Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lupus-prone mice show reduced production of TNF-alpha and, upon long-term treatment with recombinant TNF-alpha, significant protection from disease development. Mutational analysis of the 5'-untranslated region (UTR) and 3'-UTR of the mouse TNF-alpha gene reveals a marked degree of polymorphism. Transient expression experiments in the RAW 264.7 macrophage-like cell line using the luciferase reporter system suggest an important role for the mutations in the 3'-UTR in the biosynthesis of TNF-alpha, and provide a molecular explanation for the reduced TNF-alpha production in lupus-prone NZW mice.
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PMID:Mutational analysis of TNF-alpha gene reveals a regulatory role for the 3'-untranslated region in the genetic predisposition to lupus-like autoimmune disease. 860 27

Naturally occurring polyreactive anti-DNA mAbs derived from a nonimmunized (NZB x NZW)F1 mouse with spontaneous lupus erythematosus penetrated and accumulated in the nuclei of a variety of cultured cells. These mAbs and their F(ab')2 and Fab' fragments, covalently coupled to fluorescein, peroxidase, or a 15-mer polynucleotide, also translocated to the cell nuclei. A 30-amino acid peptide corresponding to the combined sequences of the complementary-determining regions 2 and 3 of the heavy chain variable region of one mAb was able to penetrate into the cytoplasm and nucleus of cells of several lines. This peptide recognized DNA and was strongly polyreactive. Streptavidin-peroxidase conjugates complexed with the N-biotinylated peptide were rapidly translocated into cells. Similarly, peroxidase or anti-peroxidase polyclonal antibodies covalently coupled to the N-cysteinylated peptide through an heterobifunctional maleimide cross-linker were also rapidly internalized and frequently accumulated in nuclei. The peptide carrying 19 lysine residues at its N-terminal was highly effective in transfecting 3T3 cells with a plasmid containing the luciferase gene. Thus, penetrating mAbs and derived peptides are versatile vectors for the intracellular delivery of proteins and genes.
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PMID:Polyreactive anti-DNA monoclonal antibodies and a derived peptide as vectors for the intracytoplasmic and intranuclear translocation of macromolecules. 957 29

Previous work has documented that the earliest observable response in mammalian cells following ultraviolet (UV) irradiation is the activation of plasma membrane-associated Src tyrosine kinases. These molecules then trigger a signalling cascade that results in activation of the transcription factor AP-1 which subsequently transactivates the early immediate genes including c-jun. This pathway has been postulated to play a protective role against UV damage. As aminoquinoline antimalarials such as chloroquine are known to downregulate several photoinduced cutaneous disorders including LE-specific skin disease, we asked whether chloroquine might be capable of modulating this early limb of the UV light response. A431 cells (a human epidermal keratinocyte cell line) that had been transfected with a c-jun luciferase reporter gene construct were then treated with physiologically relevant concentrations of chloroquine followed by exposure to 0-125 J/m2 of UV-B from a bank of unfiltered FS20 lamps. Chloroquine pretreatment resulted in a dose-dependent increase in luciferase activity in permanently transfected A431 cells (luciferase activity was increased by 45% at 2.5 x 10(-5) M chloroquine and 125 J/m2 of UV-B). Hydroxychloroquine pretreatment also resulted in an increase in luciferase activity. Primaquine, an 8-aminoquinoline, did not influence the UV-B induced c-jun activity. Furthermore, chloroquine did not have a similar impact on HSP-70 gene activity during heat shock. These studies suggest that the beneficial effect of the 4-aminoquinoline antimalarials in various photodermatoses including cutaneous LE might result in part from the capacity of these drugs to enhance the protective early limb of the UV response.
Lupus 1998
PMID:4-Aminoquinoline antimalarials enhance UV-B induced c-jun transcriptional activation. 960 37

As reported previously in human monocytes, a human lung epithelial cell line, A549, showed de novo induction of 15-Lipoxygenase-1 (15-LO-1) in response to interleukins-13 (IL-13) and -4 (IL-4). In this cell line, 15-LO-1 expression, by RT-PCR and western blotting, was observed following 6 and 24 h of exposure to human IL-13 (ED50 5 ng/ml) and IL-4 (ED50 0.2 ng/ml). We have previously shown that no cis-acting regulatory elements exist within the 15-LO-1 promoter region. To define IL-13 and IL-4 responsive trans-acting elements, we identified a region (DP2: -353 to -304 bp site) within the 15-LO-1 promoter (by footprinting experiments) to which IL-13-responsive elements (or factors) bind specifically (Kelavkar et al, 1998, Mol Biol Rep 25, 173-182). To further delineate this region, we constructed (by site-directed mutagenesis) several deletion mutants in the 'LOPB5' region containing the 29 bp within the -353 to -304 bp of the DP2 core element. These were: DP3 (site totally deleted), DP4 (5 bp deleted at the center of the site), DP5 (8 bp at the 5'-end of the site) and DP6 (13 bp at the 3'-end of the site). Cotransfection of these deletion constructs (driving luciferase reporter genes) was associated with 90% (DP4, DP5 and DP6) or 100% (DP3) abrogation of promoter activity at 24 h. Purification of nuclear protein extracts from IL-13 and IL-4-stimulated A549 cells, using a DP2 core containing affinity column, identified a 150 kDa protein under non-denaturing conditions, and two, 70 and 85 kDa proteins under denaturing conditions. These were not detectable by Coomassie blue staining in control nuclear protein extracts. Matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) of the tryptic digests of these proteins, identified one as the 86 kDA Lupus KU autoantigen protein P86 and the second as the 70 kDa Lupus KU autoantigen protein P70. Gel shift and supershift experiments using monoclonal antibodies toward Ku antigen and its individual subunits, and utilizing DP2 and other mutant oligonucleotides with purified nuclear protein extracts from control and cytokine-treated A549 cells, confirmed our findings. Furthermore, electroporation of neutralizing anti-Ku70, Ku 80 and Ku70/80 antibodies into A549 cells totally suppressed IL-13 and IL-4-stimulated 15-LO-1 induction in these cells. Further, immunoprecipitation experiments data suggests that IL-4 and IL-13 activate Ku antigens and 15-LO-1 expression through distinct signaling events. In summary, in A549 cells, Ku antigen is induced in response to the cytokines, IL-13 and -4, and a 29 bp region within the -353 to -304 bp region of the 15-LO-1 promoter is required for its binding and subsequent induction of 15-LO-1 gene expression. The findings may provide an important link between the established dysregulated function of Ku antigen in auto-immune diseases, such as systemic lupus erythematosus and thyroiditis, and the increasingly recognized 'anti-inflammatory' role of 15-LO-1.
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PMID:Ku autoantigen (DNA helicase) is required for interleukins-13/-4-induction of 15-lipoxygenase-1 gene expression in human epithelial cells. 1119

A single-nucleotide polymorphism (SNP), identified at nucleotide position -844 in the 5' promoter of the FasL gene, lies within a putative binding motif for CAAT/enhancer-binding protein beta (C/EBPbeta). Electrophoretic mobility shift and supershift assays confirmed that this element binds specifically to C/EBPbeta and demonstrated that the two alleles of this element have different affinities for C/EBPbeta. In luciferase reporter assays, the -844C genotype had twice the basal activity of the -844T construct, and basal expression of Fas ligand (FasL) on peripheral blood fibrocytes was also significantly higher in -844C than in -844T homozygous donors. FasL is located on human chromosome 1q23, a region that shows linkage to the systemic lupus autoimmune phenotype. Analysis of 211 African American systemic lupus erythematosus patients revealed enrichment of the -844C homozygous genotype in these systemic lupus erythematosus patients compared with 150 ethnically matched normal controls (p = 0.024). The -844C homozygous genotype may lead to the increased expression of FasL, to altered FasL-mediated signaling in lymphocytes, and to enhanced risk for autoimmunity. This functionally significant SNP demonstrates the potential importance of SNPs in regulatory regions and suggests that differences in the regulation of FasL expression may contribute to the development of the autoimmune phenotype.
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PMID:A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. 1249 92

Human beta2-glycoprotein I (beta2GPI), also known as apolipoprotein H, has been implicated in haemostasis and the production of anti-phospholipid antibodies. There is a wide range of interindividual variation in beta2GPI plasma levels that is thought to be under genetic control, but its molecular basis remains unknown. To understand the genetic basis of beta2GPI variation, we analyzed the 5' flanking region of the beta2GPI gene for mutation detection by DHPLC and identified a point mutation at the transcriptional initiation site (-1C-->A) with a carrier frequency of 12.1%. The mutation was associated with significantly lower beta2GPI plasma levels (P < 0.0001) and low occurrence of anti-phospholipid antibodies in lupus patients (4.8% antibody-positive group vs. 16.6% in the antibody-negative group; P = 0.019). Northern blot analysis confirmed that the -1C-->A mutation was associated with lower mRNA levels and it reduced the reporter (luciferase) gene expression by twofold. Electrophoretic gel mobility shift assay (EMSA) revealed that the -1C-->A mutation disrupts the binding for crude hepatic nuclear extracts and purified TFIID. These results suggest that the substitution of C with A at the beta2GPI transcriptional initiation site is a causative mutation that affects its gene expression at the transcriptional level and ultimately beta2GPI plasma levels and the occurrence of anti-phospholipid antibodies.
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PMID:A functional polymorphism at the transcriptional initiation site in beta2-glycoprotein I (apolipoprotein H) associated with reduced gene expression and lower plasma levels of beta2-glycoprotein I. 1260 74

FcgammaRIIb, the immunoreceptor tyrosine-based inhibitory motif-containing receptor for IgG (Mendelian Inheritance in Man no. 604590), plays an important role in maintaining the homeostasis of immune responses. We have identified 10 novel single-nucleotide polymorphisms in the promoter region of human FCGR2B gene and characterized two functionally distinct haplotypes in its proximal promoter. In luciferase reporter assays, the less frequent promoter haplotype leads to increased expression of the reporter gene in both B lymphoid and myeloid cell lines under constitutive and stimulated conditions. Four independent genome-wide scans support linkage of the human FcgammaR region to the systemic lupus erythematosus (SLE; Online Mendelian Inheritance in Man no. 152700) phenotype. Our case-control study in 600 Caucasians indicates a significant association of the less frequent FCGR2B promoter haplotype with the SLE phenotype (odds ratio = 1.65; p = 0.0054). The FCGR2B haplotype has no linkage disequilibrium with previously identified FCGR2A and FCGR3A polymorphisms, and after adjustment for FCGR2A and FCGR3A, FCGR2B showed a persistent association with SLE (odds ratio = 1.72; p = 0.0083). These results suggest that an expression variant of FCGR2B is a risk factor for human lupus and implicate FCGR2B in disease pathogenesis.
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PMID:A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. 1515 43

Systemic lupus erythematosus (SLE) T cells display reduced expression of TCR zeta protein. Recently, we reported that in SLE T cells, the residual TCR zeta protein is predominantly derived from an alternatively spliced form that undergoes splice deletion of 562 nt (from 672 to 1233 bases) within the 3' untranslated region (UTR) of TCR zeta mRNA. The stability and translation of the alternatively spliced form of TCR zeta mRNA are low compared with that of the wild-type TCR zeta mRNA. We report that two adenosine-uridine-rich sequence elements (AREs), defined by the splice-deleted 3' UTR region, but not an ARE located upstream are responsible for securing TCR zeta mRNA stability and translation. The stabilizing effect of the splice-deleted region-defined AREs extended to the luciferase mRNA and was not cell type-specific. The findings demonstrate distinct sequences within the splice-deleted region 672 to 1233 of the 3' UTR, which regulate the transcription, mRNA stability, and translation of TCR zeta mRNA. The absence of these sequences represents a molecular mechanism that contributes to altered TCR zeta-chain expression in lupus.
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PMID:Stability and translation of TCR zeta mRNA are regulated by the adenosine-uridine-rich elements in splice-deleted 3' untranslated region of zeta-chain. 1711 3

In humans, maternal cells are present in the affected tissues of children with inflammatory myopathy, scleroderma, and neonatal lupus. It is unknown if maternal cell microchimerism (MCM) contributes to the pathology of disease. We sought to understand the factors that affect MCM to serve as a baseline for future mechanistic studies. Using a mouse model, we bred female mice transgenic for the luciferase (Luc) reporter gene to wild-type (WT) males. The WT offspring were sacrificed at various postnatal ages. DNA was extracted from multiple organs, and real-time PCR amplification was used to quantify Luc transgene as a marker for maternally derived cells. Sensitivity was one to two transgenic cells per 100,000 WT cells. MCM was noted in 85% of mice and 45% of tissues assayed. The average quantity of MCM was 158 maternal cells per 100,000 neonatal cells. The organs displaying the highest frequency and quantity of MCM were heart and lung (P < 0.001). Postnatal age up to 21 days did not appear to affect levels of MCM (P = 0.47), whereas increasing parity may increase levels of MCM. The data show that MCM is a common occurrence in healthy newborn mice, that it is present in their major organs, and that there are organ specific differences. This may represent differential migration of maternal cells or varying receptivity of specific fetal organs to microchimerism. Pregnancy history appears to play a role in maternal cell trafficking. The role of MCM in pregnancy and disease pathogenesis remains to be elucidated.
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PMID:Murine maternal cell microchimerism: analysis using real-time PCR and in vivo imaging. 1825 32

Protein phosphatase 2A (PP2A) is a major serine/threonine protein phosphatase in eukaryotic cells and is involved in many essential aspects of cell function. The catalytic subunit of the enzyme (PP2Ac), a part of the core enzyme, has two isoforms, alpha (PP2Ac alpha) and beta (PP2Ac beta), of which PP2Ac alpha is the major form expressed in vivo. Deregulation of PP2A expression has been linked to several diseases, but the mechanisms that control the expression of this enzyme are still unclear. We conducted experiments to decipher molecular mechanisms involved in the regulation of the PP2Ac alpha promoter in human primary T cells. After preparing serially truncated PP2Ac alpha promoter luciferase constructs, we found that the region stretching around 240 bases upstream from the translation initiation site was of functional significance and included a cAMP response element motif flanked by three GC boxes. Shift assays revealed that CREB/phosphorylated CREB and stable protein 1 could bind to the region. Furthermore, we demonstrated that methylation of deoxycytosine in the CpG islands limited binding of phosphorylated CREB and the activity of the PP2Ac alpha promoter. In contrast, the binding of stable protein 1 to a GC box within the core promoter region was not affected by DNA methylation. Primary T cells treated with 5-azacitidine, a DNA methyltransferase inhibitor, showed increased expression of PP2Ac alpha mRNA. We propose that conditions associated with hypomethylation of CpG islands, such as drug-induced lupus, permit increased PP2Ac expression.
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PMID:Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac alpha promoter determines CREB binding and activity. 1915 97


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