrating ACTH-like immunoreactivity in central nerves and in antral gastrin cells is directed towards the COOH-terminal part of the hormone. A peptide corresponding to this part, the corticotrophin-like intermediate peptide (CLIP) is manufactured by the pars intermedia of the pituitary. CLIP is devoid of adrenocortical activity but has recently been shown to possess insulin-releasing activity. The occurrence of CLIP-like peptides in antral gastrin cells may indicate a role for such peptides in the gastrointestinal regulation of insulin release. The simultaneous occurrence of enkephalin-like and ACTH-like immunoreactivity in the antral gastrin cells is of particular interest since a large precursor molecule, containing both the enkephalin and the ACTH sequence has recently been identified.     

Relation of endogenous opioid peptides and morphine to neuroendocrine functions.

Morphine and the endogenous opioid peptides (EOP) exert similar effects on the neuroendocrine system. When adminstered acutely, they stimulate growth hormone (GH), prolactin (PRL), and adrenocorticotropin (ACTH) release, and inhibit release of luteinizing hormone (LH), follicle stimulating hormone (FSH),and thyrotropin (TSH). Recent studies indicate that the EOP probably have a physiological role in regulating pituitary hormone secretion. Thus injection of naloxone (opiate antagonist) alone in rats resulted in a rapid fall in serum concentrations of GH and PRL, and a rise in serum LH and FSH, suggesting that the EOP help maintain basal secretion of these hormones. Prior administration of naloxone or naltrexon inhibited stress-induced PRL release, and elevated serum LH in castrated male rats to greater than normal castrate levels. Studies on the mechanisms of action of the EOP and morphine on hormone secretion indicate that they have no direct effect on the pituitary, but act via the hypothalamus. There is no evidence that the EOP or morphine alter the action of the hypothalamic hypophysiotropic hormones on pituitary hormone secretion; they probably act via hypothalamic neurotransmitters to influence release of the hypothalamic hormones into the pituitary portal vessels. Preliminary observations indicate that they may increase serotonin and decrease dopamine metabolism in the hypothalamus, which could account for practically all of their effects on pituitary hormone secretion.     

Histochemistry and function of bombesin-like peptides

Bombesin-like peptides are a group of brain-gut peptides found in several neuronal groups in the central nervous system and in peripheral intrinsic gut neurons and sensory neurons. The SIF cells (small intensely fluorescent cells) of the sympathetic ganglia also contain immunoreactivity for these peptides. These peptides are present in some pulmonary endocrine cells and tumors originating from these cells. Chromatographic studies suggest that several different peptides, possibly originating from at least two different precursors, are present in mammalian tissues. Authentic amphibian peptide bombesin does not appear to be found in mammalian tissues. Functional studies indicate that these peptides may be involved in many important functions, including sensory transmission, regulation of central autonomic pathways, thermoregulation, secretion of pituitary hormones, gastric and pancreatic secretion, food intake and satiety.     

Distribution of ACTH-like immunoreactivity in rat brain and gastrointestinal tract.

Immunocytochemistry reveals ACTH-like immunoreactivity to reside not only in the pituitary but also in central nerves and in central nerves and in antral gastrin cells. In all probability, the central nerves store a peptide identical with or closely resembling true ACTH. Their pattern of distribution is, in some regions, similar to that of enkephalin-immunoreactive nerves. The antiserum demonstrating ACTH-like immunoreactivity in central nerves and in antral gastrin cells is directed towards the COOH-terminal part of the hormone. A peptide corresponding to this part, the corticotrophin-like intermediate peptide (CLIP) is manufactured by the pars intermedia of the pituitary. CLIP is devoid of adrenocortical activity, but has recently been shown to possess insulin-releasing activity. The occurrence of CLIP-like peptides in antral gastrin cells may indicate a role for such peptides in the gastrointestinal regulation of insulin release. The simultaneous occurrence of enkephalin-like and ACTH-like immunoreactivity in the antral gastrin cells is of particular interest since a large precursor molecule, containing both the enkephalin and the ACTH sequence has recently been identified.     

Gastrin and ACTH-like immunoreactivity occurs in two ultrastructurally distinct cell types of rat antropyloric mucosa

Summary The properties of endocrine cells of rat antropyloric mucosa, which simultaneously store both gastrin and ACTH-like immunoreactivity have been examined. In freely fed animals all or nearly all antral gastrin cells contain also large quantities of ACTH-like immunoreactivity. Following three days of fasting the gastrin cell content of ACTH-like peptides is drastically reduced, but increases rapidly upon refeeding of the starved animals for 30 min. At the electron microscopical level, the vast majority of cells storing both gastrin and ACTH-like peptides are identified as G cells but, in addition, a few, previously unrecognized, endocrine cells have also been found to store both types of peptides. The latter new cell type has tentatively been labelled the G_a cell. In normal freely fed animals the G cell is characterized by the occurrence of both electron-dense and electron-lucent granules. Correlative immunocytochemical and ultrastructural studies indicate that gastrin and the ACTH-like peptides are both stored in the cytoplasmic granules. Our results indicate that the gastrin cells release their content of ACTH-like peptides in response to fasting and that this release is blocked by refeeding. The differential release of two hormone-like substances from the same endocrine cell type is of great interest for analysis of mechanisms of peptide hormone release.     

The immune system as a regulator of thyroid hormone activity

It has been known for decades that the neuroendocrine system can both directly and indirectly influence the developmental and functional activity of the immune system. In contrast, far less is known about the extent to which the immune system collaborates in the regulation of endocrine activity. This is particularly true for immune-endocrine interactions of the hypothalamus-pituitary-thyroid axis. Although thyroid-stimulating hormone (TSH) can be produced by many types of extra-pituitary cells--including T cells, B cells, splenic dendritic cells, bone marrow hematopoietic cells, intestinal epithelial cells, and lymphocytes--the functional significance of those TSH pathways remains elusive and historically has been largely ignored from a research perspective. There is now, however, evidence linking cells of the immune system to the regulation of thyroid hormone activity in normal physiological conditions as well as during times of immunological stress. Although the mechanisms behind this are poorly understood, they appear to reflect a process of local intrathyroidal synthesis of TSH mediated by a population of bone marrow cells that traffic to the thyroid. This hitherto undescribed cell population has the potential to microregulate thyroid hormone secretion leading to critical alterations in metabolic activity independent of pituitary TSH output, and it has expansive implications for understanding mechanisms by which the immune system may act to modulate neuroendocrine function during times of host stress. In this article, the basic underpinnings of the hematopoietic-thyroid connection are described, and a model is presented in which the immune system participates in the regulation of thyroid hormone activity during acute infection.     

Cell Volume-Induced Hormone Secretion: Signal Transduction and Specificity

Maintenance of the cell volume within physiological limits under anisosmotic conditions is an important prerequisite for survival and functioning of the cell. Cell volume alterations are also involved in numerous cellular events and are recently considered to be integrated into a physiological signal transduction network. Cell swelling induced by anisosmotic environment, hormones, oxidative stress, or substrate uptake evokes an immediate secretory burst of the material (peptide hormones, enzymes) stored in secretory vesicles from various types of cells (endocrine cells, neurons, leukocytes, exocrine pancreatic cells). The dynamics of this secretion are indistinguishable from those induced by specific secretagogues. This regulated secretion does not require a rise in the intracellular Ca²⁺. Using various tissues (pituitary, pancreatic islets, brain structures), hormones (prolactin, insulin, thyrotropin - releasing hormone - TRH, oxytocin), and inhibitors, we found that hormone secretion induced by cell swelling is not depressed by inhibition of stretch-activated channels (GdCl₃), mercury-sensitive aquaporins, protein kinase C (bisindolylmaleimide), microtubules and microfilaments (colchicine, cytochalasin)and does not involve arachidonic acid metabolites, prostaglandins and leukotrienes (indomethacin, NDGA). The blockade of Na⁺-K⁺-dependent ATPase, that of Na⁺ channels, or that of K⁺ channels exerted no effect on hyposmolarity-induced hormone secretion in pituitary cells. Norepinephrine, a physiological inhibitor of secretion of insulin, did not inhibit hypotonicity-induced secretion from pancreatic islets. The participation of such a general biophysical phenomenon in physiological reactions raises a question of its specificity. Cell swelling induced by an isosmotic ethanol-containing medium evoked release of TRH from hypothalamic paraventricular nucleus and posterior pituitary, while oxytocin (known to be engaged in the water and salt regulation) release was not stimulated. Neirofiziologiya/Neurophysiology, Vol. 37, No. 2, pp. 177–180, March–April, 2005.     

Immunohistochemical localization of hormones and peptides in the human pituitary cells in a case of hypercortisolism by ACTH secreting microadenoma

This study assesses the action of hypercortisolism on the hormone and peptide periadenoma region of removed ACTH-producing microadenoma. Our findings show that cortisol excess affects both ACTH and GH production, with no immunoreaction for these hormones. The remaining pituitary hormones (TSH, FSH and PRL) and POMC-derived peptides (betaEnd, alphaMSH and betaMSH) were not modified. Likewise, we observed pituitary immunoreactive cells for Neurotensin (NT), Intestinal vasoactive peptide (VIP), Substance P (SP) and Angiotensin-II (Ang-II). The colocalization demonstrated that NT was expressed in thyrotrope and gonadotrope cells, VIP in gonadotrope cells and SP in corticotrope cells. The results about Ang-II were inconclusive. On the other hand, immunoreaction for the NPY and Gal peptides were not present. In the adenomatous cells, the peptide NT is present in ACTH cells as well as SP. These results suggest a peptide regulation of pituitary cells in the pathological state that can differ between normal and tumoural cells of the same pituitary.     

Rat atrial natriuretic factor suppresses proopiomelanocortin-derived peptides secretion from both anterior and intermediate lobe cells and growth hormone release from anterior lobe cells of rat pituitary in vitro

Synthetic rat atrial natriuretic factor (ANF) was found to attenuate, in a dose-dependent manner, basal and corticotropin-releasing factor-induced secretion of proopiomelanocortin-derived peptides from cultured anterior and intermediate lobe cells of rat pituitary. ANF was also found to suppress basal and growth hormone-releasing factor-stimulated secretion of growth hormone from anterior lobe cells of rat pituitary. These results, together with reports of the existence of ANF-positive neurons in the hypothalamus and ANF-positive fibers in the median eminence, suggest that hypothalamic ANF is probably involved in the regulation of pituitary hormone secretion, especially that of proopiomelanocortin-derived peptides and growth hormone.     

Actions of PACAP and VIP on melanotrope cells of Xenopus laevis

The neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are implicated in the regulation of gene expression and hormone secretion in mammalian melanotrope cells and a mammalian pro-opiomelanocortin (POMC)-producing tumor cell line, but the physiological relevance of this regulation is elusive. The purpose of the present study was to establish if these peptides affect biosynthetic and secretory processes in a well-established physiological model for endocrine cell functioning, the pituitary melanotrope cells of the amphibian Xenopus laevis, which hormonally control the process of skin color adaptation to background illumination. We show that both PACAP and VIP are capable of stimulating the secretory process of the Xenopus melanotrope cell. As the peptides are equipotent, they may exert their actions via a VPAC receptor. Moreover, PACAP stimulated POMC biosynthesis and POMC gene expression. Strong anti-PACAP immunoreactivity was found in the pituitary pars nervosa (PN), suggesting that this neurohemal organ is a source of neurohormonal PACAP action on the melanotropes in the intermediate pituitary. We propose that the PACAP/VIP family of peptides has a physiological function in regulating Xenopus melanotrope cell activity during the process of skin color adaptation.     

Adenohypophysial cell types in the lamprey pituitary: current state of the art

Adenohypophysial cell types in the pituitary of adult sea lampreys, Petromyzon marinus, was localized by means of immunocytochemical and lectin cytochemical techniques. At least four types of adenohypophysial hormone cells are present in the pituitary of adult sea lampreys. The first type of cell is ACTH-like and occupies most parts of the rostral pars distalis (RPD), but a few scattered ACTH-like cells are also present in the proximal pars distalis (PPD). The second type of cell is MSH-like and occupies the whole pars intermedia. The third type of cell is GH/PRL-like and occupies the dorsal half of the PPD. These GH/PRL-like cells were initially detected by heterologous immunocytochemistry using antibodies to salmon GH, salmon PRL and blue shark GH, after hydrated autoclave pretreatment of sections. Later, by use of an antiserum raised against a synthetic peptide corresponding to the partial sequence of lamprey GH/PRL, the same cells as those containing GH/PRL-like immunoreactivity were stained positively. Similarity of the topographic distributions between lamprey GH/PRL-like cells and gnathostome fish GH cells in the pituitary suggests that GH/PRL-like cells in the lamprey may be GH cells. The last type of cell is GTH-like and occupies the ventral half of the PPD. Although GTH has not yet been isolated from the lamprey pituitary, our immunocytochemical data suggest that GTH-like material in the sea lamprey pituitary is more closely related to mammalian-like LH, rather than to FSH or TSH. These four types of adenohypophysial cells occupy most parts of the lamprey adenohypophysis and indeed there is little room for TSH or PRL cells. Thus, the present study further suggests that GH and LH-like GTH are ancestral forms of GH/PRL/SL family and glycoprotein hormones, respectively.     

Intermediate filament expression in non-neoplastic pituitary cells.

Fifty-one non-neoplastic human pituitary glands, including examples with Crooke's hyalinization or amyloidosis, were examined by an immunoperoxidase method using antibodies to keratin, vimentin, neurofilaments (NFs), glial fibrillary acidic protein (GFAP), desmin, actin, S-100 protein and a variety of pituitary hormones. It was confirmed that most of the epithelial cells in the pituitary gland express keratin immunoreactivity. These cells included endocrine cells in the anterior lobe, endocrine cells and squamous metaplastic cells in the pars tuberalis, columnar and ciliated epithelia forming follicular structures and salivary-type epithelium in the pars intermedia, and anterior lobe cells infiltrating the posterior lobe. This study also demonstrated that keratin and NFs may be co-expressed in endocrine cells in the pituitary anterior lobe, that keratin, vimentin and GFAP may be co-expressed in the epithelial cells forming cyst-like follicle in the pars intermedia, and that vimentin and GFAP may be co-expressed in folliculo-stellate cells and pituicytes. In addition, the GFAP and S-100 protein-negative high columnar epithelium in the pars intermedia tended to be positive for adrenocorticotropic hormone and melanocyte stimulating hormone, while the low columnar epithelium with the co-expression of GFAP and S-100 protein was negative for pituitary hormones.     

Cellular distribution of insulin, glucagon, pancreatic polypeptide hormone and somatostatin in the fetal and adult pancreas of the guinea pig: a comparative immunohistochemical study

Antibodies to insulin, glucagon, pancreatic polypeptide hormone and somatostatin were utilized to demonstrate the cellular localization of the hormones in pancreatic tissue of fetal guinea pig of advanced gestation by immunofluorescence histochemistry. The topographical distribution of the 4 endocrine cell types was compared with those of the adult pancreas and was found to be significantly different particularly for cells immunostaining for insulin, glucagon and somatostatin. These observations suggest changes in histogenesis of pancreatic endocrine cells during transition from fetal to postnatal and adult life. The presence of the 4 islet hormones in the fetal pancreas of this species implies that they may be important in fetal metabolism and growth.     

The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas

OBJECTIVES: Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), was recently identified in the stomach. Ghrelin is produced in a population of endocrine cells in the gastric mucosa, but expression in intestine, hypothalamus and testis has also been reported. Recent data indicate that ghrelin affects insulin secretion and plays a direct role in metabolic regulation and energy balance. On the basis of these findings, we decided to examine whether ghrelin is expressed in human pancreas. Specimens from fetal to adult human pancreas and stomach were studied by immunocytochemistry, for ghrelin and islet hormones, and in situ hybridisation, for ghrelin mRNA. RESULTS: We identified ghrelin expression in a separate population of islet cells in human fetal, neonatal, and adult pancreas. Pancreatic ghrelin cells were numerous from midgestation to early postnatally (10% of all endocrine cells). The cells were few, but regularly seen in adults as single cells at the islet periphery, in exocrine tissue, in ducts, and in pancreatic ganglia. Ghrelin cells did not express any of the known islet hormones. In fetuses, at midgestation, ghrelin cells in the pancreas clearly outnumbered those in the stomach. CONCLUSIONS: Ghrelin is expressed in a quite prominent endocrine cell population in human fetal pancreas, and ghrelin expression in the pancreas precedes by far that in the stomach. Pancreatic ghrelin cells remain in adult islets at lower numbers. Ghrelin is not co-expressed with any known islet hormone, and the ghrelin cells may therefore constitute a new islet cell type.     

Cellular and molecular interactions of thymus with endocrine organs and nervous system.

T-cell ontogenesis has been disclosed to depend on the interactions of thymus with endocrine glands and nervous system as follows: i/ Thymic deprivation not only impaired the immunological development but also brought about the dysgenesis of pituitary anterior lobe. Conversely, hypophysectomy resulted in thymus atrophy with the disturbed immune responses. ii/ Binding of pituitary acidophilic cell hormones to their receptors on thymus epithelial cells (TECs) augmented the release of thymic hormonal peptides (THPs) in vitro. iii/ Elevation of blood glucocorticoid level after stress caused atrophy of thymus cortex through double positive thymocyte apoptosis. Morpho-molecular alterations of cytoplasm preceded nuclear damage in the apoptotic thymocytes. iv/ Administration of thymosin to the streptozotocin-induced diabetic mice repressed mononuclear cell infiltration to the pancreatic islets. v/ Autonomic nerve fibers innervate thymic parenchyma. Binding of acetylcholines (Achs) to Ach receptors on TECs enhanced protein synthetic activity which seemed to connect with THP production. vi/ Thymectomy not only depressed the immune responses but also accelerated the reduction of leaming and memory ability with aging. The operation appears to disturb the brain adrenoceptor functions and to suppress the regulatory roles of hypothalamus to other nervous tissues. vii/ Several kinds of THPs, separated from the culture supernatant of TEC line by high performance liquid chromatography, showed a favorable effect on the thymocytes at different stage of differentiation and maturation. viii/ Thymosin, thymulin and THPs were capable of proliferating and differentiating thymocytes in vitro. However, the administration of each thymic product to the thymus-deprived animals could not restore from their "wasting disease". Since TECs are composed of a heterogeneous population, it would be one of essential ways for isolating "true thymus hormone" (TTH) to use the material which consists of functionally homogeneous subset of TECs. ix/ An additional grafting of pituitary gland to the thymus-grafted nude mice improved the disturbed T-cell ontogeny. Accordingly, the administration of "TTH" and pituitary acidophilic cell hormones might be more hopeful procedure for rescuing the thymus-deprived animals from "wasting disease".     

Different ghrelin localisation in adult human and rat endocrine pancreas

Ghrelin is an endocrine peptide that has been identified in gastric oxyntic glands and that induces growth hormone secretion in the pituitary gland. This growth hormone secretagogue is expressed in many tissues such as stomach, pituitary gland, thyroid, testis, placenta and pancreas. Initial studies of ghrelin focused on its role as a circulating orexigenic signal. However, ghrelin has also been found to be involved in the modulation of glucose homeostasis. Although a number of studies have reported ghrelin expression in developing pancreas, the location of ghrelin-immunoreactive cells in adult pancreas (epsilon cells) remains controversial. In this study, we have analysed the distribution of pancreatic epsilon cells in adult human and rat islets by immunohistochemistry and in situ hybridisation. In humans, our immunohistochemical analysis has shown that ghrelin is expressed in glucagon-secreting cells, whereas in rats, it is present in insulin-secreting cells. Similar observations have been revealed by in situ hybridisation.     

Influence of endogenous opiates on anterior pituitary function

In general, the endogenous opioid peptides (EOP), morphine (MOR), and related drugs exert similar effects on acute release of pituitary hormones. Thus administration of opiates produces a rapid increase in release of prolactin (PRL), growth hormone (GH), adrenocorticotropin (ACTH), and antidiuretic hormone (ADH), and a decrease in release of gonadotropins and thyrotropin (TSH). Although not yet fully established, there is growing evidence that the EOP participate in the physiological regulation of pituitary hormone secretion. Thus naloxone (NAL), a specific opiate antagonist, has been shown to reduce basal serum levels of PRL and GH, and to elevate serum levels of LH and follicle stimulating hormone in male rats. Other reports have shown that NAL can inhibit the stress-induced rise in serum PRL, raise the castration-induced increase in serum LH to greater than normal castrate values, and counteract the inhibitory effects of estrogen and testosterone on LH secretion. Opiates appear to have no direct action on the pituitary, but there is evidence that they can alter activity of hypothalamic dopamine and serotonin in modulating secretion of pituitary hormones.