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)

CD95 plays a critical role in the homeostasis of the immune system, and has been reported to participate in T cell death during HIV infection. Here we report that the response to CD3-TCR stimulation of CD4(+) T cells from HIV-infected individuals and CD4(+) T cells from healthy donors incubated in vitro with HIV-1(Lai) depends on the manner the CD3-TCR complex is engaged. While stimulation by anti-CD3 antibodies in solution induced CD4 T cell apoptosis both in the absence or presence of anti-CD95 antibodies, stimulation by immobilized anti-CD3 antibodies rendered CD4(+) T cells resistant to CD95-mediated death and led to increased CD4 T cell proliferation in response to CD95 ligation. CD95 ligation of CD4(+) T cells led to the activation of caspases, while costimulation induced by anti-CD3 and anti-CD95 mAb prevented the full processing of caspase-3 and caspase-8. Proliferation of CD4(+) T cells induced by CD3-TCR and CD95 costimulation was decreased by treatments with a caspase-1 inhibitor or with neutralizing antibodies to IL-1ss, indicating a requirement for caspase-1-mediated IL-1beta processing and secretion. Our findings suggest a novel mechanism whereby in addition to its role in inducing T cell apoptosis, CD95 signaling during HIV infection may also provide a costimulatory signal leading to an enhancement of CD4 T cell proliferation in response to CD3-TCR complex engagement.
Eur J Immunol 2001 Dec
PMID:Role of CD95-activated caspase-1 processing of IL-1beta in TCR-mediated proliferation of HIV-infected CD4(+) T cells. 1174 71

The human myeloid HL-60 cell line and its cell variant HL-525 were used to study signaling events leading to apoptosis induction by phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC) enzymes. Unlike parental cells, HL-525 cells are PKC-beta deficient and resistant to PMA-induced apoptosis. These cells regain susceptibility to apoptosis induction after transfection with a PKC-beta expression vector. By using this vector and specific neutralizing monoclonal antibodies (mAbs), it was established that PMA-induced apoptosis also called for an interaction between cell-surface alpha(5)beta(1)-integrin and its deposited ligand fibronectin (FN), which is downstream of PKC-beta activation. Experiments with mAbs, the PKC-beta vector, and exogenous FN revealed that the next step entailed an interaction between secreted tumor necrosis factor-alpha and its type I receptor. By using a sphingomyelinase inhibitor, it was concluded that the subsequent step involved ceramide production. Moreover, a permeable ceramide was effective in inducing apoptosis in both HL-60 and HL-525 cells, and this induction was caspase-1 and/or -4 dependent because an inhibitor of these caspases abrogated the induced apoptosis. Based on these and related differentiation studies, we conclude that the above signaling events, the early ones in particular, are shared with PMA-induced macrophage differentiation in the HL-60 cells. It is likely that once these cells acquire their macrophage phenotype and perform their tasks, they become superfluous and are eliminated from the body by a self-triggered apoptotic process that involves our proposed signaling scheme.
Mol Carcinog 2001 Dec
PMID:Protein kinase C-beta, fibronectin, alpha(5)beta(1)-integrin, and tumor necrosis factor-alpha are required for phorbol diester-induced apoptosis in human myeloid leukemia cells. 1174 31

MNEI (monocyte/neutrophil elastase inhibitor) is a 42 kDa serpin superfamily protein characterized initially as a fast-acting inhibitor of neutrophil elastase. Here we show that MNEI has a broader specificity, efficiently inhibiting proteases with elastase- and chymotrypsin-like specificities. Reaction of MNEI with neutrophil proteinase-3, an elastase-like protease, and porcine pancreatic elastase demonstrated rapid inhibition rate constants >10(7) M(-1) s(-1), similar to that observed for neutrophil elastase. Reactions of MNEI with chymotrypsin-like proteases were also rapid: cathepsin G from neutrophils (>10(6) M(-1) s(-1)), mast cell chymase (>10(5) M(-1) s(-1)), chymotrypsin (>10(6) M(-1) s(-1)), and prostate-specific antigen (PSA), which had the slowest rate constant at approximately 10(4) M(-1) s(-1). Inhibition of trypsin-like (plasmin, granzyme A, and thrombin) and caspase-like (granzyme B) serine proteases was not observed or highly inefficient (trypsin), nor was inhibition of proteases from the cysteine (caspase-1 and caspase-3) and metalloprotease (macrophage elastase, MMP-12) families. The stoichiometry of inhibition for all inhibitory reactions was near 1, and inhibitory complexes were resistant to dissociation by SDS, further indicating the specificity of MNEI for elastase- and chymotrypsin-like proteases. Determination of the reactive site of MNEI by N-terminal sequencing and mass analysis of reaction products identified two reactive sites, each with a different specificity. Cys(344), which corresponds to Met(358), the P(1) site of alpha1-antitrypsin, was the inhibitory site for elastase-like proteases and PSA, while the preceding residue, Phe(343), was the inhibitory site for chymotrypsin-like proteases. This study demonstrates that MNEI has two functional reactive sites corresponding to the predicted P(1) and P(2) positions of the reactive center loop. The data suggest that MNEI plays a regulatory role at extravascular sites to limit inflammatory damage due to proteases of cellular origin.
Biochemistry 2001 Dec 25
PMID:The serpin MNEI inhibits elastase-like and chymotrypsin-like serine proteases through efficient reactions at two active sites. 1174 53

Huntington's disease (HD) is an autosomal dominant condition, resulting from a mutation in huntingtin (htt). Htt is a novel protein, and its normal function is at present not well understood. Nuclear translocation of mutant htt in vitro up-regulates expression of the cell death gene caspase-1. We have demonstrated in a transgenic HD mouse model that caspase-1 and caspase-3 are transcriptionally up-regulated and activated. Underscoring the relevancy of these findings, recent results suggest that caspase-1 is activated in brains of humans with HD. Caspase activation results in the proteolytic cleavage of key cellular targets, including htt, leading to cell dysfunction. Caspase activation leading to cell dysfunction and death correlates with disease progression. In HD-transgenic mice, caspase inhibition resulted in a delayed onset of symptoms, a slowed progression, and prolonged survival. Caspase inhibition is a therapeutic strategy that merits evaluation in humans with HD.
Neuroscientist 2001 Dec
PMID:Caspases in Huntington's disease. 1176 25

In retinitis pigmentosa, retinal detachment, age-related macular degeneration, and glaucoma, retinal neuronal cells are damaged by a common mechanism, apoptosis. Because apoptosis is an active process that requires de novo expression of a "death message", this process can be controlled by inhibiting the expression of the "death message". We first studied whether a retinal ischemia-reperfusion model can be used as a model for retinal neuronal apoptosis. In the retinal ischemia-reperfusion injuries, typical features of apoptosis, including TUNEL-positive cells, DNA ladder formation, and ultrastructural features of apoptosis were found. Using the model, systematic research to identify the "death message" was done by DNA microarray analysis. About 200 messages were found to be up- or down-regulated during the process of retinal ischemia-reperfusion. These genes were divided into four groups: (1) transcription factor genes, (2) cell cycle-related genes, (3) reactive oxygen scavenger genes and (4) molecular chaperon genes. The possible roles of such genes in neuronal apoptosis following retinal ischemia-reperfusion injury were studied. In the model, reactive oxygen species produced by reperfusion was found to generate lipid peroxides and induced up-regulation of a transcription factor, c-Jun, that further induced aberrant expression of cell cycle-related genes such as cyclin D1 in amacrine cells. However, because no controlled expression of cell cycle-related genes takes place in retinal neurons, amacrine cells died by a G1 arrest mechanism. On the other hand, horizontal cells never expressed cyclin D1 and the cells were found to die by necrosis. The study revealed a possible mechanism of retinal neuronal apoptosis and it also became apparent that different types of neurons use different "death messages". Furthermore, the possibility that inhibition of a "death message" sometimes induces necrosis rather than apoptosis was shown. This means that we need to try inhibition of the death mechanism upstream rather than downstream. Administration of thioredoxin, an endogenous reactive oxygen species that blocks generation of lipid peroxides and thus inhibits the death process upstream, was found to be neuroprotective against retinal ischemia-reperfusion injury. Aberrant expression of c-Jun and cyclin D1 was down-regulated by the treatment. Possible roles of caspases were also studied by using the ischemia-reperfusion injury, RCS rat, and excessive light exposure damage in wild type and caspase-1 deficient mice. Also, application of adeno-associated virus that carries Bcl-xL was tested to find possible neuroprotective effects on RCS rats. Our studies showed that caspase-1 played a more important role in the retinal photoreceptors and caspase-3 was important in neurons in the inner nuclear layer. Caspase-2 was found to be a major caspase in the retinal ganglion cell layer. In agreement with the findings, caspase-1 deficient mice showed less prominent light damage than wild type mice. Gene therapy by Bcl-xL was effective to protect retinal photoreceptor damage in RCS rats.
Nippon Ganka Gakkai Zasshi 2001 Dec
PMID:[Retinal neuronal cell death: molecular mechanism and neuroprotection]. 1180 59

Infection of HeLa cells with poliovirus leads to rapid shut-off of host cell transcription by RNA polymerase II. Previous results have suggested that both the basal transcription factor TBP (TATA-binding protein) and transcription activator proteins such as CREB (cyclic AMP-responsive element-binding protein) and Oct-1 (the octamer-binding factor) are cleaved by the viral-encoded protease, 3C(Pro). Here we demonstrate that the transcriptional activator (and tumor suppressor) p53 is degraded by the viral protease 3C both in vivo and in vitro. Unlike other transcription factors that are directly cleaved by 3C(pro), degradation of p53 requires a HeLa cell activity in addition to 3C(Pro). The degradation of p53 by 3C(Pro) does not appear to involve the ubiquitin pathway of protein degradation. Vaccinia virus infection of HeLa cells leads to inactivation of the cellular activity required for 3C(Pro)-mediated degradation of p53. The vaccinia-encoded protein (CrmA) is known to inhibit caspase I (ICE protease) that converts inactive IL-1beta to an active secreted form. Incubation of HeLa cells with caspase I inhibitor Z-VAD-fmk does not interfere with 3C(Pro)-mediated degradation of p53. The cellular activity present in extracts of HeLa cells can be fractionated through phosphocellulose. A partially purified fraction that elutes at 0.6 M KCl from phosphocellulose contains the activity that degrades p53 in a 3C(Pro)-dependent manner. These results suggest that both poliovirus-encoded protease 3C(Pro) and a cellular activity are required for the degradation of p53 observed in cells infected with poliovirus.
Virology 2001 Dec 20
PMID:Poliovirus 3C protease-mediated degradation of transcriptional activator p53 requires a cellular activity. 1187 95

This article describes currently available intracardiac ultrasound (ICE) technology contrasting it with intravascular ultrasound (IVUS), highlighting their differences. General and specific clinical applications, limitations and future developments of ICE are addressed. ICE is possible because lower frequency transducers (in contrast to higher frequency IVUS devices) have been miniaturized and mounted onto catheters capable of percutaneous insertion into the heart. Since the recent availability of a steerable, 5.5--10MHz phased-array catheter with full Doppler capability, these lower frequency transducers are not only capable of enhanced penetration, permitting high-resolution two-dimensional (2D) imaging but can also provide haemodynamic data. ICE facilitates electrophysiologic procedures by guiding trans-septal catheterization, enabling endocardial anatomy visualization, ensuring ablation electrode/tissue contact and promptly diagnosing procedural complications. Promising non-electrophysiologic applications include guidance of percutaneous closure of septal defects, percutaneous mitral balloon valvuloplasty and complex cardiac biopsy. Current limitations include monoplanar imaging and narrow field of view. Expanded diagnostic techniques such as tissue Doppler, multiplane, three dimensional (3D) and multimodality imaging represent future refinements. ICE is now a clinical tool. With the introduction of the newest phased-array transducer, with full Doppler capability, ICE has the potential to play an important role in diagnostic and therapeutic interventional procedures. Further refinement and miniaturization hold the key to primary operator controlled, integrated ultrasound-guided interventional devices.
Eur J Echocardiogr 2001 Dec
PMID:Intracardiac echocardiography. 1188 17

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that induces apoptosis in a number of cell systems, including osteoblasts. Transforming growth factor beta1 (TGF-beta1) is an abundant growth factor that is known to stimulate bone formation. This study was designed to examine the role of TGF-beta1 on TNF-alpha-induced apoptosis in murine osteoblastic MC3T3-E1 cells. Total RNA was extracted from MC3T3-E1 cells treated with 20 ng/ml of TNF-alpha, 10 ng/ml of TGF-beta1, or combination, for 6 h. TNF-alpha exerted a variety of effects on the apoptotic gene expression in osteoblasts. Ribonuclease protection assays (RPA) revealed that TNF-alpha upregulated the mRNA levels of caspase-1, -7, -11, -12, and FAS. Western blot analysis showed enhanced processing of caspase-1, -7, -11, and -12, with the appearance of their activated enzymes 24 h after TNF-alpha treatment. In addition, caspase-3-like activity was significantly activated following TNF-alpha treatment. Levels of cleaved poly(ADP-ribose) polymerase and FAS protein were also elevated by TNF-alpha. Finally, Hoechst staining, terminal deoxynucleotidyl-transferase nick-end labeling (TUNEL) assay, and oligonucleosome ELISA all indicated that TNF-alpha induced apoptosis. In contrast, the addition of TGF-beta1 attenuated all of the aforementioned effects of TNF-alpha. Our results demonstrate that TGF-beta1 can decrease TNF-alpha-induced apoptosis in murine osteoblasts at least in part by attenuating TNF-alpha-induced caspase gene expression.
Biochim Biophys Acta 2002 Dec 16
PMID:TGF-beta1 inhibits multiple caspases induced by TNF-alpha in murine osteoblastic MC3T3-E1 cells. 1243 78

Originally identified as the gamma interferon-inducing factor, interleukin-18 (IL-18) was rediscovered as a proinflammatory cytokine related to the IL-1 family of cytokines that plays an important role in both innate and adaptive immune responses against viruses and intracellular pathogens. Despite its importance in inducing and regulating immune responses, relatively little is known about its production in HIV infection. We report here significantly (P < 0.05) elevated levels of this cytokine in the sera of human immunodeficiency virus (HIV)-infected/AIDS patients compared to those of HIV-seronegative healthy persons. Surprisingly, the peripheral blood mononuclear cells (PBMC) from HIV-infected/AIDS patients were compromised in the ability to upregulate IL-18 gene expression and produce this cytokine with and without lipopolysaccharide (LPS) stimulation. A significant positive correlation (P < 0.05) existed between the concentration of IL-18 in serum and its production from PBMC of HIV-seronegative healthy individuals but not those of HIV-infected/AIDS patients. Furthermore, the patients' PBMC expressed relatively reduced levels of activated caspase-1 constitutively as well as in response to LPS stimulation. Our data suggest the involvement of transforming growth factor beta (TGF-beta) in suppressing IL-18 production from the patients' PBMC for the following reasons. (i) In in vitro studies it suppressed the production of IL-18 from PBMC. (ii) Its levels were significantly higher in the plasma of patients compared to that of control subjects. (iii) A significant negative correlation existed between the concentrations of TGF-beta in plasma and of IL-18 in serum of the patients. The elevated levels of IL-18 in the serum of HIV-infected individuals may contribute to AIDS pathogenesis, whereas its compromised production from their PBMC in response to stimuli may reduce their innate defense to opportunistic intracellular pathogens.
J Virol 2002 Dec
PMID:Elevated levels of circulating interleukin-18 in human immunodeficiency virus-infected individuals: role of peripheral blood mononuclear cells and implications for AIDS pathogenesis. 1243 70

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.
J Immunol 2002 Dec 01
PMID:Caspase-1-deficient mice have delayed neutrophil apoptosis and a prolonged inflammatory response to lipopolysaccharide-induced acute lung injury. 1244 48


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