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Pathophysiological Responses to Endotoxin in Humans
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Anthony F. Suffredini, Naomi P. O’Grady
Recombinant soluble type I IL-1 receptor is an alternative means of blocking IL-1-mediated responses. When given prior to endotoxin administration, the incidence of chills was less and blood levels of IL-1β were decreased (35). However, IL-1R1 has a high af finity for both IL-1 β and IL-lra, and following endotoxin and IL-1 receptor administration, levels of IL-lra decreased compared to controls. This resulted in a loss of IL-lra anti-inflammatory effects and enhanced levels of cell-associated IL-1 β, and blood TNF, IL-8, and C-reactive protein levels (35). IL-1R1 did not attenuate the leukopenia, leukocytosis, platelet decrease, lactoferrin levels, or cardiovascular responses (35). Thus, results from studies inhibiting IL-1 effects with either IL-lra and type I soluble IL-1 receptor suggest that circulating IL-1 contributes only to a limited degree to endotoxin responses in humans.
Hereditary Diffuse Gastric Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Fewer than one-third of diffuse gastric cancers are attributed to H. pylori infection (which induces mutations in the IL1B and IL1RN genes on chromosome 2q14.1) and somatic mutations in the KRAS gene on chromosome 12p12.1. The IL1B (interleukin 1-beta) gene on chromosome 2q14.1 encodes a subunit of interleukin-1 (i.e., IL1B), a cytokine involved in physiologic and pathophysiologic immune and inflammatory responses. The IL1RN (interleukin-1 receptor antagonist) gene on chromosome 2q14.1 encodes a protein that binds to IL1 receptors (IL1R1) and inhibits the biologic activity of IL1-alpha (IL1A) and IL1-beta (IL1B) [17].
Treating the Underlying Causes of Synovitis, Degenerative Joint Disease and Osteoarthritis in Primary Care
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
IL-1 was the first cytokine discovered in the 1980s [34]. It has long been considered the most potent catabolic cytokine. It coordinates systemic host defense responses to pathogens or various injuries. In the joint, it is released by synovial macrophages [35] as well as by chondrocytes [36]. It results in the downregulation of chondrocyte type II and proteoglycan synthesis. It also stimulates and enhances the release of chondrocyte-mediated cartilage destructive enzymes including matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which is a family of peptidases (21). IL-1 has two known isoforms – IL-1α and IL-1β – and both bind to the IL-1R1 (IL-receptor type 1). IL-1α is released intracellularly upon cell death and IL-1β is considered to act as an extracellular cytokine (Figure 24.2.)
Survival genes expression analysis following ionizing radiation to LiCl treated KG1a cells
Published in International Journal of Radiation Biology, 2020
Yogesh Kumar Verma, Ajay Kumar Singh, Gangenahalli Ugraiah Gurudutta
Further, we identified signaling pathways for significantly regulated genes at different exposure. Pathways showing upregulation of ≥20 genes belonging to apoptosis, cell cycle, adhesion, cancer and inflammation. Clustering of samples showed similarity in differential expression of genes at 4/8 Gy and Li4 Gy/Li8 Gy. These genes are likely to be involved in similar biological processes. To identify the role of cell death/survival-related genes, the differentially expressed genes were analyzed on DAVID server. Radiation exposure, at 4 and 8 Gy, caused expression of NTRK1, IL1R1, CSF2RB, TNFRSF10D and TP53. LiCl treatment was found to reduce the expression of TP53 whereas expression of IL1R1, TNFRSF10D and NTRK1 was upregulated. NTRK1 is a receptor for NGF, which through PI3K and AKT pathway inhibits the BAD protein (pro-apoptotic) (Agaram et al. 2016) (Supplementary Figure 4). On the other hand, IL1R1 signaling activates NFκB transcription factor leading to the expression of survival-related genes like IAP, Bcl-XL and Bcl-2 (Oeckinghaus and Ghosh 2009).
‘Prototypical’ proinflammatory cytokine (IL-1) in multiple sclerosis: role in pathogenesis and therapeutic targeting
Published in Expert Opinion on Therapeutic Targets, 2020
Alessandra Musella, Diego Fresegna, Francesca Romana Rizzo, Antonietta Gentile, Francesca De Vito, Silvia Caioli, Livia Guadalupi, Antonio Bruno, Ettore Dolcetti, Fabio Buttari, Silvia Bullitta, Valentina Vanni, Diego Centonze, Georgia Mandolesi
A wide range of cells express IL-1R1, from peripheral T cells to CNS tissue, making effective the IL-1 signaling both in peripheral and brain compartments. At the peripheral level, accumulating evidence suggests that DCs and a specific subset of effector T cells express IL-1R1. In particular, Th17 cells express a high level of this receptor compared to Th1 and Th2 cells. IL-1 signaling seems indeed critical in the induction of antigen-specific Th-17 cells during EAE. Several reviews extensively described this aspect [7,8]. Recently it is emerged that IL-1 signaling together with IL-23 is required to maintain the pathogenic potency of a subset of GM-CSF-producing Th cells [70]. Endothelial cells (EC) and astrocytes also express high levels of IL-1R1, providing an important role in the regulation of multiple phases of EAE disease. Among these, BBB transmigration of leucocytes, neuroinflammation by recruitment of other leukocytes, and differentiation/reactivation of leucocytes in effector myeloid cells and lymphocytes within the perivascular space have been suggested [61,71,72]. IL-1R1, which seems not expressed on resting microglia, is upregulated in proliferating microglia in the adult mouse CNS and, in turn, regulates the proliferation of these cells [73]. Accordingly, gene therapy with centrally administered IL-1ra-expression vectors or IL-1ra delivered intarcerebroventricularly (icv), ameliorated EAE symptoms in association with a reduced neuroinflammation not only following a preventive treatment but also when applied therapeutically [57,74,75].
Novel therapeutic targets and drug development for the precision treatment of COPD
Published in Expert Review of Precision Medicine and Drug Development, 2019
IL-1 is the master cytokine of inflammation and affects most cells and organs and is primarily produced by macrophages, monocytes and fibroblasts. IL-1A and IL-1B genes encode IL −1 α and IL-1 β, respectively. Both exert their effect by binding to IL-1 receptor 1 (IL-1R1) expressed in almost all cells. Unlike most other pro-inflammatory cytokines, IL-1 exerts its effects at receptor and nucleus level. It stimulates local and systemic inflammation by facilitating the recruitment of inflammatory cells. Unfortunately, drugs targeting IL-1 have not shown efficacy in COPD. A recent, 1-year study of anti-IL-1R1 (MEDI8968) in 324 subjects with COPD (600 mg loading of anti-IL-1 intravenously on day 1 followed by 300 mg subcutaneous every 4 weeks for a total of 14 doses) demonstrated no reduction in exacerbation frequency nor improvements in lung function and health status [38].