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)

Having recently described the injurious role of caspase-1-mediated production of the proinflammatory cytokine IL-18 in ischemic acute renal failure (ARF), we report here on the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH(2)-OPH (OPH-001) on caspase-1, IL-18, neutrophil infiltration, and renal function in ischemic ARF. C57BL/6 mice with ischemic ARF treated with OPH-001 had a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice. OPH-001 significantly reduced the increase in caspase-1 activity and IL-18 and prevented neutrophil infiltration in the kidney during ischemic ARF. To evaluate whether this lack of neutrophil infiltration was contributing to the protection against ischemic ARF, a model of neutrophil depletion was developed. Neutrophil-depleted mice had a small (18%) reduction in serum creatinine during ischemic ARF but no reduction in ATN score despite a lack of neutrophil infiltration in the kidney. Remarkably, caspase-1 activity and IL-18 were significantly increased in the kidney in neutrophil-depleted mice with ARF. In addition, IL-18 antiserum-treated neutrophil-depleted mice with ischemic ARF had a significant (75%) reduction in serum creatinine and a significant reduction in ATN score compared with vehicle-treated neutrophil-depleted mice. These results suggest a novel neutrophil-independent mechanism of IL-18-mediated ischemic ARF.
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PMID:Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice. 1239 44

A growing body of evidence has shown that bacterially challenged bone-forming osteoblasts are a significant source of an array of cytokines and chemokines that can support immune responses during bone disease. In the present study, Staphylococcus aureus and Salmonella, two common pathogens of bone, were investigated for their ability to induce production of two related inflammatory cytokines, interleukin-1beta (IL-1beta) and IL18, in osteoblasts. Cultured mouse osteoblasts were found to respond rapidly to either bacterial challenge by upregulation in the levels of mRNA encoding both IL-1beta and IL-18. Surprisingly, this mRNA expression did not translate into intracellular accumulation of IL-1beta or IL-18 precursor proteins or secretion of mature cytokines, despite the presence of detectable caspase-1 activity in these cells. These studies demonstrate that although osteoblasts can secrete a number of key proinflammatory mediators in response to bacterial pathogens, IL-1beta and IL-18 are not among this number. We suggest that osteoblasts are an unlikely source of these cytokines during the progression of bacterial infection of bone.
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PMID:Bacterial infection of osteoblasts induces interleukin-1beta and interleukin-18 transcription but not protein synthesis. 1243 85

Caspase-1, the prototypic caspase, is known to process the cytokines IL-1beta and IL-18 to mature forms but it is unclear whether, like other caspases, it can induce apoptosis by activation of downstream protease cascades. Neutrophils are known to express caspase-1, to release IL-1beta and to undergo rapid, caspase-dependent apoptosis. We examined apoptosis and IL-1beta production in peripheral blood neutrophils of caspase-1-deficient and wild-type mice. Constitutive apoptosis of caspase-1-deficient neutrophils was delayed compared with wild-type neutrophils and LPS-mediated inhibition of apoptosis was absent, but caspase-1-deficient neutrophils were susceptible to Fas-mediated apoptosis. LPS-stimulated IL-1beta production was absent from caspase-1-deficient neutrophils. To ascertain whether these differences in apoptosis and IL-1beta production would alter the response to acute lung injury, we studied pulmonary neutrophil accumulation following intratracheal administration of LPS. Caspase-1-deficient mice showed increased, predominantly neutrophilic pulmonary inflammation, but inflammation had resolved in both wild-type and deficient animals by 72 h after LPS instillation. IL-1beta production was increased in wild-type lungs but was also detected in caspase-1-deficient mice. We conclude that caspase-1 modulates apoptosis of both peripheral blood and inflammatory neutrophils, but is not essential for IL-1beta production in the lung.
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PMID:Caspase-1-deficient mice have delayed neutrophil apoptosis and a prolonged inflammatory response to lipopolysaccharide-induced acute lung injury. 1244 48

Amebiasis is a major cause of morbidity and mortality worldwide. Invasion by Entamoeba histolytica trophozoites causes secretion of proinflammatory cytokines from host epithelial cells, leading to a local acute inflammatory response, followed by lysis of colonic cells. Extracellular cysteine proteinases from amebic trophozoites are key virulence factors and have a number of important interactions with host defenses, including cleavage of immunoglobulin G (IgG), IgA, and complement components C3 and C5. Amebic lysates have also been shown to activate the precursor to interleukin 1-beta (proIL-1beta), mimicking the action of caspase-1. IL-18 is also a central cytokine, which induces gamma interferon (IFN-gamma) and activates macrophages, one of the main host defenses against invading trophozoites. Because proIL-18 is also activated by caspase-1, we evaluated whether amebic proteinases had a similar effect. Instead, we found that recombinant proIL-18 was cleaved into smaller fragments by the complex of surface-associated and released amebic proteinases. To evaluate the function of an individual proteinase from the complex pool, we expressed an active surface proteinase, EhCP5, which is functional only in E. histolytica. Recombinant EhCP5 expressed in Pichia pastoris had kinetic properties similar to those of the native enzyme with respect to substrate specificity and sensitivity to proteinase inhibitors. In contrast to the activation of proIL-1beta by amebic lysates, the purified proteinase cleaved proIL-18 and mature IL-18 to biologically inactive fragments. These studies suggest that the acute host response and amebic invasion result from a complex interplay of parasite virulence factors and host defenses. E. histolytica may block the host inflammatory response by a novel mechanism, inactivation of IL-18.
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PMID:A surface amebic cysteine proteinase inactivates interleukin-18. 1259 42

Interleukin 12 (IL-12) and IL-18 act synergistically to stimulate interferon gamma (IFN-gamma) production; moreover, IL-1 and tumor necrosis factor (TNF) may also augment IFN-gamma synthesis. We have investigated the relative contributions of these cytokines in the production of IFN-gamma and TNF by the Gram-positive bacterium Staphylococcus epidermidis, using the specific cytokine inhibitors IL-18 binding protein (IL-18BP), IL-1 receptor antagonist (IL-1Ra), anti-IL-12 antibodies (anti-IL-12 Ab), and TNF binding protein. Inhibition of caspase-1 reduced IFN-gamma and IL-1beta levels (by 80 and 67%, respectively) when heat-killed S. epidermidis was added to whole human blood cultures. IL-18BP reduced S. epidermidis-induced IFN-gamma (77% maximal suppression). In contrast, blocking IL-1 receptors by IL-1Ra had no effect on IFN-gamma production. Blocking endogenous IL-12 and TNF reduced IFN-gamma production by 69 and 36%. S. epidermidis-induced TNF-alpha was inhibited by IL-18BP and IL-1Ra, but not anti-IL-12 Ab, whereas IL-8 production was unaffected by any of the specific cytokine blocking agents. In conclusion, S. epidermidis stimulates IFN-gamma which is IL-18, IL-12 and TNF-dependent, but IL-1 independent.
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PMID:Regulation of Staphylococcus epidermidis-induced IFN-gamma in whole human blood: the role of endogenous IL-18, IL-12, IL-1, and TNF. 1267 Apr 45

After exposure of the skin to microbes, the host develops skin-specific inflammation and an acquired immune response, in which keratinocytes (KC) and Langerhans cells play critical roles respectively. We established two animal models. (i) We examined the importance of KC-derived IL-18 for the systemic IgE response by using a skin transplantation model. As previously reported, transgenic mice (KCASP1Tg), that over-express caspase-1 in their KC, display high serum levels of IgE, and spontaneously develop chronic dermatitis by production of IL-18 and IL-1beta. We examined the capacity of transplantation of cutaneous lesions from KCASP1Tg to induce IgE production in wild-type or mutant mice with a syngeneic background. Transplantation of active cutaneous lesions, that expressed high levels of IL-18 and IL-1beta, induced long-lasting IgE production in wild-type mice without elevation of circulating IL-18 and IL-1beta. Furthermore, IL-18R-, CD4- or stat6-deficient mice transplanted with the lesions did not produce IgE, indicating that this IgE response is initiated by IL-18, and dependent on host-derived CD4(+) T cells and stat6. (ii) We investigated IL-18 secretion from KC upon stimulation with microbe products. Freshly isolated KC from wild-type mice secreted IL-18 in response to Protein A purified from Cowan 1 strain of Staphylococcus aureus (SpA), which often exacerbates human skin diseases, including atopic dermatitis. Cutaneous application of SpA increased serum levels of IL-18 and IgE. These results indicate that local accumulation of IL-18 triggers systemic IgE responses without exposure to antigen.
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PMID:Persistent secretion of IL-18 in the skin contributes to IgE response in mice. 1269 61

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes.
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PMID:Modulation of the inflammatory process by statins. 1269 8

Members of the caspase family of cysteine proteases have been firmly established to play key roles in signal transduction cascades that culminate in apoptosis (programmed cell death). Caspases are normally expressed as inactive precursor enzymes (zymogens) that become activated during apoptosis and proceed to dismantle the cell from within. To date, three major apoptosis-associated pathways to caspase activation have been elucidated. Certain caspases, such as caspase-1, also occupy important positions in signaling pathways associated with immune responses to microbial pathogens. In this situation, caspase activation is associated with the maturation of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and IL-18, and not apoptosis per se. Here, we discuss the current understanding of how caspases are activated during apoptosis and inflammation and the roles these proteases play in either context.
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PMID:Caspase-activation pathways in apoptosis and immunity. 1275 66

Objective. - Mice with targeted deletion of caspase-1 (interleukin-1beta (IL-1beta)-converting enzyme) lack the active forms of IL-1beta and IL-18, two cytokines implicated in maladaptive ventricular remodeling following cardiac injury. We, therefore, investigated the extent of ventricular dilation in caspase-1-knockout (KO) mice. Methods and results. - Transthoracic echocardiography was performed at days 1, 4, and 9 following left anterior descending artery ligation in caspase-1-KO and wild-type (WT) control animals, including M-mode and short-axis imaging at both mid-papillary and apical levels. Although initial post-operative mortality was lower in KO than in WT animals (21.4% WT, 12.0% KO, P < 0.001), there was no difference in mortality between 24 h and 9 d (P = n.s.). Caspase-1 KOs exhibited significantly less mid-papillary ventricular dilatation at days 4 and 9 compared to day 1 post-myocardial infarction (MI) (P < 0.05). Caspase-1 KOs also had a marked (50%) reduction in the level of matrix metalloproteinase 3 (MMP-3), although no significant changes occurred in other MMPs or in tissue inhibitors of metalloproteinase 1 levels by immunoblot analysis. Although IL-beta plasma levels were not detectable, both IL-18 levels and the rate of apoptosis in remodeling, non-infarcted muscle were significantly higher in WT compared to caspase-1-KO animals.Conclusion. - Mice lacking caspase-1 exhibited both improved peri-infarct survival and a decreased rate of ventricular dilatation, possibly due in part to a decrease in MMP-3 activity, IL-18 production, and a reduction in the rate of apoptosis after experimental MI.
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PMID:Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. 1278 86

Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.
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PMID:Interleukin-18 and host defense against infection. 1279 54


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