The effect of inflammatory factors and their inhibitors on the hematopoietic stem cells fate

Inflammatory cytokines exert different effects on hematopoietic stem cells (HSCs), lead to the development of various cell lineages in bone marrow (BM) and are thus a differentiation axis for HSCs. The content used in this article has been obtained by searching PubMed database and Google Scholar search engine of English-language articles (1995–2020) using “Hematopoietic stem cell,” “Inflammatory cytokine,” “Homeostasis,” and “Myelopoiesis.” Inflammatory cytokines are involved in the differentiation and proliferation of hematopoietic progenitors to compensate for cellular death due to inflammation. Since each of these cytokines differentiates HSCs into a specific cell line, the difference in the effect of these cytokines on the fate of HSC progenitors can be predicted. Inhibitors of these cytokines can also control the inflammatory process as well as the cells involved in leukemic conditions. In general, inflammatory signaling can specify the dominant cell line in BM to counteract inflammation and leukemic condition via stimulating or inhibiting hematopoietic progenitors. Therefore, detection of the effects of inflammatory cytokines on the differentiation of HSCs can be an appropriate approach to check inflammatory and leukemic conditions and the suppression of these cytokines by their inhibitors allows for control of homeostasis in stressful conditions.     

The genomic context of retrocopies increases their chance of functional relevancy in mammals

Described as “junk” DNA, pseudogenes are dead structures of previously active genes present in genomes. Pseudogenes are categorized into two main classes: processed pseudogenes, formed through retrotransposition, and non-processed pseudogenes, typically originated from gene decay following duplication events. The term “processed pseudogene” has changed to “retrocopy” since they are likely to evolve new functional roles and became a retrogene. Here, we surveyed 38,080 retrocopies from chimpanzee, dog, human, mouse, and rat genomes to assess their potential adaptive value. The retrocopies inserted in the same chromosome of the parental gene have higher chances of remain potentially “active” (absence of premature stop codons and frameshifts) (~26.1%), while those placed into a different chromosome have a twofold decrease chance of continuing potentially “active” (~7.52%). The genomic context of their placement seems associated with their expression. Retrocopies placed in intragenic regions and the same sense of the “host” gene have higher chances of being expressed relative to other genomic contexts. The proximity of retrocopies to their parental gene is associated with a lower decay rate, and their location likely influence their expression. Thus, despite their unclear role, retrocopies are probably involved in adaptive processes. Our results evidence natural selection acting in retrocopies.     

The interleukins,interferons, transforming growth factors,and their assays: An overview

This review has focused on the interleukin, interferon, and transforming growth factor families of cytokines. The complexity of the cytokine network of interrelating peptides with multiple overlapping regulatory functions is just beginning to be understood. Most of the biologic activities attributed to each cytokine are based on in vitro analysis from a “macroimmunologic” perspective, and therefore only represents a “best guess” of the true potential role of these substances in human immunology. It is also important to keep in mind that the in vivo biologic effects of many of these cytokines are exerted in an autocrine and/or paracrine fashion (at a “microimmunologic” level), thus in this in vivo milieu, cytokines may simultaneously be acting synergistically or antagonistically. The significance of their in vivo biologic effects may be distinct from those in vitro effects determined in the cellular immunology laboratory. Through the development of new sensitive immunoassays that can function at the level of a single cell and modern molecular biologic and immunocytochemistry techniques, an appreciation of how the in vivo pleotropic effects of cytokines are regulated is developing.     

Shedding light on the immunomodulatory properties of galectins: Novel regulators of innate and adaptive immune responses

Galectins are a large family of structurally related β-galactoside-binding proteins that play a pivotal role in the control of cell differentiation, proliferation, activation and apoptosis of many different cell types including immune cells. By crosslinking specific glycoconjugates, different members of the galectin family behave as pro-inflammatory or anti-inflammatory “cytokine-like” mediators, acting at different levels of innate and adaptive immune responses. Here we will review recent advances on the role of galectins in key events of the immune and inflammatory response, such as tolerance induction, cell cycle progression, cell adhesion, chemotaxis, antigen presentation and apoptosis. In particular we will examine the influence of individual members of the galectin family in the physiology of different immune cell types involved in innate and adaptive immune responses. Moreover, we will discuss the importance of these sugar-binding proteins as therapeutic targets in Th1- and Th2-mediated immune disorders, an exciting area for future research. Published in 2004.     

Pharmacological control of the immune response by blockade of the early hormonal changes following antigen injection.

Antigen injection into mice induces a rapid increase in blood levels of gonadotropins. Suppression of these hormonal changes by a combination of drugs acting on the neuroendocrine regulation as well as on cell membrane receptors results in a blockade of antibody synthesis and specific “tolerance.” In addition, remarkable suppression of transplantation immunity is achieved.     

Interferon-gamma sensitizes the human salivary gland cell line, HSG, to tumor necrosis factor-alpha induced activation of dual apoptotic pathways

Activated immune cells secrete proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interferon–gamma (IFN-gamma) and Fas ligand (FasL) and these cytokines have been reported to induce apoptosis in numerous cell types. Apoptotic cell death has been associated with the progression of numerous autoimmune diseases. Proinflammatory cytokines are reportedly involved in apoptosis in the salivary glands of patients with Sjögren’s syndrome (SS); an autoimmune disorder characterized by the destruction of salivary and lachrymal glands. In this study, we used the HSG cell line to determine if exposure to proinflammatory cytokines induces apoptosis in human salivary gland cells. In addition, we identified the mediators controlling the apoptotic process in response to TNF alpha and IFN gamma. TNF-alpha and IFN-gamma induced apoptosis in HSG cells and resulted in the activation of caspase 8 and the “death receptor” pathway. We further determined that caspase 9 and the “mitochondrial” pathway was also activated. Induction of the intrinsic and extrinsic pathways in HSG cells resulted in substrate cleavage by effector caspases, in particular the cleavage of alpha II spectrin, an autoantigen in Sjögren’s syndrome. Our results suggest that HSG cells provide a model system to study processes regulating proinflammatory cytokine-induced apoptotic cell death.     

Structural basis for the regulation of phytohormone receptors

Phytohormones are central players in diverse plant physiological events, such as plant growth, development, and environmental stress and defense responses. The elucidation of their regulatory mechanisms through phytohormone receptors could facilitate the generation of transgenic crops with cultivation advantages and the rational design of growth control chemicals. During the last decade, accumulated structural data on phytohormone receptors have provided critical insights into the molecular mechanisms of phytohormone perception and signal transduction. Here, we review the structural bases of phytohormone recognition and receptor activation. As a common feature, phytohormones regulate the interaction between the receptors and their respective target proteins (also called co-receptors) by two types of regulatory mechanisms, acting as either “molecular glue” or an “allosteric regulator.” However, individual phytohormone receptors adopt specific structural features that are essential for activation. In addition, recent studies have focused on the molecular diversity of redundant phytohormone receptors.     

Reprogramming cell fates: reconciling rarity with robustness

The stunning possibility of “reprogramming” differentiated somatic cells to express a pluripotent stem cell phenotype (iPS, induced pluripotent stem cell) and the “ground state” character of pluripotency reveal fundamental features of cell fate regulation that lie beyond existing paradigms. The rarity of reprogramming events appears to contradict the robustness with which the unfathomably complex phenotype of stem cells can reliably be generated. This apparent paradox, however, is naturally explained by the rugged “epigenetic landscape” with valleys representing “preprogrammed” attractor states that emerge from the dynamical constraints of the gene regulatory network. This article provides a pedagogical primer to the fundamental principles of gene regulatory networks as integrated dynamic systems and reviews recent insights in gene expression noise and fate determination, thereby offering a formal framework that may help us to understand why cell fate reprogramming events are inherently rare and yet so robust.     

Guest-Editorial Introduction: Converging Evolutionary Patterns in Life and Culture

The natural world demonstrates signs of spatial–temporal order, an order that appears to us through a series of recognizable, recurring and consecutive patterns, i.e. regularities in forms, functions, behaviors, events and processes. These patterns lend insight into the modes and tempos of evolution and thus into the units, levels, and mechanisms that underlie the evolutionary hierarchy. Contributors to this special issue analyze converging patterns in the biological and sociocultural realm across and beyond classic divisions between micro- and macro-evolution; horizontal/reticulate and vertical evolution; phylogeny, ontogeny and ecology; synchronic and diachronic sociocultural and linguistic research; and tree and network diagrams. Explanations are sought in complexity theory, major transitions of evolution, and process and mechanism approaches to change; and consequences for notions such as “life”, “species”, “biological individuality”, “units” and “levels” of evolution are given.     

IL-4 and IL-13 receptors: Roles in immunity and powerful vaccine adjuvants

The roles of interleukin (IL)-4 and IL-13 during both innate and adaptive Th2 mediated immunity have received considerable scrutiny, however, mechanisms by which these cytokines influence the cellular interactions involved in negatively modulating the development of effective Th1 immunity are poorly characterized. In this article we discuss the recent advances in IL-4/IL-13 biology, mainly (i) role of these cytokines in allergic inflammation, atopic dermatitis, cancer, transplant rejection, bacterial/viral infections, and specifically the therapeutic potential of IL-13Rα2, (ii) insights into how “alarmin” stimulation activate IL-4/IL-13 at the lung mucosae, (iii) how these two cytokines modulate antigen-specific CD8⁺ T cell quality/avidity in a vaccine route dependent manner and (iv) finally discuss the potential of using transient inhibition of IL-4 and/or IL-13 at the vaccination site as a platform vaccine technology to induce strong sustained high quality CD8⁺ T cell immunity for protection against many chronic mucosal pathogens such as HIV-1.     

A biologic radar system for the assessment of body mass the model of a geometry sensitive endocrine system is presented

Appetite control, pubarchal timing, and catch-up growth all seem to depend, to some extent, on body mass. Information regarding this variable may be supplied to the central nervous system (“ponderostat”) by a humoral radar system employing an insulin-like molecule or dependent substrate as a signal. The intensity of this signal would vary as a function of the organism's total adipose cell surface area, which, in turn, is a product of cell size and number. The geometry of a sphere (adipose cell) is such that surface area change per unit volume change increases as the radius of the sphere is reduced. Signal shifts then are maximal when cell volume is minimal. Divergence of the adipose signal from an age-appropriate norm could influence “ponderostat” activity and, in turn, brain centers mediating appetitive and various endocrine systems. Total caloric intake and the timing of this intake with respect to somatic maturity appear to affect adipose cell volume and number respectively. If shifts in adipose surface area provide a signal source regarding organismic mass, and if this surface area reflects the quantity and chronology of antecedent nutritional events, there are obvious implications for the role of nutrition during “critical periods” in the subsequent operation of the complex systems subserving appetite, somatic growth and sexual maturation.     

Autoimmunity and the microbiome: T‐cell receptor mimicry of “self” and microbial antigens mediates self tolerance in holobionts

I propose a T‐cell receptor (TcR)‐based mechanism by which immunity mediates both “genetic self” and “microbial self” thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross‐reactivity with “self,” resulting in selection for a TcR repertoire mimicking “genetic self.” Second, evolution has selected for a “microbial self” that mimics “genetic self” so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR‐microbiome mimicry “holoimmunity” to denote immune tolerance to the “holobiont self.” Logically, microbiome‐host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross‐react with host antigens producing “holoautoimmunity.”

     

Can tumorigenesis result from in vivo “transfection” of a normal cell with DNA escaped from disintegrating nontransformed cells?

In this paper I present a hypothetical step on the route to turmorigenesis which may be common to many of the tumorogenic events taking place in vivo. According to this hypothesis portions of DNA from normal nontransformed dying cells may escape degradation, “transfect” other cells and under appropriate conditions also induce transformation. When various high risk factors for carcinogenesis are examined this hypothesis may easily fit into each of them. In addition, recent reports of experimental “transfection” indirectly support this hypothesis. It could now be argued that aging, ionizing radiation, immunosuppressive drugs, genetic errors, defects in DNA repair, immunodeficiency states, chronic infections and chronic inflammatory diseases may all increase the availability of free DNA or the readiness of cells to accommodate “transfection” DNA, or both. Thus the risk of cancer associated with these situations may be explained by increased chance for “transfection” with DNA.It is suggested that the minimal requirements for cell transformation consist of a certain sequence of DNA which does not have to be integrated into the nucleus at once, it may instead accumulate piece by piece so that the first “transfection” of a cell may occur long before transformation takes place. If the “transfecting” DNA sequence does not fulfil the minimal requirements for maintaining a state of repetitive uncontrolled mitosis, then this cell may wait silently or remain a benign tumor until “boosted” with an ultimate complementary DNA sequence to develop into a fully fledged cancer.     

Mouse ES cells maintained in different pluripotency-promoting conditions differ in their neural differentiation propensity

Prior to differentiation, embryonic stem (ES) cells in culture are maintained in a so-called “undifferentiated” state, allowing derivation of multiple downstream cell lineages when induced in a directed manner, which in turn grants these cells their “pluripotent” state. The current work is based on a simple observation that the initial culture condition for maintaining mouse ES cells in an “undifferentiated” state does impact on the differentiation propensity of these cells, in this case to a neuronal fate. We point out the importance in judging the “pluripotency” of a given stem cell culture, as this clearly demonstrated that the “undifferentiated” state of these cells is not necessarily a “pluripotent” state, even for a widely used mouse ES cell line. We partly attribute this difference in the initial value of ES cells to the naïve-to-primed status of pluripotency, which in turn may affect early events of the differentiation in vitro.     

Question 7: The Vesicle World: The Emergence of Cellular Life can be Related to Properties Specific to Vesicles

The question “What was the minimum number of genes necessary in the early cell” is rephrased as “Is it feasible to assume that early cells had no genes?” It is shown that a kind of primitive life process could exist on the basis only of properties specific to vesicles, and that it would have the potential to evolve into more complex cell-like processes.     

Immunomodulatory activity of extracellular heat shock proteins and their autoantibodies

HSP are groups of stress‐inducible proteins which contribute to quality control by assisting the correct folding of both nascent and denatured proteins, and promoting the degradation of unrecoverable denatured proteins. HSP also help to maintain cellular homeostasis and protect from cell death through a mechanism called thermotolerance. Cells subjected to mild stress induce HSP which then protect them against subsequent stress. However, in cells subjected to severe stress, HSP promote apoptosis. Besides these intracellular events, HSP also exist in extracellular fluids, and have been shown to contribute to immunomodulation. In innate immunity extracellular HSP, like various microbial substances, induce various proinflammatory cytokines. In acquired immunity they interact with antigenic polypeptides and assist in antigen presentation. The extracellular HSP are so‐called adjuvant. Release of HSP from cells is triggered by stress and trauma, and is thus regarded as an immunological “danger signal”. In addition, anti‐HSP autoantibodies are frequently found in patients with autoimmune diseases and inflammatory disorders, and these autoantibodies can modulate the “danger signal” triggered by extracellular HSP.     

On a possible relationship between bacterial endospore formation and the origin of eukaryotic cells

The acquisition of intracellular organelles, including mitochondria and plastids and a membrane-bounded nucleus, have been postulated to be key events in the development of the eukaryotic from the prokaryotic ancestral cell. The two major hypotheses to account for such acquisitions are: (1) primitive cells originally obtained organelles by engulfing free-living prokaryotes which then entered into symbiotic association (“endosymbiosis”) with them; (2) organelles arose through the engulfment by the primitive cell of part of its own cytoplasm. To some extent, the former hypothesis has received most support, because endosymbiosis is known to occur in extant organisms, whilst the latter hypothesis has received less support, because cytoplasmic engulfment by prokaryotes is not now thought to occur. However, during the process of endospore formation by extant bacteria, the protoplast within the single cell is observed to divide in a unique manner such that the cell in effect engulfs a portion of its own cytoplasm. The process is strikingly similar to the engulfment suggested by the second hypothesis to have initiated the evolution of eukaryotes. The engulfed cytoplasm is bounded by a double membrane within the “mother cell” and contains enzymes, ribosomes and a complete genome. In many respects this parallels the supposed primitive eukaryotic state and, it is argued, confers potential advantages on the cell, particularly through the control that the “mother cell” can exert on the enclosed compartment. It is hypothesized that bacterial endospore formation is therefore one product of evolution from an early engulfment event that led also to the development of complex eukaryotic cells.