| 1. |
- Henningsson, Louise, 1979, et al.
(författare)
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Disease-dependent local IL-10 production ameliorates collagen induced arthritis in mice
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a chronic destructive autoimmune disease characterised by periods of flare and remission. Today’s treatment is based on continuous immunosuppression irrespective of the patient’s inflammatory status. When the disease is in remission the therapy is withdrawn but withdrawal attempts often results in inflammatory flares, and re-start of the therapy is commenced when the inflammation again is prominent which leads both to suffering and increased risk of tissue destruction. An attractive alternative treatment would provide a disease-regulated therapy that offers increased anti-inflammatory effect during flares and is inactive during periods of remission. To explore this concept we expressed the immunoregulatory cytokine interleukin (IL)-10 gene under the control of an inflammation dependent promoter in a mouse model of RA - collagen type II (CII) induced arthritis (CIA). Haematopoetic stem cells (HSCs) were transduced with lentiviral particles encoding the IL-10 gene (LNT-IL-10), or a green fluorescence protein (GFP) as control gene (LNT-GFP), driven by the inflammation-dependent IL-1/IL-6 promoter. Twelve weeks after transplantation of transduced HSCs into DBA/1 mice, CIA was induced. We found that LNT-IL-10 mice developed a reduced severity of arthritis compared to controls. The LNT-IL-10 mice exhibited both increased mRNA expression levels of IL-10 as well as increased amount of IL-10 produced by B cells and non-B APCs locally in the lymph nodes compared to controls. These findings were accompanied by increased mRNA expression of the IL-10 induced suppressor of cytokine signalling 1 (SOCS1) in lymph nodes and a decrease in the serum protein levels of IL-6. We also found a decrease in both frequency and number of B cells and serum levels of anti-CII antibodies. Thus, inflammation-dependent IL-10 therapy suppresses experimental autoimmune arthritis and is a promising candidate in the development of novel treatments for RA.
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| 2. |
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| 3. |
- Kannius-Janson, Marie, 1969, et al.
(författare)
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The tissue-specific regulation of the carboxyl ester lipase gene in exocrine pancreas differs significantly between mouse and human.
- 2000
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Ingår i: The Biochemical journal. - 0264-6021. ; 351 Pt 2, s. 367-76
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Tidskriftsartikel (refereegranskat)abstract
- The carboxyl ester lipase (CEL) gene is highly expressed in exocrine pancreas and expression of the human CEL gene is mediated by a strong tissue-specific enhancer, which is absolutely necessary for high-level expression. The mouse promoter, on the other hand, does not contain a corresponding enhancer element, but instead is totally dependent on another pancreas-specific element. This element is identified as a pancreatic transcription factor 1 (PTF 1)-binding site. The human CEL promoter also contains a putative PTF 1 element located at a position corresponding to the essential PTF 1 site in the mouse promoter. However, nucleotide changes in the human promoter 5' flanking this PTF 1 site have created an overlapping CCAAT/enhancer-binding protein (C/EBP)-like binding motif, interfering with the binding of PTF 1. Hence, our findings provide an example of genetic divergence between species not accompanied by difference in function.
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| 4. |
- Levin, Malin, 1973, et al.
(författare)
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Evaluation of macrophage-specific promoters using lentiviral delivery in mice.
- 2012
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Ingår i: Gene therapy. - : Springer Science and Business Media LLC. - 1476-5462 .- 0969-7128. ; 19:11, s. 1041-7
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Tidskriftsartikel (refereegranskat)abstract
- In gene therapy, tissue-specific promoters are useful tools to direct transgene expression and improve efficiency and safety. Macrophage-specific promoters (MSPs) have previously been published using different delivery systems. In this study, we evaluated five different MSPs fused with green fluorescent protein (GFP) to delineate the one with highest specificity using lentiviral delivery. We compared three variants of the CD68 promoter (full length, the 343-bp proximal part and the 150-bp proximal part) and two variants (in forward and reverse orientation) of a previously characterized synthetic promoter derived from elements of transcription factor genes. We transduced a number of cell lines and primary cells in vitro. In addition, hematopoietic stem cells were transduced with MSPs and transferred into lethally irradiated recipient mice. Fluorescence activated cell sorting analysis was performed to determine the GFP expression in different cell populations both in vitro and in vivo. We showed that MSPs can efficiently be used for lentiviral gene delivery and that the 150-bp proximal part of the CD68 promoter provides primarily macrophage-specific expression of GFP. We propose that this is the best currently available MSP to use for directing transgene expression to macrophage populations in vivo using lentiviral vectors.
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| 5. |
- Lidberg, Ulf, 1962, et al.
(författare)
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Genomic organization, sequence analysis, and chromosomal localization of the human carboxyl ester lipase (CEL) gene and a CEL-like (CELL) gene.
- 1992
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Ingår i: Genomics. - 0888-7543. ; 13:3, s. 630-40
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Tidskriftsartikel (refereegranskat)abstract
- The gene encoding human carboxyl ester lipase (CEL), including 1628 bp of the 5'-flanking region, has been isolated and characterized from two overlapping lambda phage clones. The gene spans 9832 bp and contains 11 exons interrupted by 10 introns. The exons range in size from 88 to 204 bp, except for the last exon, which is 841 bp. A major and a minor transcription initiation site were determined 13 and 7 bp, respectively, upstream of the initiator methionine. The nucleotide sequence is identical with that of the previously reported cDNA, except for the third nucleotide in the 5'-untranslated sequence, a C, which in the cDNA is a T. A TAAATA sequence is present 26 nt upstream from the major CAP site, and within the 5'-flanking region there are several putative transcription factor binding sites. Seven Alu repetitive sequence elements are present in the region analyzed. The organization of the human CEL gene is similar to that of the recently reported rat pancreatic cholesterol esterase gene. The CEL gene was assigned to chromosome 9q34-qter, which confirms the recently reported results of Tayler et al. (1991, Genomics 10: 425-431). A previously unknown gene with a striking homology to the human CEL gene, here called the CEL-like gene (CELL), has also been isolated and characterized, including 1724 bp of the 5'-flanking region. The CELL gene, which most likely is a psuedogene, spans 4846 bp, and due to the absence of a 4.8-kb segment, the CEL gene exons 2-7 are not present in the CELL gene. Despite these differences, the CELL gene is transcribed. We have also assigned the CELL gene to a separate locus at chromosome 9q34-qter.
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| 6. |
- Lidberg, Ulf, 1962, et al.
(författare)
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Transcriptional regulation of the human carboxyl ester lipase gene in exocrine pancreas. Evidence for a unique tissue-specific enhancer.
- 1998
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Ingår i: The Journal of biological chemistry. - 0021-9258. ; 273:47, s. 31417-26
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Tidskriftsartikel (refereegranskat)abstract
- The human carboxyl ester lipase (CEL) is an important enzyme for the intestinal absorption of dietary lipids. The gene is highly expressed in exocrine pancreas and in the mammary gland during pregnancy and lactation. In this paper, we have focused on its transcriptional regulation in exocrine pancreas. Reporter gene analysis in cell cultures reveals that a high level of tissue-specific expression is established by the proximal 839 base pairs of the 5'-flanking region. This is due to a strong enhancer, located at -672 to -637. Transfections in mammary gland-derived cells reveal that the enhancer is pancreas-specific and does not contribute to the mammary gland expression. This indicates that the expression of the CEL gene in the mammary gland and pancreas, respectively, is due to two different regulatory systems. Further characterizations of the enhancer reveal that it is composed of two closely located cis-elements. The proximal element mediates a positive effect, whereas the distal element exerts a silencing effect on the positive proximal element. The functional enhancer complex is composed of ubiquitously expressed factors, since similar interactions are achieved with nuclear extracts from cells derived from other tissues. However, no enhancer activity is achieved in such cells. Hence, the net enhancer activity is the result of a tissue-specific balance between factors interacting with the two elements. Since none of the described cis-elements show any clear homology to known cis-elements, we propose that the interacting complex is composed of yet unidentified transcription factors.
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| 7. |
- Madeyski, K, et al.
(författare)
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Characterization of the gorilla carboxyl ester lipase locus, and the appearance of the carboxyl ester lipase pseudogene during primate evolution.
- 1999
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Ingår i: Gene. - 0378-1119. ; 239:2, s. 273-82
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Tidskriftsartikel (refereegranskat)abstract
- In this study we report on the isolation and characterization of the gorilla carboxyl ester lipase gene, CEL, and the corresponding CEL pseudogene. We also report on the age of the CEL pseudogene. The gorilla CEL gene is 10.5kb long and comprises 11exons intervened by introns similar to the situation in man, mouse and rat. The encoded protein is 998amino acids long and includes a 23amino acid-long leader peptide. Comparison of the coding sequence, excluding exon 11, of CEL from gorilla and man reveals a 97% similarity. Exon 11, which encodes the characteristic proline rich repeats, contains 39 repeated units in gorilla compared to 16 in man. A truncated CEL pseudogene, with the same organization as that found in man, is also shown to be present in the gorilla genome. The gorilla CEL pseudogene is 4.9kb in length and consists of 5exons interrupted by introns. Southern analysis of the gorilla CEL locus shows that the locus is arranged in a similar way as in man with the functional CEL gene being the most 5' one. To bring further insight to the events involved in the rearrangement of the CEL locus, genomic Southern analyses were performed across several primates; Homo sapiens, Pan troglodytes, Gorilla gorilla, Pongo pygmaeus and Macaca arctoides. Results presented show that the CEL gene duplication occurred prior to the separation of Hominidae (man, chimpanzee, gorilla and orangutan) from Old World monkeys (macaque). The deletion of the original CEL gene giving rise to the truncated version of the CEL gene seems, however, to be restricted to man and the great apes only.
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| 9. |
- Perman, Jeanna, 1981, et al.
(författare)
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The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction.
- 2011
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Ingår i: The Journal of clinical investigation. - : American Society for Clinical Investigation. - 1558-8238 .- 0021-9738. ; 121:7, s. 2625-40
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Tidskriftsartikel (refereegranskat)abstract
- Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1α through its interaction with a hypoxia-responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.
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| 10. |
- Aminoff, A, et al.
(författare)
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Allele-specific regulation of MTTP expression influences the risk of ischemic heart disease.
- 2010
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Ingår i: Journal of lipid research. - 0022-2275 .- 1539-7262. ; 51:1, s. 103-11
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Tidskriftsartikel (refereegranskat)abstract
- Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.
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