Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interleukin-1 beta-converting enzyme (ICE) family of proteases is an important component of the mechanism of the apoptotic process, but the physiologic roles of the different homologs during apoptosis remain unclear. Significant information about the roles of proteolysis in apoptosis will be gained through identification of the distal substrates through which these proteases achieve their pro-apoptotic effects. Identification of these substrates therefore remains an important challenge. A subset of autoantibodies from patients with systemic lupus erythematosus (SLE) recognize molecules that are specifically cleaved early during apoptosis. Several of the identified autoantigens are nuclear proteins (PARP, U1-70 kDa, and DNA-PKcs) that are substrates for CPP32 in vitro and in apoptotic cells. Of note, these substrates are catalytic proteins involved in homeostatic pathways, suggesting that abolition of homeostasis is one fundamental feature ensuring the rapid irreversibility of the apoptotic process. Identification of the other substrates for this protease family will provide the tools to assess the roles of the different proteases in apoptotic death.
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PMID:Macromolecular substrates for the ICE-like proteases during apoptosis. 901 54

Proteolytic cleavage by caspases is the central event in cells undergoing apoptosis. Cleaved proteins are often targeted by autoantibodies, suggesting that the cleavage of self Ags enhances immunogenicity and is prone to induce an autoimmune response. We found autoantibodies that immunoprecipitated a 140-kDa RNA-associated protein, provisionally designated Pa, in 11 of 350 patient sera that were positive for antinuclear Abs in an immunofluorescence test. The Pa protein gave rise to three fragments with m.w. ranging from 120-130 kDa during anti-Fas-activated apoptosis. Pure caspase-3 cleaved the Pa protein into a 130-kDa fragment corresponding to the largest of these three products. Peptide sequence analysis of a tryptic digest from immunoaffinity-purified Pa showed 100% identity to human RNA helicase A (RHA). The identity of Pa with RHA was further confirmed by immunoblotting with rabbit anti-RHA Ab using anti-Pa immunoprecipitates as substrates. All 10 anti-RHA-positive patients who were clinically analyzed were diagnosed as having systemic lupus erythematosus, and 7 of them had lupus nephritis. RHA is a multifunctional protein with roles in cellular RNA synthesis and processing. Inactivation of RHA by cleavage may be an important part of the process leading to programmed cell death. The cleaved RHA fragments that are produced during apoptosis may trigger an autoimmune response in systemic lupus erythematosus.
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PMID:Human RNA helicase A is a lupus autoantigen that is cleaved during apoptosis. 1057 Mar 20

Autoantibodies directed to nuclear antigens are serological hallmarks of autoimmune rheumatic diseases such as systemic lupus erythematosus. Although much more is known about the molecular identity and functions of targeted self-antigens, with few exceptions, evidence that autoantibodies to these targets have a particular function and contribute directly to the pathological process is lacking. Here we show that human autoantibodies reacting with the zinc fingers of poly(ADP-ribose) polymerase involved in the recognition of damaged DNA totally prevent the cleavage of poly(ADP-ribose) polymerase by caspase-3, a process that normally occurs during early apoptosis. Furthermore, these antibodies, which are frequent in certain autoimmune rheumatic and bowel diseases, affect the characteristic features of apoptosis and increase cell survival ex vivo. This new observation is important, because failure to remove autoimmune or abnormal cells can give rise to prolonged autoimmune stimulation and tumor formation.
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PMID:Inhibition of caspase-3-mediated poly(ADP-ribose) polymerase (PARP) apoptotic cleavage by human PARP autoantibodies and effect on cells undergoing apoptosis. 1072 54

Captopril is an orally active inhibitor of angiotensin-converting enzyme (ACE) which is widely used as an anti-hypertensive agent. In addition to its ability to reduce blood pressure, captopril has a number of other biological activities. Recently the drug was shown to inhibit Fas-induced apoptosis in human activated peripheral T cells and human lung epithelial cells. In this study, we investigated whether captopril blocks activation-induced apoptosis in murine T cell hybridomas, and found that captopril inhibited IL-2 synthesis and apoptotic cell death upon activation with anti-CD3 antibody. In addition, captopril inhibited an inducible caspase-3-like activity during activation-induced apoptosis. On the other hand, captopril did not interfere with Fas signalling, since anti-Fas antibody-induced apoptosis in Fas+ Jurkat cells was unaffected by the drug. Furthermore, we examined whether captopril blocks activation-induced apoptosis by interfering with expression of Fas, Fas ligand (FasL), or both on T cell hybridomas. FasL expression on activated T cells was significantly inhibited by captopril, whereas up-expression of Fas was partially inhibited, as assessed by cell surface staining. Taking all data together, we conclude that captopril prevents activation-induced apoptosis in T cell hybridomas by interfering with T cell activation signals. Captopril has been reported to induce systemic lupus erythematosus syndrome, and our findings may be useful for elucidating the mechanism of captopril-induced autoimmunity.
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PMID:Angiotensin-converting enzyme inhibitor captopril prevents activation-induced apoptosis by interfering with T cell activation signals. 1097 19

The apoptosis-defective lpr (fas) mutation in MRL mice causes the early onset of a lupus-like autoimmune disease with concomitant inflammation. In order to analyse the consequences of the impaired Fas-dependent apoptosis on inflammation, the susceptibility to apoptosis of polymorphonuclear leukocytes (PMN), obtained from MRL lpr/lpr mice, has been studied. Peritoneal PMN from lpr/lpr and control (+/+) mice were recruited with a mild inflammatory stimulus. The number of cells collected from the peritoneal cavity of young lpr/lpr mice was comparable to that obtained from age-matched control mice, indicating that PMN homeostasis is maintained regardless of the loss-of-function Fas mutation. Recruited neutrophils were exposed in culture to apoptosis-inducing stimuli. Treatment with agonist anti-Fas antibody increased apoptosis of +/+ PMN, but did not affect lpr/lpr PMN which do not express Fas on their surface. However, lpr/lpr PMN could undergo both spontaneous and stimulus-induced apoptosis in a fashion comparable to or higher than that of control +/+ mice. Analysis of mRNA expression revealed that lpr/lpr PMN have reduced expression of IL-18, whereas IL-1beta, IFNgamma, caspase 1 and caspase 3 are expressed at levels comparable to those of +/+ cells. However, caspase-3-like activity was higher in PMN from lpr/lpr mice than in +/+ cells, and correlated with enhanced apoptosis. It could be concluded that in young, uncompromised lpr/lpr mice, PMN homeostasis is still fully regulated through the involvement of Fas-independent, compensatory, apoptotic mechanisms. This could include an increased participation of caspase 3 in the apoptotic pathway, consequent to enhanced activation of the enzyme and to the decreased production of IL-18, which acts as a competitive caspase 3 substrate.
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PMID:Neutrophil apoptosis in autoimmune Fas-defective MRL lpr/lpr mice. 1156 32

To identify candidate autoantigens associated with arthritis, a rat chondrocyte cDNA library was immunoscreened with serum from a patient with rheumatoid arthritis. One isolated cDNA encoded part of AHNAK, a 700-kDa phosphoprotein with DNA binding properties, that appears to be involved in several signal transduction pathways. Immunoreactivity against an in vitro translated human AHNAK fragment was detected in 4.6% (5/109) of patients with rheumatoid arthritis, 29.5% (18/61) of patients with systemic lupus erythematosus (SLE), and 1.2% (2/172) of blood donors. Anti-AHNAK antibodies reacted with a recombinant human AHNAK fragment and with native AHNAK from C32 cell lysates. In vitro translated AHNAK fragment could be cleaved by granzyme B and caspase-3. Anti-AHNAK positive SLE patients had a higher frequency of homogeneous antinuclear antibody staining patterns and a lower frequency of recent mucosal ulcerations. This is the first report that AHNAK can be targeted by the immune system in autoimmune disease.
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PMID:Identification of AHNAK as a novel autoantigen in systemic lupus erythematosus. 1186 58

Peripheral T cell apoptosis is upregulated in active SLE, in parallel with high expression of both membrane-bound and soluble (s) Fas. Previous studies postulated that sFas down-regulates apoptosis in vitro through its blockade of the Fas-L of cytotoxic cells. We have investigated the extent of apoptosis and sFas levels in 14 patients with active (group A) and 11 with inactive SLE (group B). Fas was predominantly expressed by CD3+ cells from group A, whose increased serological levels of sFas were linearly correlated with the TUNEL positive cell population, whereas low titers paralleled a mild level of apoptosis in group B. This association was also investigated by measuring the effect of sFas on both cell proliferation and caspase activation. We found that incubation with sFas greatly suppressed proliferation of CD3+ cells, especially in group B, and in control cells from healthy donors whose content of CPP32 active products was significantly increased. We postulate that sFas promotes a pro-apoptogen effect, which would explain the high susceptibility to apoptosis in active lupus, and that the apoptosis program itself includes release of sFas to spread the death signal.
Lupus 2003
PMID:Enhancement of T cell apoptosis correlates with increased serum levels of soluble Fas (CD95/Apo-1) in active lupus. 1258 20

DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinase that has critical roles in DNA double-strand break repair, as well as B- and T-cell antigen receptor rearrangement. The DNA-PK enzyme consists of the Ku regulatory subunit and a 450-kDa catalytic subunit termed DNA-PK(CS). Both of these subunits are autoantigens associated with connective tissue diseases such as systemic lupus erythematosus (SLE) and scleroderma. In this report, we show that DNA-PK(CS) is cleaved during poliovirus infection of HeLa cells. Cleavage was visible as early as 1.5 h postinfection (hpi) and resulted in an approximately 40% reduction in the levels of native protein by 5.5 hpi. Consistent with this observation, the activity of the DNA-PK(CS) enzyme was also reduced during viral infection, as determined by immunoprecipitation kinase assays. Although it has previously been shown that DNA-PK(CS) is a substrate of caspase-3 in vitro, the protein was still cleaved during poliovirus infection of the caspase-3-deficient MCF-7 cell line. Cleavage was not prevented by infection in the presence of a soluble caspase inhibitor, suggesting that cleavage in vivo was independent of host caspase activation. DNA-PK(CS) is directly cleaved by a picornaviral 2A protease in vitro, producing a fragment similar in size to the cleavage product observed in vivo. Taken together, our results indicate that DNA-PK(CS) is cleaved by the 2A protease during poliovirus infection. Proteolytic cleavage of DNA-PK(CS) during poliovirus infection may contribute to inhibition of host immune responses. Furthermore, cleavage of autoantigens by viral proteases may target these proteins for the autoimmune response by generating novel, or "immunocryptic," protein fragments.
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PMID:Proteolytic cleavage of the catalytic subunit of DNA-dependent protein kinase during poliovirus infection. 1516 25

Humans and mice with systemic lupus erythematosus (SLE) and related autoimmune diseases have reduced numbers of NK T cells. An association between NK T cell deficiency and autoimmune disease has been identified. However, the mechanisms for reduction of NK T cell number in patients with SLE are unknown. In the present study we report that NK T cells from active SLE patients are highly sensitive to anti-CD95-induced apoptosis compared with those from normal subjects and inactive SLE patients. CD226 expression is deficient on NK T cells from active SLE patients. The expression of one antiapoptotic member protein, survivin, is found to be selectively deficient in freshly isolated NK T cells from active SLE patients. CD226 preactivation significantly up-regulates survivin expression and activation, which can rescue active SLE NK T cells from anti-CD95-induced apoptosis. In transfected COS7 cells, we confirm that anti-CD95-mediated death signals are inhibited by activation of the CD226 pathway through stabilization of caspase-8 and caspase-3 and through activation of survivin. We therefore conclude that deficient expression of CD226 and survivin in NK T cells from active SLE is a molecular base of high sensitivity of the cells to anti-CD95-induced apoptosis. These observations offer a potential explanation for high apoptotic sensitivity of NK T cells from active SLE, and provide a new insight into the mechanism of reduction of NK T cell number in SLE and understanding the association between NK T cell deficiency and autoimmune diseases.
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PMID:CD226 expression deficiency causes high sensitivity to apoptosis in NK T cells from patients with systemic lupus erythematosus. 2261 Dec 49

T cells isolated from patients with systemic lupus erythematosus (SLE) express low levels of CD3zeta-chain, a critical molecule involved in TCR-mediated signaling, but the involved mechanisms are not fully understood. In this study we examined caspase-3 as a candidate for cleaving CD3zeta in SLE T cells. We demonstrate that SLE T cells display increased expression and activity of caspase-3. Treatment of SLE T cells with the caspase-3 inhibitor Z-Asp-Glu-Val-Asp-FMK reduced proteolysis of CD3zeta and enhanced its expression. In addition, Z-Asp-Glu-Val-Asp-FMK treatment increased the association of CD3zeta with lipid rafts and simultaneously reversed the abnormal lipid raft preclustering, heightened TCR-induced calcium responses, and reduced the expression of FcRgamma-chain exclusively in SLE T cells. We conclude that caspase-3 inhibitors can normalize SLE T cell function by limiting the excessive digestion of CD3zeta-chain and suggest that such molecules can be considered in the treatment of this disease.
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PMID:Increased caspase-3 expression and activity contribute to reduced CD3zeta expression in systemic lupus erythematosus T cells. 1611 36


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