1,721,055 research outputs found
Editorial: Regulation of Soluble Immune Mediators by Non-Coding RNAs
Full text linkNon-coding RNAs (ncRNAs), defined as transcripts that do not encode proteins, are known since long time for their role in translation (i.e. transfer RNAs, ribosomal RNAs) and in splicing events (i.e. small nuclear and small nucleolar RNAs). However, only recently, the revolutionary advances in deep sequencing technology brought to light several new classes of ncRNA, classified according to their length into “short” ncRNAs (<200 nucleotides, that includes piwi-associated RNAs, endogenous short-interfering RNAs, microRNAs, Y-RNAs and others), and “long” ncRNAs (lncRNAs, >200 nucleotides) (1). Cytokines are crucial soluble messengers of the immune system that regulate and sustain inflammation and immunity. Cytokine expression is tightly regulated, reflecting the need of the immune system to tailor the magnitude and duration of its responses to induce pathogen clearance, but not tissue damage. Thus, understanding cytokine regulation is crucial to gain insight and eventually manipulate undesired immune responses. In this Research Topic, 53 authors contributed 11 articles touching on many of the combined roles of ncRNAs on the production of cytokines and their consequential effect on cytokine-related functional outputs, as well as inflammatory/autoimmune pathologies
Comparative expression of TNF-alfa alleles from normal and autoimmune-prone mice MHC haplotypes.
No full textTriggering of anti-tumor activity through melanoma-specific transduction of a constitutively active Tumor Necrosis Factor (TNF) R1 chimeric receptor in the absence of TNFa.
No full textTumor necrosis factor-a (TNF-a) has been intensively studied because of the specific toxicity of this cytokine toward cells that undergo malignant transformation. However, its proinflammatory and immunoregulatory properties always represented a drawback to the TNF-a administration in cancer therapy. In this study, we describe an adenovirus-based strategy in which the tumoricidal activity of TNF-a can be selectively triggered to eradicate tumors without administering TNF-a. This strategy might allow us to prevent TNF-a effects on normal tissues and, therefore, to bypass its systemic toxic effects. We inserted the constitutively active version of the Mr 55,000 TNF receptor, which was shown previously (F. Bazzoni et al., Proc. Natl. Acad. Sci. USA, 92: 5376–5380, 1995) to be capable of killing cells upon expression in the absence of its ligand, into a replicationdeficient adenovirus, and under the control of a melanoma-specific promoter/ enhancer element. We show that, upon infection, the recombinant gene reaches high level of expression in melanoma cell lines and triggers apoptosis by activating the caspase cascade. Expression and function of this receptor is restricted to melanoma cell lines, because morphology, viability, and proliferation of other cell types exposed to the recombinant adenovirus infection are not affected. We show for the first time that a TNF-like apoptotic response can be triggered in the absence of TNF-a and can be selectively confined to specific cellular targets. Killing activity and tissue specificity of the recombinant TNF receptor adenovirus, together with the advantage of triggering a TNF-like antitumor activity in the absence of TNF-a itself, are ideal features for a vector that might be the choice for gene therapy aimed to eradicate malignant cells
How do tumor necrosis factor receptors work?
No full textQuite suddenly, a new level of understanding has been attached to the TNF ligand and receptor families. Many of the proximal transducers that signal the presence of TNF or its homologs have been identified, and certain components of the distal signaling pathway have emerged as well. We lack, however, a "movie" of the events that transpire when TNF binds its receptors on the surface of a cell. The facts in hand permit an educated approximation
TNF, apoptosis and autoimmunity: A common thread?
No full textA subset of cytokine mediators belonging to the tumor necrosis factor (TNF) family cause apoptosis, acting through receptors and signaling pathways that have recently come to light. Further, at least one autoimmune disease results from a defined defect of apoptosis (mutations of the Fas ligand or its receptor). It is offered that many, and perhaps most autoimmune diseases may result from primary defects of apoptosis. Such defects may cause reflexive overproduction of TNF and other pro-apoptotic cytokines. The collateral damage produced by these mediators may be of pathogenetic importance in complex autoimmune disorders such as rheumatoid arthritis and Crohn disease, wherein TNF blockade is known to have ameliorative effects
Chimeric TNF receptors with constitutive signalling activity.
No full textMany hormone and cytokine receptors are crosslinked by their specific ligands, and multimerization is an essential step leading to the generation of a signal. In the case of the tumor necrosis factor (TNF) receptors (TNF-Rs), antibody-induced crosslinking is sufficient to trigger a cytolytic effect. However, the quaternary structural requirements for signaling--i.e., the formation of dimers, trimers, or higher-order multimers--have remained obscure. Moreover, it has not been clear whether the 55-kDa or 75-kDa TNF-R is responsible for initiation of cytolysis. We reasoned that an obligate receptor dimer, targeted to the plasma membrane, might continuously signal the presence of TNF despite the actual absence of the ligand. Such a molecule, inserted into an appropriate vector, could be used to project receptor-specific "TNF-like" activity to specific cells and tissues in vivo. Accordingly, we constructed sequences encoding chimeric receptors in which the extracellular domain of the mouse erythropoietin receptor (Epo-R) was fused to the "stem," transmembrane domain, and cytoplasmic domain of the two mouse TNF-Rs. Thus, the Epo-R group was used to drive dimerization of the TNF-R cytoplasmic domain. These chimeric proteins were well expressed in a variety of cell lines and bound erythropoietin at the cell surface. Both the 55-kDa and the 75-kDa Epo/TNF-R chimeras exerted a constitutive cytotoxic effect detected by cotransfection or clonogenic assay. Thus, despite the lack of structural homology between the cytoplasmic domains of the two TNF-Rs, a similar signaling endpoint was observed. Moreover, dimerization (rather than trimerization or higher-order multimerization) was sufficient for elicitation of a biological response
Tumor Necrosis Factor: from production to action
No full textThis article gives an overview of the mechanisms underlying TNF biosynthesis and its multiple biological activitie
Implementation of a combined bioinformatics and experimental approach to address lncRNA mechanism of action: The example of NRIR
Full text linkn this study, we demonstrate the benefit of applying combined strategies to analyze lncRNA action based on bioinformatics and experimental information. This strategy was developed to identify the molecular function of negative regulator of interferon response (NRIR), a type I interferon-stimulated gene (ISG), that we have previously demonstrated to be involved in the upregulation of a subset of ISGs in LPS-stimulated human monocytes. In this study, we provide experimental evidence that NRIR is localized in cellular nuclei, enriched on the chromatin fraction, and upregulates ISGs acting at the transcriptional level. In silico analysis of secondary structures identified distinct NRIR structural domains, comprising putative DNA- and protein-binding regions. In parallel, the presence of a putative DNA-binding domain in NRIR and the five putative NRIR- binding sites in the promoter of NRIR-target genes support the function of NRIR as a transcriptional regulator of its target genes. By use of integrated experimental/bioinformatics approaches, comprising database and literature mining together with in silico analysis of putative NRIR-binding proteins, we identified a list of eight transcription factors (TFs) shared by the majority of NRIR-target genes and simultaneously able to bind TF binding sites enriched in the NRIR-target gene promoters. Among these TFs, the predicted NRIR:STAT interactions were experimentally validated by RIP assay
REGULATION OF B-CELL–ACTIVATING FACTOR (BAFF)/B LYMPHOCYTE STIMULATOR (BLyS) EXPRESSION IN HUMAN NEUTROPHILS
No full textThe expression and production of cytokines by cells of the innate immune system, including monocytes/macrophages, dendritic and NK cells, play a critical role not only in defensive and inflammatory but also in immunoregulatory and anti-/pro-tumoral processes. Studies performed in the last years have well ascertained that polymorphonuclear neutrophils can also be induced to express and produce chemokines, proinflammatory, anti-inflammatory, immunoregulatory, angiogenic and fibrogenic cytokines, as well as ligands belonging to the TNF superfamily. Among the latter group of molecules, B-cell-activating factor (BAFF)/B lymphocyte stimulator (BLyS), known to be essential for B lymphocyte homeostasis and related pathologies, has recently been identified as one of the factors potentially expressed by human neutrophils. The addition of this novel TNF superfamily member, and more recently also of the closely related "A Proliferation-Inducing Ligand" (APRIL), to the list of cytokines produced by neutrophils not only testifies to the continuous growth of this area of investigation, but also implies the involvement of neutrophils in B-cell-dependent autoimmune diseases and tumors
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