-
Brain, Behavior, and Immunity May 2007A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The... (Review)
Review
A number of observations and discoveries over the past 20 years support the concept of important physiological interactions between the endocrine and immune systems. The best known pathway for transmission of information from the immune system to the neuroendocrine system is humoral in the form of cytokines, although neural transmission via the afferent vagus is well documented also. In the other direction, efferent signals from the nervous system to the immune system are conveyed by both the neuroendocrine and autonomic nervous systems. Communication is possible because the nervous and immune systems share a common biochemical language involving shared ligands and receptors, including neurotransmitters, neuropeptides, growth factors, neuroendocrine hormones and cytokines. This means that the brain functions as an immune-regulating organ participating in immune responses. A great deal of evidence has accumulated and confirmed that hormones secreted by the neuroendocrine system play an important role in communication and regulation of the cells of the immune system. Among protein hormones, this has been most clearly documented for prolactin (PRL), growth hormone (GH), and insulin-like growth factor-1 (IGF-I), but significant influences on immunity by thyroid-stimulating hormone (TSH) have also been demonstrated. Here we review evidence obtained during the past 20 years to clearly demonstrate that neuroendocrine protein hormones influence immunity and that immune processes affect the neuroendocrine system. New findings highlight a previously undiscovered route of communication between the immune and endocrine systems that is now known to occur at the cellular level. This communication system is activated when inflammatory processes induced by proinflammatory cytokines antagonize the function of a variety of hormones, which then causes endocrine resistance in both the periphery and brain. Homeostasis during inflammation is achieved by a balance between cytokines and endocrine hormones.
Topics: Animals; Growth Hormone; Humans; Insulin-Like Growth Factor I; Neuroimmunomodulation; Neurosecretory Systems; Prolactin; Psychoneuroimmunology; Receptors, Cytokine
PubMed: 17198749
DOI: 10.1016/j.bbi.2006.11.010 -
Scientific Reports Jul 2017The hormone prolactin promotes lactational differentiation of mammary epithelial cells (MECs) via its cognate receptor and the downstream JAK2-STAT5a signalling pathway....
The hormone prolactin promotes lactational differentiation of mammary epithelial cells (MECs) via its cognate receptor and the downstream JAK2-STAT5a signalling pathway. In turn this regulates transcription of milk protein genes. Prolactin signalling depends on a cross-talk with basement membrane extracellular matrix (ECM) via β1 integrins which activate both ILK and Rac1 and are required for STAT5a activation and lactational differentiation. Endocytosis is an important regulator of signalling. It can both enhance and suppress cytokine signalling, although the role of endocytosis for prolactin signalling is not known. Here we show that clathrin-mediated endocytosis is required for ECM-dependent STAT5 activation. In the presence of ECM, prolactin is internalised via a clathrin-dependent, but caveolin-independent, route. This occurs independently from JAK2 and Rac signalling, but is required for full phosphorylation and activation of STAT5. Prolactin is internalised into early endosomes, where the master early endosome regulator Rab5b promotes STAT5 phosphorylation. These data reveal a novel role for ECM-driven endocytosis in the positive regulation of cytokine signalling.
Topics: Animals; Biomarkers; Cell Differentiation; Cell Line; Clathrin; Endocytosis; Epithelial Cells; Extracellular Matrix; Female; Gene Knockdown Techniques; Mammary Glands, Animal; Prolactin; RNA, Small Interfering; STAT5 Transcription Factor; Signal Transduction
PubMed: 28676702
DOI: 10.1038/s41598-017-04783-6 -
Proceedings of the National Academy of... Aug 1992Prolactin has been shown to have an immunoregulatory role in the rodent immune response. A prolactin-like molecule has also been found in mouse splenocytes and a human...
Prolactin has been shown to have an immunoregulatory role in the rodent immune response. A prolactin-like molecule has also been found in mouse splenocytes and a human B-lymphoblastoid cell line. We have evaluated whether human peripheral blood mononuclear cells (PBMCs) synthesize and/or secrete prolactin. We used the polymerase chain reaction (PCR) to generate a 276-base-pair prolactin product from human PBMCs, and Southern blot analysis confirmed that it was related to prolactin. Western blotting using a polyclonal antibody to prolactin indicated that cell extracts prepared from human PBMCs contained a high molecular mass (60-kDa) immunoreactive prolactin. To determine whether this PBMC prolactin was being secreted, we developed a highly sensitive and specific hormonal enzyme-linked immunoplaque assay. With this assay, we were able to detect human prolactin secretion from concanavalin A (Con A)- or phytohemagglutinin-stimulated PBMCs but not from unstimulated PBMCs. We next sought to determine whether this secreted prolactin could function as an autocrine growth factor in lymphoproliferation. We observed that anti-human prolactin antiserum significantly inhibited human PBMC proliferation in response to Con A or phytohemagglutinin. We conclude that a prolactin-like molecule is synthesized and secreted by human PBMCs and that it functions in an autocrine manner as a growth factor for lymphoproliferation.
Topics: Base Sequence; Blotting, Southern; Blotting, Western; Cell Line; DNA; DNA Replication; Enzyme-Linked Immunosorbent Assay; Exons; Female; Growth Substances; Humans; Immune Sera; Leukocytes, Mononuclear; Lymphocytes; Molecular Sequence Data; Oligodeoxyribonucleotides; Placenta; Polymerase Chain Reaction; Pregnancy; Prolactin; RNA, Messenger
PubMed: 1502189
DOI: 10.1073/pnas.89.16.7713 -
European Journal of Heart Failure Aug 2010Peripartum cardiomyopathy (PPCM) is a cause of pregnancy-associated heart failure. It typically develops during the last month of, and up to 6 months after, pregnancy in... (Review)
Review
Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy.
Peripartum cardiomyopathy (PPCM) is a cause of pregnancy-associated heart failure. It typically develops during the last month of, and up to 6 months after, pregnancy in women without known cardiovascular disease. The present position statement offers a state-of-the-art summary of what is known about risk factors for potential pathophysiological mechanisms, clinical presentation of, and diagnosis and management of PPCM. A high index of suspicion is required for the diagnosis, as shortness of breath and ankle swelling are common in the peripartum period. Peripartum cardiomyopathy is a distinct form of cardiomyopathy, associated with a high morbidity and mortality, but also with the possibility of full recovery. Oxidative stress and the generation of a cardiotoxic subfragment of prolactin may play key roles in the pathophysiology of PPCM. In this regard, pharmacological blockade of prolactin offers the possibility of a disease-specific therapy.
Topics: Antihypertensive Agents; Cardiology; Cardiomyopathies; Cathepsin D; Europe; Female; Humans; Incidence; Inflammation; Natriuretic Peptide, Brain; Oxidative Stress; Postpartum Period; Pregnancy; Pregnancy Complications; Prognosis; Prolactin; Risk Factors; Societies, Medical
PubMed: 20675664
DOI: 10.1093/eurjhf/hfq120 -
Clinical Endocrinology Dec 2014The peptide hormone kisspeptin is essential for human reproduction, acting on the hypothalamus to stimulate gonadotrophin-releasing hormone (GnRH) secretion. Kisspeptin... (Clinical Trial)
Clinical Trial
BACKGROUND
The peptide hormone kisspeptin is essential for human reproduction, acting on the hypothalamus to stimulate gonadotrophin-releasing hormone (GnRH) secretion. Kisspeptin is currently being evaluated as a novel therapeutic for women with infertility. However, some animal studies suggest that kisspeptin may also stimulate growth hormone (GH), prolactin and thyroid-stimulating hormone (TSH) secretion, with implications for its safety; no previous study has investigated whether kisspeptin stimulates these pituitary hormones in humans.
AIM
To determine whether kisspeptin-54 modulates GH, prolactin and TSH secretion in healthy women.
DESIGN AND PARTICIPANTS
Prospective, single-blinded, placebo-controlled, one-way crossover study. Five healthy women received 7 days of twice-daily subcutaneous bolus vehicle (month 1) or 6·4 nmol/kg kisspeptin-54 (month 2).
MEASUREMENTS
Serum samples were analysed post hoc for GH, prolactin and TSH.
RESULTS
Mean serum GH, PRL and TSH did not change during the first 4 h following kisspeptin-54 injection when compared with vehicle. The mean frequency or amplitude of GH pulses (which influence GH function) did not change acutely following kisspeptin-54 injection when compared with vehicle. No chronic changes in serum GH, PRL or TSH were observed over the 7-day period of twice-daily kisspeptin-54 injections when compared with vehicle.
CONCLUSION
While we cannot exclude any effect of kisspeptin-54 on GH, prolactin or TSH secretion, we observed no significant changes in these hormones at a dose of kisspeptin-54 administration known to stimulate gonadotrophin secretion in a small study of healthy women. These data have important implications for the potential of kisspeptin to treat patients with infertility.
Topics: Adult; Cross-Over Studies; Female; Human Growth Hormone; Humans; Kisspeptins; Prolactin; Single-Blind Method; Thyrotropin; Young Adult
PubMed: 24863252
DOI: 10.1111/cen.12512 -
Reproductive Biology and Endocrinology... May 2006The prostate is a key gland in the sexual physiology of male mammals. Its sensitivity to steroid hormones is widely known, but its response to prolactin is still poorly...
BACKGROUND
The prostate is a key gland in the sexual physiology of male mammals. Its sensitivity to steroid hormones is widely known, but its response to prolactin is still poorly known. Previous studies have shown a correlation between sexual behaviour, prolactin release and prostate physiology. Thus, here we used the sexual behaviour of male rats as a model for studying this correlation. Hence, we developed experimental paradigms to determine the influence of prolactin on sexual behaviour and prostate organization of male rats.
METHODS
In addition to sexual behaviour recordings, we developed the ELISA procedure to quantify the serum level of prolactin, and the hematoxilin-eosin technique for analysis of the histological organization of the prostate. Also, different experimental manipulations were carried out; they included pituitary grafts, and haloperidol and ovine prolactin treatments. Data were analyzed with a One way ANOVA followed by post hoc Dunnet test if required.
RESULTS
Data showed that male prolactin has a basal level with two peaks at the light-dark-light transitions. Consecutive ejaculations increased serum prolactin after the first ejaculation, which reached the highest level after the second, and started to decrease after the third ejaculation. These normal levels of prolactin did not induce any change at the prostate tissue. However, treatments for constant elevations of serum prolactin decreased sexual potency and increased the weight of the gland, the alveoli area and the epithelial cell height. Treatments for transient elevation of serum prolactin did not affect the sexual behaviour of males, but triggered these significant effects mainly at the ventral prostate.
CONCLUSION
The prostate is a sexual gland that responds to prolactin. Mating-induced prolactin release is required during sexual encounters to activate the epithelial cells in the gland. Here we saw a precise mechanism controlling the release of prolactin during ejaculations that avoid the detrimental effects produced by constant levels. However, we showed that minor elevations of prolactin which do not affect the sexual behaviour of males, produced significant changes at the prostate epithelium that could account for triggering the development of hyperplasia or cancer. Thus, it is suggested that minute elevations of serum prolactin in healthy subjects are at the etiology of prostate abnormal growth.
Topics: Animals; Circadian Rhythm; Ejaculation; Epithelial Cells; Haloperidol; Injections, Subcutaneous; Male; Osmolar Concentration; Pituitary Gland, Anterior; Prolactin; Prostate; Rats; Rats, Wistar; Sexual Behavior, Animal
PubMed: 16707016
DOI: 10.1186/1477-7827-4-28 -
Cell Reports Feb 2019Altered physiological states require neuronal adaptation. In late pregnancy and lactation, a sub-population of the mouse hypothalamic tuberoinfundibular dopaminergic...
Altered physiological states require neuronal adaptation. In late pregnancy and lactation, a sub-population of the mouse hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons alters their behavior to synthesize and release met-enkephalin rather than dopamine. These neurons normally release dopamine to inhibit prolactin secretion and are activated by prolactin in a short-loop feedback manner. In lactation, dopamine synthesis is suppressed in an opioid-dependent (naloxone-reversible) manner, meaning that prolactin secretion is disinhibited. Conditional deletion of the prolactin receptor in neurons reveals that this change in phenotype appears to be driven by prolactin itself, apparently through an alteration in intracellular signaling downstream of the prolactin receptor that favors enkephalin production instead of dopamine. Thus, prolactin effectively facilitates its own secretion, which is essential for lactation and maternal behavior. These studies provide evidence of a physiologically important, reversible alteration in the behavior of a specific population of hypothalamic neurons in the adult brain.
Topics: Animals; Dopaminergic Neurons; Female; Hypothalamus; Mice; Phenotype; Pregnancy; Prolactin
PubMed: 30759390
DOI: 10.1016/j.celrep.2019.01.067 -
The Journal of Clinical Investigation Dec 1979Metabolic clearance rates (MCR) and production rates (PR) of prolactin (PRL) have been determined by the constant infusion to equilibrium technique in 11 normal...
Metabolic clearance rates (MCR) and production rates (PR) of prolactin (PRL) have been determined by the constant infusion to equilibrium technique in 11 normal subjects, 6 patients with hyperthyroidism, 4 patients with hypothyroidism, and 9 patients with hyperprolactinemia. PRL MCR was also determined tin four patients during dopamine infusion. Mean PRL MCR was 46 +/- 1 ml/min per m2 in women and 44 +/- 3 ml/min per m2 in men, and was significantly correlated with body mass (r = 0.84, P less than 0.001). In contrast with controls, PRL MCR was higher in hyperthyroidism (MCR = 52 +/- 8 ml/min per m2, P less than 0.05), was slightly lower in hypothyroidism (MCR = 38 +/- 10 ml/min per m2, P = NS), and was significantly correlated with serum thyroxine (r = 0.46, P less than 0.02). PRL MCR was lower than controls in hyperprolactinemia (MCR = 40 +/- 5 ml/min per m2, P less than 0.01) and was inversely correlated with serum PRL (r = -0.72, P less than 0.001). PRL MCR was not significantly changed by dopamine infusion. Mean PRL PR for women and men was 211 +/- 74 and 187 +/- 44 micrograms/d per m2, respectively (P = NS). In hyperthyroidism the PRL PR was elevated (PR = 335 +/- 68 micrograms/d per m2, P less than 0.02), but in hypothyroidism the increase (PR = 233 +/- 159 micrograms/d per m2) was not significant. In hyperprolactinemia the PRL PR was extremely high (PR = 31,000 +/- 29,000 micrograms/d per m2). Dopamine infusion decreased RPL PR from 270 to 66 micrograms/d per m2 indicating that its effect was on pituitary PRL secretion and not PRL metabolism. To evaluate possible circulating PRL heterogeneity that might arise during infusion, gel filtration of infusate and serum obtained during the MCR procedure was performed. Labeled monomeric PRL (peak III, Kav (partition coefficient) = 0.4) was partially converted to two larger forms (peaks I and II) in vivo. Peak I (Kav = 0) was 30--40% immunoprecipitable, although peak II (Kav = 0.2) was not immunoprecipitable. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of peak I resulted in greater than or equal to 90% conversion to peak III and restoration of full immunoactivity. Thus, peak I is a noncovalently linked aggregate that is partially immunoactive, and therefore able to alter MCR determinations. These studies demonstrate the impact of hormone heterogeneity on MCR estimations and suggest that gel filtration of immunoprecipitable material be an integral part of future MCR measurements.
Topics: Adenoma; Adult; Aged; Dopamine; Female; Graves Disease; Humans; Hypothyroidism; Male; Metabolic Clearance Rate; Middle Aged; Pituitary Neoplasms; Prolactin; Thyroxine
PubMed: 583048
DOI: 10.1172/JCI109629 -
PloS One 2019Increasing evidence suggests that signaling through the prolactin/prolactin receptor axis is important for stimulation the growth of many cancers including glioblastoma...
Increasing evidence suggests that signaling through the prolactin/prolactin receptor axis is important for stimulation the growth of many cancers including glioblastoma multiforme, breast and ovarian carcinoma. Efficient inhibitors of signaling have previously been developed but their applicability as cancer drugs is limited by the short in vivo half-life. In this study, we show that a fusion protein, consisting of the prolactin receptor antagonist PrlRA and an albumin binding domain for half-life extension can be expressed as inclusion bodies in Escherichia coli and efficiently refolded and purified to homogeneity. The fusion protein was found to have strong affinity for the two intended targets: the prolactin receptor (KD = 2.3±0.2 nM) and mouse serum albumin (KD = 0.38±0.01 nM). Further investigation showed that it could efficiently prevent prolactin mediated phosphorylation of STAT5 at 100 nM concentration and above, similar to the PrlRA itself, suggesting a potential as drug for cancer therapy in the future. Complexion with HSA weakened the affinity for the receptor to 21±3 nM, however the ability to prevent phosphorylation of STAT5 was still prominent. Injection into rats showed a 100-fold higher concentration in blood after 24 h compared to PrlRA itself.
Topics: Animals; Cell Line, Tumor; Half-Life; Humans; Male; Phosphorylation; Prolactin; Rats; Rats, Wistar; Receptors, Prolactin; Recombinant Fusion Proteins; STAT5 Transcription Factor; Tissue Distribution
PubMed: 31063493
DOI: 10.1371/journal.pone.0215831 -
Cleveland Clinic Journal of Medicine Jun 2004
Review
Topics: Female; Humans; Hyperprolactinemia; Infertility; Menstruation; Prolactin
PubMed: 15242301
DOI: 10.3949/ccjm.71.6.457