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Frontiers in Immunology 2014Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel... (Review)
Review
Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuroimmune communications mediated by dopamine. Studies of dendritic cells (DCs) revealed that they express the whole machinery to synthesize and store dopamine, which may act in an autocrine manner to stimulate dopamine receptors (DARs). Depending on specific DARs stimulated on DCs and T cells, dopamine may differentially favor CD4(+) T cell differentiation into Th1 or Th17 inflammatory cells. Regulatory T cells can also release high amounts of dopamine that acts in an autocrine DAR-mediated manner to inhibit their suppressive activity. These dopaminergic regulations could represent a driving force during autoimmunity. Indeed, dopamine levels are altered in the brain of mouse models of multiple sclerosis (MS) and lupus, and in inflamed tissues of patients with inflammatory bowel diseases or rheumatoid arthritis (RA). The distorted expression of DARs in peripheral lymphocytes of lupus and MS patients also supports the importance of dopaminergic regulations in autoimmunity. Moreover, dopamine analogs had beneficial therapeutic effects in animal models, and in patients with lupus or RA. We propose models that may underlie key roles of dopamine and its receptors in autoimmune diseases.
PubMed: 24711809
DOI: 10.3389/fimmu.2014.00117 -
Advances in Experimental Medicine and... 1995Testicular steroidogenesis takes place almost exclusively in Leydig cells. Some metabolism of the androgens produced by Leydig cells takes place in seminiferous tubules,... (Review)
Review
Testicular steroidogenesis takes place almost exclusively in Leydig cells. Some metabolism of the androgens produced by Leydig cells takes place in seminiferous tubules, especially in the immature animal (e.g. aromatization and 5 alpha- reduction). Luteinizing hormone (LH) is the main tropic regulator of Leydig cell function, without which quantitatively important androgen production is not possible. LH acts through a receptor that belongs to the seven times cell membrane spanning, G protein associated, receptor family, and cyclic AMP is the main second messenger of its signal transduction. Information about the involvement of other signal transduction systems in LH action has also emerged recently. The action of LH is under manyfold modulation by other hormones (e.g. prolactin, growth hormone and insulin), growth factors and bioactive peptides. In this modulation, various paracrine and autocrine mechanisms play an important role. Seminiferous tubules influence the development and function of adjacent Leydig cells through several growth factors. When germ cells are damaged, Leydig cells in the vicinity proliferate faster. Leydig cell morphology also depends on the germ cell composition in the neighbouring seminiferous tubules, and certain stages of the seminiferous epithelial cycle increase the Leydig cell capacity to produce testosterone. Also negative modulation of Leydig cells by Sertoli/germinal cell derived factors has been demonstrated. However, the physiological importance of the paracrine and modulatory influences of the different hormones and growth factors still remains obscure since almost all information has so far been obtained from in vitro studies. In the study of testicular steroidogenesis, the main switch of the function, LH action, is well known whereas the role of the "in house" circuits of paracrine and autocrine regulation remain to be elucidated.
Topics: Amino Acid Sequence; Animals; Endocrine Glands; Hormones; Humans; Male; Molecular Sequence Data; Steroids; Testis
PubMed: 7484435
DOI: 10.1007/978-1-4899-0952-7_3 -
Biophysical Journal Apr 2005Cell-culture assays are routinely used to analyze autocrine signaling systems, but quantitative experiments are rarely possible. To enable the quantitative design and...
Cell-culture assays are routinely used to analyze autocrine signaling systems, but quantitative experiments are rarely possible. To enable the quantitative design and analysis of experiments with autocrine cells, we develop a biophysical theory of ligand accumulation in cell-culture assays. Our theory predicts the ligand concentration as a function of time and measurable parameters of autocrine cells and cell-culture experiments. The key step of our analysis is the derivation of the survival probability of a single ligand released from the surface of an autocrine cell. An expression for this probability is derived using the boundary homogenization approach and tested by stochastic simulations. We use this expression in the integral balance equations, from which we find the Laplace transform of the ligand concentration. We demonstrate how the theory works by analyzing the autocrine epidermal growth factor receptor system and discuss the extension of our methods to other experiments with cultured autocrine cells.
Topics: Autocrine Communication; Biological Transport; Biophysics; Breast; Cell Culture Techniques; Cells, Cultured; Culture Media; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epithelial Cells; ErbB Receptors; Humans; Kinetics; Ligands; Models, Biological; Models, Theoretical; Nitric Oxide; Physiological Phenomena; Time Factors
PubMed: 15653719
DOI: 10.1529/biophysj.104.051425 -
Tissue Engineering 1995Transplantation of artificial ligand-secreting cells is envisioned as a promising technology in tissue engineering. To achieve practical control of these systems,...
Transplantation of artificial ligand-secreting cells is envisioned as a promising technology in tissue engineering. To achieve practical control of these systems, sufficiently high levels of ligand must be produced to provide adequate receptor binding and signal generation, but ligand spread into adjacent tissue regions must also be controlled. Mathematical models predict that the relative amount of ligand found either in the extracellular medium or bound to cell receptors is governed by ligand and receptor synthesis rates, receptor turnover rate, cell density, and exogenous blocking antibody concentration. To experimentally elucidate the relative contribution of these parameters, we constructed an artificial autocrine system in which all major parameters were under direct experimental control. A synthetic gene for a secretory form of human epidermal growth factor (EGF) was constructed consisting of the mature protein product fused to a foreign signal seqeunce. This was inserted into a vector behind an inducible promoter. Cells lacking endogenous receptors for EGF (EGFR) were first transfected with the gene for the human EGFR and then with the gene for EGF. Cells were selected that expressed high levels of both receptor and ligand. A tetracycline-sensitive promoter system for the artificial EGF gene allowed us to experimentally vary EGF secretion rates 20- to 200-fold. Using this system, we found that no significant amount of EGF was found in the culture medium unless the production rate of the ligand exceeded that of the receptor. Alternately, the use of EGFR-blocking antibodies allowed ligand escape into the medium. Even in the presence of high concentration of antagonistic antireceptor antibodies, however, cells were still able to consume EGF produced in an autocrine fashion. Induction of high levels of EGF production resulted in an almost 90% reduction in total receptor mass through down-regulation, but cells continued to rapidly bind, internalize, and degrade EGF. Our data suggest that cells have an unexpectedly high capacity to both bind and utilize growth factors produced in an autocrine fashion. In addition, interrupting autocrine loops may be more difficult than originally envisioned. Our artificial autocrine system should prove useful in understanding both how these systems are normally regulated and how they can be manipulated for purposes of tissue engineering.
PubMed: 19877917
DOI: 10.1089/ten.1995.1.81 -
Endocrine Development 2011Longitudinal growth is primarily influenced by the GH-IGF-I axis, which is a mixed endocrine-paracrine-autocrine system. Further, classical hormones such as thyroxine,... (Review)
Review
Longitudinal growth is primarily influenced by the GH-IGF-I axis, which is a mixed endocrine-paracrine-autocrine system. Further, classical hormones such as thyroxine, glucocorticosteroids and sex steroids play a role, as well as primarily paracrine systems. In the GH-IGF-I axis, seven disorders can be differentiated: (1) GH deficiency; (2) GHR defects; (3) defects in the GH signal transduction pathway; (4) IGF1 defects; (5) IGFALS defects; (6) IGF1R defects, and (7) IGF2 defects. Children with one of the first 3 disorders have near-normal prenatal growth, while children with defects of IGF1, IGF1R or IGF2 show prenatal as well as postnatal growth retardation. Hypothyroidism or a thyroid hormone resistance cause growth failure, but the effect of hyperthyroidism on growth is modest. Hypercortisolism causes poor growth, while FGD caused by ACTH insensitivity is associated with tall stature. Increased sex steroids in childhood cause advanced growth but even more skeletal maturation, so that adult height is decreased. Finally, the paracrine-autocrine SHOX-BNP pathway and the related CNP-NPR2 pathway are also involved in growth, as very many other growth factors and their receptors and mediators.
Topics: Adult; Animals; Bone Development; Child; Endocrine System; Growth Hormone; Hormones; Humans; Insulin-Like Growth Factor I; Models, Biological; Signal Transduction
PubMed: 21865752
DOI: 10.1159/000328119 -
Acta Physiologica (Oxford, England) May 2020Nitric oxide (NO), a highly reactive gasotransmitter, is critical for a number of cellular processes and has multiple biological functions. Due to its limited lifetime... (Review)
Review
Nitric oxide (NO), a highly reactive gasotransmitter, is critical for a number of cellular processes and has multiple biological functions. Due to its limited lifetime and diffusion distance, NO has been mainly believed to act in autocrine/paracrine fashion. The increasingly recognized effects of pharmacologically delivered and endogenous NO at a distant site have changed the conventional wisdom and introduced NO as an endocrine signalling molecule. The notion is greatly supported by the detection of a number of NO adducts and their circulatory cycles, which in turn contribute to the transport and delivery of NO bioactivity, remote from the sites of its synthesis. The existence of endocrine sites of synthesis, negative feedback regulation of biosynthesis, integrated storage and transport systems, having an exclusive receptor, that is, soluble guanylyl cyclase (sGC), and organized circadian rhythmicity make NO something beyond a simple autocrine/paracrine signalling molecule that could qualify for being an endocrine signalling molecule. Here, we discuss hormonal features of NO from the classical endocrine point of view and review available knowledge supporting NO as a true endocrine hormone. This new insight can provide a new framework within which to reinterpret NO biology and its clinical applications.
Topics: Animals; Endocrine System; Hormones; Humans; Nitric Oxide; Signal Transduction; Soluble Guanylyl Cyclase
PubMed: 31944587
DOI: 10.1111/apha.13443 -
Nature Jun 2022T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs,...
T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved. Here we combine scRNA-seq and a new CRISPR-Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.
Topics: Aging; Animals; Autocrine Communication; CRISPR-Cas Systems; Cellular Microenvironment; Epithelial Cells; Epithelium; Fibroblast Growth Factor 7; Mice; RNA-Seq; Single-Cell Analysis; Stem Cells; T-Lymphocytes; Thymus Gland
PubMed: 35614226
DOI: 10.1038/s41586-022-04752-8 -
Biological Reviews of the Cambridge... Feb 2017In the absence of the maternal genital tract, preimplantation embryos can develop in vitro in culture medium where all communication with the oviduct or uterus is...
In the absence of the maternal genital tract, preimplantation embryos can develop in vitro in culture medium where all communication with the oviduct or uterus is absent. In several mammalian species, it has been observed that embryos cultured in groups thrive better than those cultured singly. Here we argue that group-cultured embryos are able to promote their own development in vitro by the production of autocrine embryotropins that putatively serve as a communication tool. The concept of effective communication implies an origin, a signalling agent, and finally a recipient that is able to decode the message. We illustrate this concept by demonstrating that preimplantation embryos are able to secrete autocrine factors in several ways, including active secretion, passive outflow, or as messengers bound to a molecular vehicle or transported within extracellular vesicles. Likewise, we broaden the traditional view that inter-embryo communication is dictated mainly by growth factors, by discussing a wide range of other biochemical messengers including proteins, lipids, neurotransmitters, saccharides, and microRNAs, all of which can be exchanged among embryos cultured in a group. Finally, we describe how different classes of messenger molecules are decoded by the embryo and influence embryo development by triggering different pathways. When autocrine embryotropins such as insulin-like growth factor-I (IGF-I) or platelet activating factor (PAF) bind to their appropriate receptor, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway will be activated which is important for embryo survival. On the other hand, the mitogen-activated protein kinase (MAPK) pathway is activated when compounds such as hyaluronic acid and serotonin bind to their respective receptors, thereby acting as growth factors. By activating the peroxisome-proliferator-activated receptor family (PPAR) pathway, lipophilic autocrine factors such as prostaglandins or fatty acids have both survival and anti-apoptotic functions. In conclusion, considering different types of messenger molecules simultaneously will be crucial to understanding more comprehensively how embryos communicate with each other in group-culture systems. This approach will assist in the development of novel media for single-embryo culture.
Topics: Animals; Blastocyst; Cell Communication; Culture Media; Embryo, Mammalian; Phosphatidylinositol 3-Kinases
PubMed: 26608222
DOI: 10.1111/brv.12241 -
Scientific Reports Aug 2016Homeostasis of hematopoietic stem cells (HSC) in the mammalian bone marrow stem cell niche is regulated by signals of the local microenvironment. Besides juxtacrine,...
Homeostasis of hematopoietic stem cells (HSC) in the mammalian bone marrow stem cell niche is regulated by signals of the local microenvironment. Besides juxtacrine, endocrine and metabolic cues, paracrine and autocrine signals are involved in controlling quiescence, proliferation and differentiation of HSC with strong implications on expansion and differentiation ex vivo as well as in vivo transplantation. Towards this aim, a cell culture analysis on a polymer microcavity carrier platform was combined with a partial least square analysis of a mechanistic model of cell proliferation. We could demonstrate the discrimination of specific autocrine and paracrine signals from soluble factors as stimulating and inhibitory effectors in hematopoietic stem and progenitor cell culture. From that we hypothesize autocrine signals to be predominantly involved in maintaining the quiescent state of HSC in single-cell niches and advocate our analysis platform as an unprecedented option for untangling convoluted signaling mechanisms in complex cell systems being it of juxtacrine, paracrine or autocrine origin.
Topics: Autocrine Communication; Cell Differentiation; Cell Proliferation; Cells, Cultured; Hematopoietic Stem Cells; Humans; Least-Squares Analysis; Paracrine Communication; Polymers; Signal Transduction; Tissue Scaffolds
PubMed: 27535453
DOI: 10.1038/srep31951 -
Current Hypertension Reports Sep 2017The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights... (Review)
Review
The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights into its current and emerging management. Considering that the intricate control of BP is governed by a myriad of anatomical, molecular biological, biochemical, and physiological systems, multiple genes are likely to influence an individual's BP and susceptibility to develop hypertension. The long-term regulation of BP rests on renal and non-renal mechanisms. One renal mechanism relates to sodium transport. The impaired renal sodium handling in primary hypertension and salt sensitivity may be caused by aberrant counter-regulatory natriuretic and anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin-aldosterone systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension, including that associated with obesity. We present updates on the complex interactions of these two systems with dietary salt intake in relation to obesity, insulin resistance, inflammation, and oxidative stress. We review how insults during pregnancy such as maternal and paternal malnutrition, glucocorticoid exposure, infection, placental insufficiency, and treatments during the neonatal period have long-lasting effects in the regulation of renal function and BP. Moreover, these effects have sex differences. There is a need for early diagnosis, frequent monitoring, and timely management due to increasing evidence of premature target organ damage. Large controlled studies are needed to evaluate the long-term consequences of the treatment of elevated BP during childhood, especially to establish the validity of the current definition and treatment of pediatric hypertension.
Topics: Child; Early Medical Intervention; Humans; Hypertension; Insulin Resistance; Obesity; Oxidative Stress; Renin-Angiotensin System; Sodium Chloride, Dietary
PubMed: 28780627
DOI: 10.1007/s11906-017-0768-4