1,721,091 research outputs found
Suppression of inflammation and acquired immunity by IL-37
No full textIL-37 is a unique member of the IL-1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. Immune and non-immune cells produce IL-37 precursor following pro-inflammatory stimuli. Following activating cleavage by caspase-1, mature IL-37 translocates to the nucleus, where it suppresses transcription of pro-inflammatory genes. Both precursor and mature IL-37 are also secreted in the extracellular space, where they bind IL-18Rα and recruit the IL-1R8 (formerly TIR8 or SIGIRR), which transduces anti-inflammatory signals by suppressing NF-kB and MAPK and by activating Mer-PTEN-DOK pathways. During inflammation, IL-37 restores the metabolism of the cell by reducing succinate, inhibiting mTOR, and activating AMPK. Transgenic mice expressing human IL-37 and wild type mice treated with recombinant human IL-37 are protected from several experimental models of inflammation, including endotoxin shock, colitis, lung and spinal cord injury, coronary artery disease, arthritis and inflammation-induced fatigue, while also exhibiting reduced adaptive immune responses. In humans, IL-37 likely functions to limit excessive inflammation: accordingly, IL-37 levels are abnormal in patients with inflammatory and autoimmune diseases. In this review, we provide an overview of the discovery and biology of IL-37, and discuss the potential for development of this cytokine as a therapeutic agent
Anakinra therapy for non-cancer inflammatory diseases
No full textInterleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1α and IL-1β) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, including prostaglandins, cytokines, and chemokines. IL-1α is constitutively present in endothelial and epithelial cells, whereas IL-1β is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Quenching IL-1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly Mycobacterium tuberculosis, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases
Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies
No full textThe inflammatory cytokines IL-1α and IL-1β orchestrate local and systemic inflammatory responses underlying a broad spectrum of diseases. Three agents for reducing IL-1 activities are currently available. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist. Anakinra binds to the IL-1 receptor and prevents the activity of IL-1α and IL-1β. The soluble decoy receptor rilonacept and the neutralizing mAb canakinumab block IL-1β. A mAb directed against the IL-1 receptor and a neutralizing anti-human IL-1α are in clinical trials. The availability of therapies specifically targeting IL-1 unveiled the pathological role of IL-1-mediated inflammation in a broadening list of diseases. Conditions effectively treated with agents blocking IL-1 range from classic rheumatic diseases, such as RA and gout, to autoinflammatory syndromes, such as systemic JIA and FMF. However, IL-1 antagonism is also effective against highly prevalent inflammatory diseases, namely cardiovascular diseases and type 2 diabetes, conditions that are frequently encountered as co-morbidities in patients with rheumatic diseases. Thereby, IL-1 inhibition has the potential to lift the burden of disease for patients with rheumatic conditions, but also to provide clinical benefits beyond the efficacy on osteoarticular manifestations
IL-1 induces IL-1. III. Specific inhibition of IL-1 production by IFN-gamma
No full text: IL-1 possesses several biologic properties, some of which are associated with chronic inflammatory diseases. We have recently shown that IL-1 induces its own gene expression and, in the present studies, we have examined the effect of IFN-gamma on IL-1-induced IL-1 production. Whereas IFN-gamma increases the total amount of IL-1 (extracellular and cell-associated) produced after endotoxin stimulation of human PBMC, in the same cultures, IL-1-induced IL-1 production was markedly (greater than 70%) reduced in the presence of IFN-gamma. We observed this inhibition in the PBMC from over 40 human donors by employing non-cross-reacting RIA for either IL-1 beta or IL-1 alpha. IFN-gamma inhibited IL-1 beta-induced IL-1 alpha as well as IL-1 alpha-induced IL-1 beta production; furthermore, this inhibitory effect of IFN-gamma was unaffected by indomethacin. The ability of 100 U/ml of IFN-gamma to inhibit IL-1-induced IL-1 production was comparable to that accomplished by 10(-7) M dexamethasone. In contrast to its effect on IL-1 production from PBMC, IFN-gamma had no effect on the proliferative responses of T cells to IL-1. We conclude that IFN-gamma down-regulates synthesis of total IL-1-induced IL-1 production but up-regulates endotoxin-induced IL-1 production. These studies may explain the ameliorating effects of IFN-gamma in experimental models of IL-1-induced bone and cartilage degradation, in peritoneal fibrosis, and in patients with diseases associated with increased IL-1 production
IL-1 induces IL-1. IV. IFN-gamma suppresses IL-1 but not lipopolysaccharide-induced transcription of IL-1
No full text: IL-1 induces its own gene expression in human PBMC, in cultured smooth muscle and in endothelial cells. IL-1-induced IL-1 may be part of a self-amplification or an autocrine growth factor in a variety of responses, and thus the endogenous regulation of IL-1 production likely contributes to the outcome of immunologic or inflammatory responses. In the present study, IFN-gamma consistently increased LPS-induced IL-1, but reduced the total amount of IL-1-induced IL-1 from PBMC. This reduction was observed in populations of adherent cells and cells selected with anti-Leu M3 antibody. On a molar basis, IFN-gamma and IFN-alpha 2 were equally effective in reducing IL-1-induced IL-1 synthesis. In PBMC of 24 human subjects, IFN-gamma also reduced PMA-induced IL-1 synthesis (67% decrease, p less than 0.001). The augmentation of LPS-stimulated IL-1 by IFN-gamma was observed only when added at the same time as LPS, but IFN-gamma could be added 6 h after stimulation with IL-1 and still suppress IL-1 production. LPS-induced mRNA for IL-1 beta was modestly enhanced by IFN-gamma whereas mRNA levels for TNF were markedly increased. In contrast, IFN-gamma suppressed mRNA accumulation for IL-beta after stimulation with IL-1 alpha by 60 to 95%. The addition of IFN-gamma 30 min before stimulation of PBMC with IL-1 suppressed IL-1 beta mRNA for up to 30 h. The half-life of IL-1 beta mRNA of approximately 2 h was not influenced by IFN-gamma. Thus, IFN-gamma reduces IL-1-induced IL-1 synthesis by suppressing IL-1-induced transcription, whereas the same concentrations of IFN-gamma augment LPS-induced IL-1 production by increasing transcription
Interferons as inhibitors of interleukin 1 induced interleukin 1 synthesis
No full text: IL-1 induces its own gene expression in cultured smooth muscle and endothelial cells and in human PBMC. IL-1-induced IL-1 may be part of a self-amplification or autocrine event in inflammation. In the present study IFN gamma consistently increased LPS-induced IL-1, but reduced the total amount of IL-1-induced IL-1 from PBMC. On a molar basis, IFN gamma and IFN alpha 2 were equally effective. IL-6 also reduced IL-1 induced IL-1 but was approximately 300-fold less potent than the two interferons. The augmentation of LPS-stimulated IL-1 by IFN gamma was observed only when added at the same time as LPS, but IFN gamma could be added several hours after stimulation with IL-1 and still suppress IL-1 production. LPS-induced mRNA for IL-1 beta at 4 hours was enhanced by IFN gamma whereas IL-1-induced IL-1 beta mRNA was reduced by 70% in the presence of IFN gamma and this reduction was not due to increase degradation of IL-1 beta mRNA. These results suggest that in inflammatory tissues where IL-1 self amplification of its own gene expression is part of the pathological process, interferons may act to inhibit this cycle
Interleukin-6 and tumor necrosis factor in cerebrospinal fluid: changes during pyrogen fever
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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