Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Giant cell arteritis (GCA) is a common disease in the elderly. It is characterized by focal inflammatory lesions dominated by T lymphocytes and macrophages. The etiology of GCA is, however, still unknown. The aim of the present study was to determine whether lesional T cells represent clonal proliferations, and to characterize adhesion receptors that could be important for recruitment of T cells and antigen receptors involved in their activation. Temporal artery biopsies were obtained from 13 patients presenting with clinical signs of GCA. Immunohistochemistry was used to characterize cell surface receptors on CD3+ T cells in situ in the lesions of eight patients with biopsy-verified GCA. The overwhelming majority of T cells in GCA lesions expressed the TCR alpha beta receptors. In sections from three of eight patients, a small proportion of cells expressing TCR gamma delta was also seen. Almost all T cells expressed the integrin receptors, LFA-1 and VLA-1, as determined by double-staining. To characterize the clonal composition of the lesional T cell population, cells were isolated by collagenase digestion of two lesions and T cells cloned by limiting dilution in the presence of mitogenic antibodies, IL-2 and autologous feeder cells. Rearrangements of the T cell receptor (TCR) genes of the clones were analysed by Southern hybridization using probes for TCR gamma and beta genes. T cell clones established from GCA lesions exhibited heterogeneous rearrangement patterns, indicating a polyclonal origin of the cells. We conclude that GCA lesions contain T lymphocytes that are of polyclonal origin and express integrin-type adhesion receptors. This supports the hypothesis that GCA involves an inflammatory response during which polyclonal T cells adhere to arterial tissue components and accumulate in the developing lesions.
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PMID:T lymphocytes in giant cell arteritic lesions are polyclonal cells expressing alpha beta type antigen receptors and VLA-1 integrin receptors. 838 21

Human vascular endothelial cells (HUVEC) exhibit various immunological functions, i.e. expression of HLA class-II antigens after incubation with IFN-gamma or antigen presenting function. It has also been reported that HUVEC are able to produce IL-1, IL-6, GM-CSF and immunologically active cleavage products of arachidonic acid. In our study we investigated whether various cytokines, namely IL-1, IL-2, IL-6, GM-CSF and IFN-gamma, do alter the proliferative capacity of HUVEC, the production of van Willebrandt factor (vWF) and the expression of MHC class-II antigens. HUVEC were prepared by the collagenase digestion of human umbilical veins. Monolayers of cells were incubated with cytokines in different concentrations for 24 and 48 h. IFN-gamma inhibits the HUVEC [3H]thymidine uptake in a dose-dependent manner. Suppression of proliferation (40.1%) could be observed after 24 h incubation with 100 U IFN-gamma/ml. IL-1 was a more effective inhibitor of HUVEC proliferation (54% at 10 U/ml and 24 h incubation and 48.4% after 48 h) than IFN-gamma. IL-6 and GM-CSF showed an increasing effect on proliferation with 226% and 151% of the control group, respectively. IFN-gamma after an incubation period of 12 h and IL-1 after 24 h reduced the vWF content by about 30%. Bright MHC class-II expression was induced only by IFN-gamma. In conclusion, some of the immunoregulative cytokines might play an important role in the control of HUVEC proliferation.
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PMID:Effects of interleukin-1, -2, -4, -6, interferon-gamma and granulocyte/macrophage colony stimulating factor on human vascular endothelial cells. 850 49

In specimens taken from the posterior lip of the cervix uteri we determined the collagenase activity and the glycosaminoglycan concentration. In biopsies obtained from the lower uterine segment during cesarian section we measured cytokines (IL-8, IL-2, TNF alpha) and matrix metalloproteinases (MMP-8, MMP-9). We found that the release of collagenases is critically involved in the process of cervical dilatation. The glycosaminoglycan concentration increases during pregnancy and shows remarkable changes of the distribution patterns of the different glycosaminoglycans. The parturition is characterized by a dramatic loss of most of the glycosaminoglycans. Furthermore, the IL-8 shows a close correlation to the clinical feature of cervical ripening and is closely associated with the release of MMP-8 and MMP-9. Summarizing the process of cervical maturation and dilatation is a complex enzymatic controlled process with substantial remodelling of the cervical extracellular matrix. The cytokines IL-8 seems to play an essential role in triggering the process of cervical dilatation.
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PMID:Biochemical events in cervical ripening dilatation during pregnancy and parturition. 855 80

The effect of a panel of cytokines on the proliferation and type IV collagenase production was studied in four melanoma cell lines of different origin, tumorigenicity and metastatic capacity. TGF-b, TNF-a and to a lesser extent, IL-1a exhibited antiproliferative effect on the cell lines, with some lines showing varying degree of resistance. The sensitivity did not correlate directly with the origin or the biological behavior of the tumor lines, suggesting that cytokine resistance of advanced stage melanoma cells may be relative. IL-2, IL-10 and IL-12 displayed little or no effect on proliferation. The effect of cytokines on metalloproteinase production showed a cell line dependent pattern. Interestingly, those cytokines that exhibited the most pronounced antiproliferative activity, also proved most effective in stimulating collagenase secretion, often simultaneously, in the same line. The results indicate that pleiotropic cytokines can have positive and negative effects simultaneously on various steps of tumor progression.
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PMID:Cytokine sensitivity of metastatic human melanoma cell lines-- simultaneous inhibition of proliferation and enhancement of gelatinase activity. 965 95

Tumor cell invasion and metastasis are a complex multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases. Tissue inhibitor of metalloproteinase-1 (TIMP-1) acts as a negative regulator of matrix metalloproteinases and thus prevents tumor cell invasion and metastasis by preserving extracellular matrix integrity. In the present study, we investigated whether increasing serum TIMP-1 levels by gene transfer would decrease experimental pulmonary metastasis of melanoma in C57BL/6 mice. Female animals bearing B16F10 melanoma pulmonary metastasis were injected intramuscularly twice per week with 100 microg of plasmid DNA encoding the human TIMP-1 cDNA (TIMP-1pDNA). Substantive levels of serum human TIMP-1 were observed 3 days after single injection and were found for 6 days thereafter. Pulmonary metastasis was significantly reduced in the mice following 4 weeks of TIMP-1 treatment as compared to the controls that were treated with the plasmid DNA vector alone. Further reduction of pulmonary metastasis and increase in survival were realized by intraperitoneal injection of 1000 U of IL-2 twice per week in combination with TIMP-1 treatment. In a parallel in vitro study, a 3-fold increase in TIMP-1 expression was observed in NIH3T3 cells after IL-2 treatment. Therefore, up-regulation of TIMP-1 expression by IL-2 likely contributed to the additive effect of IL-2 and TIMP-1 in reducing metastatic disease in the animal model. In conclusion, our findings support the potential of TIMP-1 gene therapy for the prevention of metastatic melanoma.
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PMID:Gene therapy of melanoma pulmonary metastasis by intramuscular injection of plasmid DNA encoding tissue inhibitor of metalloproteinases-1. 1185 29

Herein we describe the case of a man who was diagnosed as having relapsing polychondritis (RP) when he was 18 years of age and was treated over the course of 2 years with numerous immunosuppressive agents, including tumor necrosis factor alpha (TNFalpha) inhibitors. His respiratory symptoms were refractory to treatment. Serum and urine samples were obtained periodically for measurement of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, anti-type II collagen (anti-CII) antibodies, and urinary type II collagen neoepitope (uTIINE) levels. The uTIINE assay is specific for collagenase cleavage products CII present in urine. ESRs and CRP levels varied widely but were rarely normal. Anti-CII antibody titers were high initially and decreased slowly and steadily for a year following the start of immunosuppressive medication, remaining low throughout the remainder of the patient's monitored disease course. The uTIINE levels were elevated prior to the initiation of TNFalpha inhibitors. Upon initiation of etanercept, they decreased abruptly to normal and stayed nearly normal. The uTIINE levels rose abruptly again upon discontinuation of TNFalpha inhibitor treatment. The dramatic decline in CII degradation, coincident with the administration of the TNFalpha inhibitors, suggested that this treatment dramatically reduced the chondritis. Serum levels of Th1 cytokines (interferon-gamma, interleukin-12 [IL-12], and IL-2) paralleled changes in uTIINE levels, while those of Th2 cytokines (IL-4, IL-5, IL-6, and IL-10) showed little or no association with disease state or uTIINE levels. These results indicate that RP might be a Th1-mediated disease process. Moreover, the uTIINE assay appears to provide an objective measure of the severity of chondritis that could assist clinical decisions regarding adjustments of steroid and other immunosuppressive therapy. This outcome measure merits investigation in a broader spectrum of RP patients.
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PMID:Urinary type II collagen neoepitope as an outcome measure for relapsing polychondritis. 1455 1

A Chlorella powder was screened using 52 in vitro assay systems for enzyme activity, receptor binding, cellular cytokine release, and B and T cell proliferation. The screening revealed a very potent inhibition of human protein tyrosine phosphatase (PTP) activity of CD45 and PTP1C with 50% inhibitory concentration (IC(50)) values of 0.678 and 1.56 microg/mL, respectively. It also showed a moderate inhibition of other PTPs, including PTP1B (IC(50) = 65.3 microg/mL) and T-cell-PTP (114 microg/mL). Other inhibitory activities and their IC(50) values included inhibition of the human matrix metalloproteinases (MMPs) MMP-1 (127 microg/mL), MMP-3 (185 microg/mL), MMP-7 (18.1 microg/mL), and MMP-9 (237 microg/mL) and the human peptidase caspases caspase 1 (300 microg/mL), caspase 3 (203 microg/mL), caspase 6 (301 microg/mL), caspase 7 (291 microg/mL), and caspase 8 (261 microg/mL), as well as release of the cytokines interleukin (IL)-1 (44.9 microg/mL), IL-2 (14.8 microg/mL), IL-4 (49.2 microg/mL), IL-6 (34.7 microg/mL), interferon-gamma (31.6 microg/mL), and tumor necrosis factor-alpha (11 microg/mL) from human peripheral blood mononuclear cells. Chlorella also inhibited B cell proliferation (16.6 microg/mL) in mouse splenocytes and T cell proliferation (54.2 microg/mL) in mouse thymocytes. The binding of a phorbol ester, phorbol 12,13-dibutyrate, to its receptors was also inhibited by Chlorella with an IC(50) of 152 microg/mL. These results reveal potential pharmacological activities that, if confirmed by in vivo studies, might be exploited for the prevention or treatment of several serious pathologies, including inflammatory disease and cancer.
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PMID:Effects of chlorella on activities of protein tyrosine phosphatases, matrix metalloproteinases, caspases, cytokine release, B and T cell proliferations, and phorbol ester receptor binding. 1529 60

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
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PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

Even today prematurity is the major cause of perinatal mortality. Prematurity has multiple causes. There is a growing body of evidence supporting the association between silent intrauterine infection and preterm birth. Bacterial products may activate macrophages ubiquitous present in the decidua, placenta and fetal membranes. These cells after activation secrete a large variety of mediators including tumour necrosis factor alpha (TNFalpha) and interleukin (IL)-1. Besides these cytokines IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, epidermal growth factor, granulocyte-colony stimulating factor and transforming growth factor beta have been identified in intrauterine tissues and in the amniotic fluid. The majority of these substances (TNFalpha, IL-1, IL-2, IL-3, IL-6) can stimulate the prostaglandin-biosynthesis by intrauterine tissues (amnion, chorion, decidua), some of them have antiinflammatory effects (IL-10, transforming growth factor alpha). These effects are mediated by receptors on the target cells; specific receptor antagonists (for example for IL-1) were found in high concentrations in amniotic fluid during normal pregnancy. This cytokine network is in a sensitive balance and probably associated with an uncomplicated course of pregnancy. Systemic or localized infections as well as tissue injury initiate the induction of the prostaglandin synthesis cascade thus leading to pregnancy loss via augmented cytokine secretion. Furthermore, cytokines may be involved in the regulation of preterm and term cervical ripening. The changes in mechanical properties of the cervix are associated with a reduction of collagen content and alterations in the glycosaminoglycan pattern within the cervical extracellular matrix. IL-1 can stimulate the synthesis of collagenases, and IL-8 may play an important role in the regulation of the invasion of neutrophilic granulocytes into the cervical stroma with subsequent degranulation and release of proteases. The cytokine-stimulated collagenase production in the fetal membranes is responsible for the reduction of their tensile strength and may be associated with rupture of the membranes. The cytokine network seems to be a sensitive regulation system. Disturbances of its balance by environmental (e.g. infection) or intrauterine influences (e. g. extension by the fetus) may lead to termination of pregnancy.
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PMID:[The role of cytokines in the induction of labor, cervical ripening and rupture of the fetal membranes]. 1676 18

Hypertrophic scar and keloids are fibroproliferative disorders of the skin which occur often unpredictably, following trauma and inflammation that compromise cosmesis and function and commonly recur following surgical attempts for improvement. Despite decades of research in these fibrotic conditions, current non-surgical methods of treatment are slow, inconvenient and often only partially effective. Fibroblasts from these conditions are activated to produce extracellular matrix proteins such as collagen I and III, proteoglycans such as versican and biglycan and growth factors, including transforming growth factor-beta and insulin like growth factor I. However, more consistently these cells produce less remodeling enzymes including collagenase and other matrix metalloproteinases, as well as the small proteoglycan decorin which is important for normal collagen fibrillogenesis. Recently, the systemic response to injury appears to influence the local healing process whereby increases in Th2 and possibly Th3 cytokines such as IL-2, IL-4 and IL-10 and TGF-beta are present in the circulating lymphocytes in these fibrotic conditions. Finally, unique bone marrow derived cells including mesenchymal and endothelial stem cells as well as fibrocytes appear to traffic into healing wounds and influence the healing tissue. On this background, clinicians are faced with patients who require treatment and the pathophysiologic basis as currently understood is reviewed for a number of emerging modalities.
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PMID:Cellular and molecular pathology of HTS: basis for treatment. 1772 69


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