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)

Direct killing of CD4+ lymphocytes by human immunodeficiency virus-1 (HIV-1) probably cannot account for the magnitude of the loss of these cells during the course of HIV-1 infection. Experimental evidence supports a pathophysiologic role of the apoptotic process in depletion of CD4 cells in acquired immunodeficiency syndrome (AIDS). The Fas-receptor/Fas-ligand (Fas-R/Fas-L) system mediates signals for apoptosis of susceptible lymphocytes and lympoblastoid cell lines. A number of investigators have recently reported increased expression of the Fas receptor in individuals with HIV infection, along with increased sensitivity of their lymphocytes to anti-Fas antibody mimicking Fas ligand. We attempted to determine the role of Fas-mediated apoptosis in disease progression and viral replication. Increased Fas-receptor (CD95) expression on CD4+ and CD8+ lymphocytes was found in a large group of HIV-1-infected patients compared with normal controls; individuals with a diagnosis of AIDS and a history of opportunistic infection had significantly more Fas receptor expression than did asymptomatic HIV-infected persons and normal blood donor controls (P < .01). Triggering of the Fas-R by agonistic anti-Fas monoclonal antibody, CH11, was preferentially associated with apoptosis in the CD4+ cells; this effect was more pronounced in lymphocytes derived from HIV+ individuals. Soluble and membrane-bound forms of Fas-L were produced in greater amounts in peripheral blood mononuclear cells (PBMC) cultures and in plasma obtained from HIV-1-infected persons than from normal controls. Furthermore, triggering of lymphocytes from HIV-infected persons by CH11 increased levels of interleukin-1beta converting enzyme (ICE), a protein associated with apoptosis. When PBMC were cultured in the presence of CH11, p24 production per number of viable cells was decreased as compared with the same PBMC without CH11 (P < .01). These findings suggest that multiple mechanisms, including increased production of Fas-L by infected PBMC, increased Fas-R expression, and induction of a protease of ICE family, may play roles in the apoptotic depletion of CD4+ cells in HIV infection.
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PMID:Role of Fas ligand and receptor in the mechanism of T-cell depletion in acquired immunodeficiency syndrome: effect on CD4+ lymphocyte depletion and human immunodeficiency virus replication. 902 59

Recently, myxoma virus was shown to encode an additional member of the serpin superfamily. The viral gene, called serp2, was cloned, and the Serp2 protein was shown to specifically bind to interleukin-1beta (IL-1beta)-converting enzyme (ICE), thus inhibiting the cleavage of pro-IL-1beta by the protease (F. Petit, S. Bertagnoli, J. Gelfi, F. Fassy, C. Boucraut-Baralon, and A. Milon, J. Virol. 70:5860-5866, 1996). Here, we address the role of Serp2 in the development of myxomatosis, a lethal infectious disease of the European rabbit. A Serp2 mutant myxoma virus was constructed by disruption of the single-copy serp2 gene and insertion of the Escherichia coli gpt gene serving as the selectable marker. A revertant virus was obtained by replacing the E. coli gpt gene by the intact serp2 open reading frame. The Serp2(-) mutant virus replicated with wild-type kinetics both in rabbit fibroblasts and a rabbit CD4(+) T-cell line (RL5). Moderate reduction of cell surface levels of major histocompatibility complex I was observed after infection with wild-type or Serp2(-) mutant myxoma virus, and both produced white pocks on the chorioallantoic membrane of the chick embryo. After the infection of European rabbits, the Serp2(-) mutant virus proved to be highly attenuated compared to wild-type myxoma virus, as demonstrated by the clinical course of myxomatosis and the survival rates of infected animals. Pathohistological examinations revealed that infection with wild-type myxoma virus resulted in a blockade of the inflammatory response at the vascular level. In contrast, rapid inflammatory reactions occurred upon infection with the Serp2(-) mutant virus. Furthermore, lymphocytes in lymph nodes derived from animals inoculated with Serp2 mutant virus were shown to rapidly undergo apoptosis. We postulate that the virulence of myxoma virus in the European rabbit can be partially attributed to an impairment of host inflammatory processes and to the prevention of apoptosis in lymphocytes. The weakening of host defense is directly linked to serp2 gene function and is likely to involve the inhibition of IL-1beta-converting-enzyme-dependent pathways.
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PMID:Serp2, an inhibitor of the interleukin-1beta-converting enzyme, is critical in the pathobiology of myxoma virus. 973 19

We previously reported that butyric acid, an extracellular metabolite from periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we examined the ability of butyric acid to induce apoptosis in peripheral blood mononuclear cells (PBMC) and the effect of bacterial lipopolysaccharide (LPS) on this apoptosis. Butyric acid significantly inhibited the anti-CD3 monoclonal antibody- and concanavalin A-induced proliferative responses in a dose-dependent fashion. This inhibition of PBMC growth by butyric acid depended on apoptosis in vitro. It was characterized by internucleosomal DNA digestion and revealed by gel electrophoresis followed by a colorimetric DNA fragmentation assay to occur in a concentration-dependent fashion. Butyric acid-induced PBMC apoptosis was accompanied by caspase-3 protease activity but not by caspase-1 protease activity. LPS potentiated butyric acid-induced PBMC apoptosis in a dose-dependent manner. Flow-cytometric analysis revealed that LPS increased the proportion of sub-G1 cells and the number of late-stage apoptotic cells induced by butyric acid. Annexin V binding experiments with fractionated subpopulations of PBMC in flow cytometory revealed that LPS accelerated the butyric acid-induced CD3(+)-T-cell apoptosis followed by similar levels of both CD4(+)- and CD8(+)-T-cell apoptosis. The addition of LPS to PBMC cultures did not cause DNA fragmentation, suggesting that LPS was unable to induce PBMC apoptosis directly. These data suggest that LPS, in combination with butyric acid, potentiates CD3(+) PBMC T-cell apoptosis and plays a role in the apoptotic depletion of CD4(+) and CD8(+) cells.
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PMID:Lipopolysaccharide stimulates butyric acid-induced apoptosis in human peripheral blood mononuclear cells. 986 91

CD4(+) T cells from patients with human immunodeficiency virus (HIV) infection undergo apoptosis at an increased rate, which leads to their depletion during disease progression. Both the Fas-Receptor (Fas-R) and interleukin-1beta (IL-1beta)-converting enzyme (ICE; caspase 1) appear to play a role in the mechanism of apoptosis of CD4(+) lymphocytes. Although Fas-R is upregulated on both CD4(+) and CD8(+) cells in HIV-infected patients, results from our laboratory and others indicate that, in patients with advanced disease, CD4(+) cells preferentially express ICE. Protease inhibitors have successfully halted the progression of HIV disease and increased CD4(+) T counts. In this study, we examined the effect of protease inhibitors on Fas-R (CD95), ICE (caspase 1) expression, apoptosis, and cell death in CD4(+) T cells of (1) HIV-infected patients who were receiving protease inhibitors, and (2) normal and patient CD4(+) T cells cultured with a protease inhibitor in vitro. Fifteen patients with advanced HIV disease on treatment showed dramatically decreased CD4(+) T-cell ICE expression, diminished apoptosis, and increased numbers of CD4(+) cells within 6 weeks of institution of protease inhibitor therapy, and before down-modulation of Fas-R (CD95) expression was evident. To determine the role of HIV infection, we studied the effect of ritonavir, a protease inhibitor, on normal and patient cells in vitro. Stimulated and unstimulated normal CD4(+) T cells, cultured with protease inhibitor, demonstrated markedly decreased apoptosis and ICE expression (P =. 01). While Fas-R expression was not significantly altered during short-term culture by such treatment, Fas-Ligand (Fas-L) membrane expression of phytohemagglutinin (PHA)-stimulated blood lymphocytes was decreased by protease inhibitor. In the presence of ritonavir, CD4(+) T cells from HIV-infected patients showed similar changes in ICE intracellular levels without alteration of Fas expression. In conclusion, protease inhibitors appear to decrease CD4(+) T-cell ICE expression and apoptosis before they affect Fas-R expression in HIV-infected patients. This action was independent of HIV infection, as similar effects were seen in CD4(+) T cells from normal controls. Some of the benefit of protease inhibitors may be related to modification of programmed cell death, which increases CD4(+) T-cell number. Whether this is due to directly to the changes effected in the caspase system remains to be determined.
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PMID:Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis in vitro and in vivo. 1126 43

The progression of HIV-1 disease appears associated with an unregulated Fas-mediated apoptosis of lymphocytes that involves the activation of ICE protease and ceramide generation and antiviral therapy may not be fully effective in the absence of a relevant impact on apoptosis. Six drug-naive HIV-1-infected symptomless patients with advanced immunodeficiency were treated with combined AZT and ddl for 4 months; plasma HIV-1 RNA levels, the counts of CD4 cells, CD4 and CD8 apoptotic lymphocytes, Fas-positive cells and ICE-positive cells, and intracellular ceramide levels were measured at base-line and after 7, 45 and 120 days of treatment. There was a prompt reduction in plasma viremia and a secondary increase in CD4 counts, but the treatment had no impact on apoptotic CD4 and CD8 lymphocytes, Fas-positive cells and ICE-positive cells, and on the intracellular levels of ceramide. A discrepancy exists between the positive impact of combined AZT and ddl treatment on plasma viral load and CD4 counts and the lack of any effect on the process of lymphocyte apoptosis. We suggest to use the measurement of apoptotic lymphocytes as a surrogate marker to predict, in combination with viral load and CD4 counts, a large proportion of the clinical effect of antiviral therapy.
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PMID:Combined antiviral therapy reduces HIV-1 plasma load and improves CD4 counts but does not interfere with ongoing lymphocyte apoptosis. 1058 2

Apoptosis induced by T cell receptor (TCR) triggering in T lymphocytes involves activation of cysteine proteases of the caspase family through their proteolytic processing. Caspase-3 cleavage was also reported during T cell stimulation in the absence of apoptosis, although the physiological relevance of this response remains unclear. We show here that the caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) blocks proliferation, major histocompatibility complex class II expression, and blastic transformation during stimulation of peripheral blood lymphocytes. Moreover, T cell activation triggers the selective processing and activation of downstream caspases (caspase-3, -6, and -7), but not caspase-1, -2, or -4, as demonstrated even in intact cells using a cell-permeable fluorescent substrate. Caspase-3 processing occurs in different T cell subsets (CD4(+), CD8(+), CD45RA(+), and CD45RO(+)), and in activated B lymphocytes. The pathway leading to caspase activation involves death receptors and caspase-8, which is also processed after TCR triggering, but not caspase-9, which remains as a proenzyme. Most importantly, caspase activity results in a selective substrate specificity, since poly(ADP-ribose) polymerase (PARP), lamin B, and Wee1 kinase, but not DNA fragmentation factor (DFF45) or replication factor C (RFC140), are processed. Caspase and substrate processing occur in nonapoptotic lymphocytes. Thus, caspase activation is an early and physiological response in viable, stimulated lymphocytes, and appears to be involved in early steps of lymphocyte activation.
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PMID:Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. 1060 47

Th1 cells that secrete IFN-gamma are particularly important in protective immunity against intracellular pathogens, including chlamydiae, and IL-18 together with IL-12 are strong inducers of IFN-gamma secretion by CD4 T cells. Because epithelial cells are known to synthesize IL-18, we investigated the effects of Chlamydia trachomatis infection of human epithelial cell lines on IL-18 secretion. We confirmed that several human epithelial cell lines constitutively express pro-IL-18 and that C. trachomatis infection causes cells to secrete mature IL-18. This was observed for several different serovars and biovars of C. trachomatis. Chlamydia-induced secretion of IL-18 from epithelial cells was regulated at the posttranscriptional level and was dependent on the activation of caspase-1. IL-1alpha or other secreted factor(s) from chlamydia-infected epithelial cells as well as chlamydial structural component(s) were not involved in inducing IL-18 secretion. Activation of caspase-1 and increased secretion of mature IL-18 was correlated with chlamydial, but not with host protein synthesis. In contrast to epithelial cell lines, fibroblast cell lines constitutively expressed much lower levels of pro-IL-18 and did not secrete mature IL-18 after chlamydial infection even though caspase-1 was activated. Taken together, the results suggest that a chlamydia-derived factor(s) is essential for the secretion of mature IL-18 through caspase-1 activation in infected epithelial cells.
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PMID:Chlamydia trachomatis infection of epithelial cells induces the activation of caspase-1 and release of mature IL-18. 1090 51

Highly active retroviral therapy has been associated with a decline in the frequency of cytopenia in patients with human immunodeficiency virus (HIV) infection. This may result from lower hematologic toxicity of newer antiviral drugs and their increased efficacy against HIV-1. Protease inhibitors, in addition to their effects on HIV replication, appear to affect various cellular functions. Recently, it was reported that ritonavir inhibited caspase-1 expression in normal CD4(+) cells. It was hypothesized that protease inhibitors may improve hematopoietic function owing to their direct effects on the bone marrow progenitor cells. When ritonavir was added to methylcellulose cultures of bone marrow cells from HIV-infected patients and normal controls, colony formation increased 2.4-fold (n = 5) in control cultures and 4-fold (n = 5) in cultures of cells from HIV-infected patients. In the presence of ritonavir, cultures of CD34(+) cells showed markedly decreased apoptosis in comparison with untreated cultures (45% decrease in apoptotic cell number; n = 6). A synthetic inhibitor of caspase 1 (Ac-Tyr-Val-Ala-Asp-aldehyde [single-letter amino acid codes]), which inhibits activation of several caspases including CPP32 and interleukin 1beta-converting enzyme (ICE or caspase 1), also decreased the rate of apoptosis and enhanced colony formation by progenitor cells derived from HIV-infected patients (3-fold; n = 5). In ritonavir-treated samples derived from HIV-infected individuals, the number of cells expressing ICE also decreased. In conclusion, HIV protease inhibitors may, by blocking the caspase-dependent apoptotic pathway, overcome inhibition of hematopoiesis seen in patients with HIV infection, an effect unrelated to their antiviral activity. (Blood. 2000;96:2735-2739)
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PMID:Protease inhibitors stimulate hematopoiesis and decrease apoptosis and ICE expression in CD34(+) cells. 1102 6

We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly increases CD4(+) and CD8(+) T cells and NK (asialoGM1(+) ) cells in the blood of tumor-bearing mice and enhances anti-metastatic activity. In this paper, we document that oral administration of bLF and bLF-hydrolysate (bLFH) is associated with strong increases in CD4(+) and CD8(+) T, as well as asialoGM1(+) cells in lymphoid tissues and lamina propria of the small intestine in mice, especially in tumor-bearing animals in which Co26Lu cells were implanted subcutaneously. Moreover, IgM(+) and IgA(+) B cells in lamina propria of the small intestine were also significantly increased by bLF and bLFH. Bovine apo-transferrin (bTF) did not exhibit such activity. In the colon, only CD8(+) cells were significantly increased by treatment with bLF, while asialoGM1(+) cells were significantly decreased. bLF and bLFH induced cytokines to activate T, B and asialoGM1(+) cells. Administration of bLF and bLFH, but not bTF, increased production of interleukin-18 (IL-18), interferon-gamma (IFN-gamma) and caspase-1 in the mucosa of the small intestine. Particularly high levels of IL-18 were found in the epithelial cells of the small intestine. Moreover, administration of bLF and bLFH, but not bTF, induced IFN-gamma presenting cells in the small intestine. Caspase-1, which processes proIL-18 to mature IL-18, was also induced in the epithelial cells of the small intestine following treatment with bLF and bLFH, but not with bTF. These results suggest that enhanced production of IL-18 and IFN-gamma and caspase-1 induction by treatment with bLF may be important for elevation of intestinal mucosal immunity.
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PMID:Activation of intestinal mucosal immunity in tumor-bearing mice by lactoferrin. 1105 Apr 73

The ICE-like families of serine proteases (caspases) have integral roles in apoptosis. These studies were performed to further understand the role of two critical caspases in relation to apoptotic regulation of the alloimmune response. A novel three-color cytofluorographic technique was utilized for measuring intracellular (in situ) caspase-1-like and caspase-3-like enzyme activity in responding CD4(+) and CD8(+) T cells over several time points of human mixed lymphocyte reactions (MLR). We found that activity levels of caspase 3 in both CD4(+) and CD8(+) responder cells began rising at day 10 of the MLR and peaked at day 14. By comparison, caspase 1 demonstrated the highest activity at day 7 in both cell subpopulations. These results coincided with the appearance of apoptotic cells among the alloreactive cells in the MLR. These findings demonstrate that intracellular caspase-1- and -3-like enzyme activity increases in both CD4(+) and CD8(+) alloreactive T cells as the primary response to allostimulatory cells progresses. While the kinetic profiles for these enzymes differed, both had a temporal association with the appearance of apoptosis in the MLR-generated cells. In all cases, the highest enzyme activity and presence of apoptosis was seen subsequent to the peak proliferative period. These results support the concept that changes in the rate and amount of apoptosis in alloreactive T cells is one mechanism by which the response to alloantigens is attenuated (i.e., tolerance) or sustained.
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PMID:Differential kinetics of intracellular caspase-1-like and caspase-3-like enzyme activity in human alloreactive CD4(+) and CD8(+) T cells undergoing apoptosis. 1123 53


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