Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infants born prematurely may develop neurocognitive deficits without an obvious cause. Oxygen, which is widely used in neonatal medicine, constitutes one possible contributing neurotoxic factor, because it can trigger neuronal apoptosis in the developing brain of rodents. We hypothesized that two caspase-1-processed cytokines, interleukin (IL)-1beta and IL-18, are involved in oxygen-induced neuronal cell death. Six-day-old Wistar rats or C57/BL6 mice were exposed to 80% oxygen for various time periods (2, 6, 12, 24, and 48 hours). Neuronal cell death in the brain, as assessed by Fluoro-Jade B and silver staining, peaked at 12 to 24 hours and was preceded by a marked increase in mRNA and protein levels of caspase 1, IL-1beta, IL-18, and IL-18 receptor alpha (IL-18Ralpha). Intraperitoneal injection of recombinant human IL-18-binding protein, a specific inhibitor of IL-18, attenuated hyperoxic brain injury. Mice deficient in IL-1 receptor-associated kinase 4 (IRAK-4), which is pivotal for both IL-1beta and IL-18 signal transduction, were protected against oxygen-mediated neurotoxicity. These findings causally link IL-1beta and IL-18 to hyperoxia-induced cell death in the immature brain. These cytokines might serve as useful targets for therapeutic approaches aimed at preserving neuronal function in the immature brain, which is exquisitely sensitive to a variety of iatrogenic measures including oxygen.
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PMID:Caspase-1-processed interleukins in hyperoxia-induced cell death in the developing brain. 1562 43

Caspase-1-deficient (-/-) mice are protected against sepsis-induced hypotension and mortality. We investigated the role of caspase-1 and its associated cytokines in a nonhypotensive model of endotoxemic acute renal failure (ARF). Mice were injected intraperitoneally with 2.5 mg of LPS that induces endotoxemic ARF. On immunoblot analysis of whole kidney, there was an increase in caspase-1 protein in LPS-treated mice compared with vehicle-treated controls. In LPS-treated mice, the glomerular filtration rate (GFR) was significantly higher in caspase-1 -/- vs. wild-type mice at 16 and 36 h after LPS. To determine the mechanism of this protection, the caspase-1-activated cytokines IL-1beta and IL-18 were investigated. IL-1beta and IL-18 protein were significantly increased in the kidneys of LPS- vs. vehicle-treated mice. To determine the role of these cytokines, mice were treated with recombinant IL-1 receptor antagonist (IL-1Ra) or IL-18-neutralizing antiserum. In LPS-treated mice, GFR was not different in IL-1Ra-treated or IL-18-neutralizing antiserum-treated or combination therapy (IL-1Ra plus IL-18-neutralizing antiserum-treated) compared with control mice. In addition, tubular cell apoptosis, neutrophil infiltration, myeloperoxidase activity, caspase-3 activity, and calpain activity were not different between wild-type and caspase-1 -/- mice with endotoxemic ARF. In LPS- vs. vehicle-treated wild-type mice, renal IL-1alpha was significantly increased. In both LPS- and vehicle-treated caspase-1 -/- mice, renal IL-1alpha was very low. In summary, caspase-1 -/- mice are functionally protected against endotoxemic ARF. Neutralization of IL-1beta and IL-18 is not functionally protective. The role of the intracellular proinflammatory cytokine IL-1alpha in endotoxemic ARF merits further study.
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PMID:Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice. 1564 89

Spermatogenesis is a phenomenon where two main processes proliferation and apoptosis, meet. Slight changes in their activities could lead to different pathologies, such as fertility disorder (excessive apoptosis) or testicular cancer (overproliferation). The IL-1 gene family includes genes which play important roles in both these processes and consists of IL-1?, IL-1ss, IL-18, the IL-1 receptor antagonist (IL-1RA), two IL-1 receptors (IL-1RI, IL-1RII), the IL-18 receptor (IL-18R?), and the receptor-associated proteins - IL-1RAcP and IL-18Rss. Caspase-1 (ICE - interleukin-1 converting enzyme), directly connected with apoptosis and responsible for the cleavage of IL-1b and IL-18, is also a member of the IL-1 family. The system of the numerous IL-1 receptors and their signal transduction involving protein cascades provokes a range of gene expressions necessary for the initiation and maintenance of inflammatory reaction. In the testis, IL-1 is constitutively expressed, where it creates a unique microenvironment for diploid gametogenic cell conversion into specialized haploid spermatozoa. It may also be an element of the physiological protection from autoimmune attack by host testicular antigens and a part of immune privilege. This review is to summarize the knowledge of the local control of spermatogenesis and immunomodulation in the male gonad. As infertility is one of the main problems of industrialized countries, study of the pathophysiology of the male genital tract appears essential in future clinical practice.
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PMID:[Function of the interleukin-1 gene system in immunomodulation, apoptosis and proliferation in the male gonad]. 1576 87

In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1alpha, IL-1beta, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1beta-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1beta-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration.
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PMID:The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. 1598 75

Interleukin (IL)-18 is a potent inflammatory cytokine of the IL-1 family. It is synthesized as an inactive precursor (pro-IL-18), which is cleaved into its functionally active form by caspase-1. Resident cells of the CNS express IL-18 and caspase-1 constitutively, thus providing a local IL-18-dependent immune response. Recent studies have highlighted a crucial role for IL-18 in mediating neuroinflammation and neurodegeneration in the CNS under pathological conditions, such as bacterial and viral infection, autoimmune demyelinating disease, and hypoxic-ischemic, hyperoxic and traumatic brain injuries. This review provides a synopsis of the current knowledge of IL-18-dependent mechanisms of action during acute neurodegeneration in immature and adult brains.
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PMID:IL-18: a key player in neuroinflammation and neurodegeneration? 1602 42

A modified version of the k-means clustering algorithm was developed that is able to analyze large compound libraries. A distance threshold determined by plotting the sum of radii of leaf clusters was used as a termination criterion for the clustering process. Hierarchical trees were constructed that can be used to obtain an overview of the data distribution and inherent cluster structure. The approach is also applicable to ligand-based virtual screening with the aim to generate preferred screening collections or focused compound libraries. Retrospective analysis of two activity classes was performed: inhibitors of caspase 1 [interleukin 1 (IL1) cleaving enzyme, ICE] and glucocorticoid receptor ligands. The MDL Drug Data Report (MDDR) and Collection of Bioactive Reference Analogues (COBRA) databases served as the compound pool, for which binary trees were produced. Molecules were encoded by all Molecular Operating Environment 2D descriptors and topological pharmacophore atom types. Individual clusters were assessed for their purity and enrichment of actives belonging to the two ligand classes. Significant enrichment was observed in individual branches of the cluster tree. After clustering a combined database of MDDR, COBRA, and the SPECS catalog, it was possible to retrieve MDDR ICE inhibitors with new scaffolds using COBRA ICE inhibitors as seeds. A Java implementation of the clustering method is available via the Internet (http://www.modlab.de).
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PMID:A hierarchical clustering approach for large compound libraries. 1604 74

During sepsis, endothelial cells are both a source and target of pro-inflammatory cytokines (e.g. IL-1alpha, IL-1beta, TNFalpha and others), which may be detrimental to vascular homeostasis. Our laboratory has demonstrated that Haemophilus somnus, a gram-negative pathogen of cattle that causes sepsis and vasculitis, and its lipooligosaccharide (LOS) induce caspases-3, -8 and -9 activation, and apoptosis of endothelial cells in vitro. In this study, we provide evidence that H. somnus LOS increases IL-1alpha and IL-1beta mRNA expression, and caspase-1 activation in endothelial cells. Addition of a caspase-1 inhibitor (YVAD), or incubation in a high extracellular potassium buffer (150 mM), reduced caspase-1 activation and significantly enhanced H. somnus LOS-mediated caspase-3 activation. Likewise, blocking the IL-1 type 1 receptor by addition of IL-receptor antagonist (IL-1ra) significantly enhanced LOS-mediated caspase-3 activation. Conversely, addition of exogenous recombinant bovine IL-1beta (100 ng/mL) to endothelial cells diminished LOS-mediated apoptosis. IL-1beta has been reported previously to protect numerous cell types from apoptosis by activating PI3 kinase/p-Akt signaling pathways. Addition of selective PI3 kinase inhibitors (e.g. wortmannin and LY294002) significantly enhanced LOS-mediated caspase-3 activation. Exposure of endothelial cells to IL-1beta or LOS increased pAkt protein as assessed by western blot. Overall, these results suggest that signaling through the IL-1 type 1 receptor diminishes H. somnus LOS-mediated apoptosis.
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PMID:Signaling through interleukin-1 type 1 receptor diminishes Haemophilus somnus lipooligosaccharide-mediated apoptosis of endothelial cells. 1612 94

Inhaled endotoxin induces an inflammatory response that contributes to the development and severity of asthma and other forms of airway disease. Here, we show that inhaled endotoxin-induced acute bronchoconstriction, TNF, IL-12p40, and KC production, protein leak, and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecule MyD88. Bronchoconstriction, inflammation, and protein leak are normal in Toll/IL-1R domain-containing adaptor inducing IFN-beta-deficient mice. MyD88 is involved in TLR, but also in IL-1R-associated kinase 1-mediated IL-1R and -18R signaling. We exclude a role for IL-1 and IL-18 pathways in this response, as IL-1R1 and caspase-1 (ICE)-deficient mice develop lung inflammation while TLR4-deficient mice are unresponsive to inhaled LPS. Significantly, using bone marrow chimera, we demonstrate that both hemopoietic and resident cells are necessary for a full MyD88-dependent response to inhaled endotoxin; bronchoconstriction depends on resident cells while cytokine secretion is mediated by hemopoietic cells.
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PMID:Both hemopoietic and resident cells are required for MyD88-dependent pulmonary inflammatory response to inhaled endotoxin. 1627 44

Activation of ST2, an orphan member of the IL-1 receptor family for 16 years, drives T helper type 2 (T(H)2) responses. The cytokine IL-33 is the specific ligand for ST2. IL-33 recapitulates much of the existing data that ST2 promotes T(H)2-type responses. The caspase-1 processing of precursor IL-33 provides a therapeutic target to control allergic diseases.
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PMID:An IL-1 family member requires caspase-1 processing and signals through the ST2 receptor. 1628 13

Many important bacterial virulence factors act as mimics of mammalian proteins to subvert normal host cell processes. To identify bacterial protein mimics of components of the innate immune signaling pathway, we searched the bacterial genome database for proteins with homology to the Toll/interleukin-1 receptor (TIR) domain of the mammalian Toll-like receptors (TLRs) and their adaptor proteins. A previously uncharacterized gene, which we have named tlpA (for TIR-like protein A), was identified in the Salmonella enterica serovar Enteritidis genome that is predicted to encode a protein resembling mammalian TIR domains, We show that overexpression of TlpA in mammalian cells suppresses the ability of mammalian TIR-containing proteins TLR4, IL-1 receptor, and MyD88 to induce the transactivation and DNA-binding activities of NF-kappaB, a downstream target of the TIR signaling pathway. In addition, TlpA mimics the previously characterized Salmonella virulence factor SipB in its ability to induce activation of caspase-1 in a mammalian cell transfection model. Disruption of the chromosomal tlpA gene rendered a virulent serovar Enteritidis strain defective in intracellular survival and IL-1beta secretion in a cell culture infection model using human THP1 macrophages. Bacteria with disrupted tlpA also displayed reduced lethality in mice, further confirming an important role for this factor in pathogenesis. Taken together, our findings demonstrate that the bacterial TIR-like protein TlpA is a novel prokaryotic modulator of NF-kappaB activity and IL-1beta secretion that contributes to serovar Enteritidis virulence.
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PMID:Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins. 1636 16


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