Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated doxorubicin-induced urokinase expression in human H69 SCLC cells by the microarray technique using Human Cancer CHIP version 2 (Takara Shuzo, Kyoto, Japan), in which 425 human cancer-related genes were spotted on glass plates (Kiguchi et al., Int J Cancer 2001;93:792-7). Microarray analysis also revealed significant induction of IL-8, a member of the CXC chemokines. We have, therefore, extended the observation by testing the effects of doxorubicin on expression of the chemokine family and provide here definitive evidence that doxorubicin induces IL-8 and MCP-1, one of the CC chemokines, at least in 2 human SCLC cells, H69 and SBC-1. IL-8 antigen levels, measured by ELISA, were markedly increased in both H69 and SBC-1 conditioned media after doxorubicin treatment, in parallel with mRNA levels; and this was dependent on the dose of doxorubicin. The ribonuclease protection assay, using a multiprobe template set for human chemokines, revealed induction of not only IL-8 but also MCP-1 in doxorubicin-treated H69 cells. MCP-1 antigen levels increased approximately 100-fold in doxorubicin-treated H69 cells. RT-PCR using specific primers for MCP-1 suggested that doxorubicin also induced MCP-1 expression in SBC-1 and SBC-3 SCLC cells. Futhermore, CAT analysis using IL-8 promoter implicated the PEA3 transcriptional factor, whose binding site was located immediately upstream of the AP-1 and NF-kappaB binding sites. Thus, it is suggested that doxorubicin induces IL-8 and MCP-1 chemokines in human SCLC cells by activating gene expression, in which at least PEA3 is involved. IL-8 and MCP-1 are major chemoattractants for neutrophils and monocytes/macrophages, respectively; therefore, extensive induction of IL-8 and MCP-1 may provoke the interaction between inflammatory/immune cells and tumor cells under doxorubicin stimulation and influence many aspects of tumor cell biology.
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PMID:Induction of IL-8 and monoclyte chemoattractant protein-1 by doxorubicin in human small cell lung carcinoma cells. 1247 21

Reorganization of skin during wound healing, inflammatory disorders, or cancer growth is the result of expression changes of multiple genes associated with tissue morphogenesis. We wanted to identify proteins involved in skin remodeling and select those that may be targeted for agonistic or antagonist therapeutic approaches in various disease processes. Full-thickness human skin was grafted to severe combined immunodeficient mice and injected intradermally with 38 different adenoviral vectors inserted with 37 different genes coding for growth factors, cytokines, proteolytic enzymes and their inhibitors, adhesion receptors, oncogenes, and tumor suppressor genes. Responses were characterized for infiltration of inflammatory cells, vascular density, matrix formation, fibroblast-like cell proliferation, and epidermal hyperplasia. Of the 17 growth factor vectors, 16 induced histological changes in human skin. Members of the VEGF and angiopoietin families induced neovascularization. PDGFs and TGF-betas stimulated connective tissue formation, and the chemokines IL-8 and MCP-1 attracted inflammatory neutrophils and monocytes, respectively. The serine protease uPA induced a vascular response similar to that of VEGF. Vectors with adhesion receptors, oncogenes and tumor suppressor genes had, with few exceptions, little effects on skin architecture. The overall results suggest that adenoviral vectors can effectively remodel the architecture of human skin for studies in morphogenesis, inflammatory skin disorders, wound healing, and cancer development.
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PMID:Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice. 1264 35

Recent epidemiological studies indicated risk reductions in ovarian cancer with consumption of acetaminophen or non-steroid anti-inflammatory drugs. Until now, there is not a systematic analysis, why these agents may reduce risk of ovarian cancer, as it has been performed to explain aspirin-reduction of colon cancer risk. This review tries to explain molecular mechanisms pertinent to acetaminophen- and NSAID-reduction of ovarian cancer. It is proposed that the major mechanism by these anti-inflammatory agents is a shared pathway dependent on the suppression of NF-kappaB activity, which may subsequently decrease transcription of growth factors, chemokines and proteases such as COX-2, VEGF, IL-8/CXCL8, MCP-1/CCL-2, MIP1alpha/CCL-3, tPA and uPA, which are shown to be elevated in ovarian carcinoma, and which play diverse roles such as inducing angiogenesis, invasion, autocrine growth loops and resistance to apoptosis. Besides these, specific mechanisms of action can be attributed to acetaminophen-reduction of ovarian cancer risk via I. Induction of specific reproductive atrophy due its sex-steroid resembling phenolic ring; II. Reduction of glutathione pools due to its NAPQI metabolite, which may play an important role for sterilizing pre-malignant ovarian lesions, since they are shown to lack proper levels of glutathione; III. Inhibition of tautomerization activity of MIF (macrophage migration inhibitory factor), which is shown to be released from ovarian cancer, and which is necessary for proper ovulation; IV. Inhibition of cytokine-induced and endothelia-origined cyclooxygenases. Except the chemosensitization studies, acetaminophen and NSAIDs should be investigated in animal models to test likely benefits in ovarian cancer, since most of their activity may origin from intervening with the cancer growth-stimulating inflammatory stimuli, rather than with the direct cellular toxicity.
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PMID:NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer. 1525 53

Myeloma is a deadly B-cell neoplasm, characterized by the monoclonal proliferation of plasma cells, the development of osteolytic lesions, and the induction of angiogenesis. Myeloma cells are predominantly localized in the marrow where they receive the appropriate survival and proliferation signals. To reach or spread over the marrow, the myeloma cells need to migrate from the vascular to the extravascular compartment of the marrow. A process called "homing". In this review, the steps of the homing scheme, analyzed in the 5TMM model, will be described. These murine models originated from spontaneously developed myeloma in elderly mice and have since been propagated by intravenous injection of myeloma cells into young syngeneic mice. These models resemble the human condition closely. The different studies reported here demonstrate that adhesion of 5TMM cells to marrow endothelial cells is partially mediated by CD44v10 and to stromal cells by CD44v6. The 5TMM cells migrate to the marrow through the effects of MCP-1, laminin-1, and IGF-1. Once past the marrow endothelium, they invade the extravascular compartment of the marrow by secreting MMP-9 and uPA. When they have settled in the marrow, they become susceptible to the effects of IGF-1, which stimulates the cells to proliferate and produce VEGF. Furthermore, studies targeting the marrow with inhibitors will be highlighted. These studies show that the 5TMM models are useful for unraveling basic biological processes and for identifying new therapeutic targets.
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PMID:Myeloma cells (5TMM) and their interactions with the marrow microenvironment. 1531 88

Atherosclerosis is still an important disease. It accounts for 39% of deaths in the U.K. and 12 million U.S citizens have atherosclerosis-associated disease. Atherosclerosis may exert clinical effects by slow narrowing, producing stable angina or dramatic rupture, producing acute coronary syndromes such as unstable angina or myocardial infarction and death. Macrophages are abundant in ruptured atherosclerotic plaques. Macrophages are innate immune effectors, i.e. they are activated without antigenic specificity. This may make them liable to indiscriminate tissue damage, since they are less selective than lymphocytes. Macrophages are recruited and activated by many signals and have an impressive armamentarium of molecules to promote tissue damage. Macrophage recruitment by abnormal endothelium over developing atherosclerotic plaques, is aided by endothelial expression of adhesion molecules (ICAM-1, VCAM, ELAM). Use of knockout mice has implicated the chemoattractant cytokine (chemokine) MCP-1 in attracting macrophage recruitment in atherosclerosis. Macrophage-activation stimuli associated with atherosclerotic risk factors include oxidised low density lipoprotein (oxLDL, "bad cholesterol"), advanced glycosylation end products (AGEs) of diabetes, angiotensin II and endothelin. Substantial work has clarified macrophage activation by OxLDL via macrophage scavenger receptors (MSRs), especially MSRA and CD36. Activated macrophages express effector molecules that kill cells and degrade extracellular matrix. These include Fas-L and nitric oxide (NO). Macrophage NO is derived from the high output inducible nitric oxide synthase (iNOS) pathway and upregulates vascular smooth muscle (VSMC) cell surface Fas, priming them for apoptosis. Activated macrophages express surface Fas-L, similar to cytotoxic T-lymphocytes and natural killer cells. Since VSMCs promote plaque stability, VSMC apoptosis may promote plaque rupture. Macrophages express multiple metalloproteinases (e.g. stromelysin) and serine proteases (e.g. urokinase) that degrade the extracellular matrix, weakening the plaque and making it rupture prone. Macrophages secrete numerous other effectors including reactive oxygen species, eicosanoids, tumour necrosis factor alpha and interleukin-1. Macrophage-derived transforming growth factor beta promotes fibrosis. Existing cardiovascular treatments including angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, aspirin, cholesterol reduction agents especially statins may inhibit macrophages. The interaction of NO-donors with macrophages and apoptosis is complex and bifunctional. Traditional anti-inflammatory agents such as glucocorticoids and cyclophosphamide have very serious side effects and are probably inappropriate. Novel anti-inflammatory agents e.g. new immunosuppressives and anti-TNF therapy may have an improved cost-benefit ratio.
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PMID:Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. 1563 83

In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 +/- 4.3 vs. 1.4 +/- 0.6%, P < 0.001). Typical "crowns" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (-11.63 +/- 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in macrophage attraction (monocyte chemotactic protein [MCP]-1, plasminogen activator urokinase receptor [PLAUR], and colony-stimulating factor [CSF]-3) and hypoxia (hypoxia-inducible factor-1alpha [HIF-1alpha]), expression of which increases in obesity and decreases after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1alpha may play roles in the attraction of macrophages in scWAT.
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PMID:Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. 1604 92

Protein farnesyltransferase inhibitors (FTIs) have shown clinical responses in hematologic malignancies, but the mechanisms are unclear. To better understand potential mechanisms of action, we have studied effects of the FTI tipifarnib on inflammatory responses in vitro and in vivo. In a human leukemia cell line THP-1, tipifarnib inhibited lipopolysaccharide (LPS)-induced transcription of chemokines [monocyte chemotactic protein (MCP)-1 and MCP-2], cytokines [interleukin (IL)-1beta, IL-6, and interferon (IFN)beta], signaling molecules (MyD88 and STAT-1), proteases [matrix metalloproteinase (MMP-9)], and receptors (urokinase receptor). Tipifarnib also inhibited LPS-induced secretion of MMP-9, IL-6, MCP-1, and IL-1beta in THP-1 cells. In primary human peripheral blood mononuclear cells, dose-dependent inhibition of LPS-induced tumor necrosis factor (TNF)-alpha, IL-6, MCP-1, and IL-1beta by tipifarnib was observed with no evidence of cytotoxicity. Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pretreatment with tipifarnib resulted in significant inhibition of TNF-alpha, IL-6, MCP-1, IL-1beta, and MIP-1alpha production. Tipifarnib had no effect in vitro or in vivo on LPS-induced IL-8. Studies in THP-1 cells to address potential mechanism(s) showed that tipifarnib partially inhibited LPS-induced p38 phosphorylation. Tipifarnib significantly inhibited inhibitory subunit of nuclear factor-kappaB (NF-kappaB) (IkappaB)-alpha degradation and p65 nuclear translocation induced by LPS, but not by tumor necrosis factor-alpha, IL-1alpha, or toll-like receptor (TLR)2 ligand, suggesting that the target for inhibition of NF-kappaB activation was exclusive to the LPS/TLR4 signal pathway. The extent of IkappaB-alpha degradation inhibition did not correlate with inhibition of Ras farnesylation, indicating that Ras was not the target for the observed anti-inflammatory activity of tipifarnib. Our findings differ from those for other FTIs, which may have relevance for their dissimilar activity in specific tumor repertoires.
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PMID:Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor tipifarnib. 1635 5

Plasminogen activators are used in thrombolytic stroke therapy. However, it is increasingly recognized that they have other actions besides fibrinolysis. In this study, we assess potential pro-inflammatory effects of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in rat cortical astrocytes. Both uPA and tPA induced rapid dose-dependent upregulation in MMP-2 and MMP-9, as demonstrated by zymography of conditioned media. In addition, a multiplex ELISA array demonstrated that patterned responses in chemokines and cytokines were also evoked. Exposure to tPA induced elevations in secreted MIP-2, MCP-1 and GRO/KC. Exposure to uPA induced elevations in secreted IFN-gamma, TNF-alpha, GMCSF, MIP-1alpha, MIP-2, MIP-3alpha, MCP-1, RANTES and fractalkine. These data suggest that plasminogen activators may trigger selected pro-inflammatory responses at the neurovascular interface. Whether these effects influence thrombolytic stroke therapy warrants further investigation.
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PMID:Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators. 1738 75

Vessel wall matrix changes occur after injury, although this has not been well studied in the venous system. This study tested the hypothesis that the thrombus dictates the vein wall response and vein wall damage is directly related to the duration of thrombus contact. To determine the injury response over time, rats underwent inferior vena cava (IVC) ligation to produce a stasis thrombus, with harvest at various time points to 28 days (d). Significant vein wall matrix changes occurred with biomechanical injury (stiffness) peaking at 7-14 d, with concurrent early reduction in total collagen, an increase in early matrix metalloproteinase (MMP)-9 and late MMP-2, and concomitant increase in tumor necrosis factor (TNF)alpha, monocyte chemoattractant(MCP)-1 and tumor growth factor (TGF)beta (all P<0.05). To isolate the effect of the thrombus and its mechanism of genesis, rats underwent 7 d or limited stasis (24 hours), non-stasis thrombosis, or non-thrombotic IVC occlusion (Silicone plug). Vein wall stiffness was increased seven-fold, with a five-fold reduction in collagen, and 5.5- to seven-fold increase in TNFalpha, MCP-1, and TGFbeta with 7 d stasis as compared with controls (all P<0.05). By Picosirus red staining analysis, collagenolysis was significantly greater with 7 d stasis injury (P=0.01) but neither MMP-9 nor MMP-2 activity correlated with injury mechanism. In addition, vein wall cellular proliferation and uPA gene expression paralled the stasis thrombotic injury. Limited stasis, non-stasis thrombosis and non-thrombotic IVC occlusion showed a lesser inflammatory response. These data suggest both a static component and the thrombus directs vein wall injury via multiple mechanisms.
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PMID:Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis. 1800 Jun 10

The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell-surface receptor involved in many physiological and pathological events that include cell migration and tissue invasion. uPAR traditional role was considered the focusing of uPA proteolytic activity on the cell surface; however, different uPAR activities have been demonstrated in the last years. In fact, cell surface uPAR functionally interacts with integrins, fMLP-receptors (fMLP-Rs) and growth factor receptors, thus regulating cell adhesion, migration and proliferation. uPAR also exists in a soluble form (suPAR) that has been detected in human body fluids. Both cell surface and suPAR can be proteolytically cleaved, thus generating truncated forms lacking the N-terminal domain and exposing the specific sequence able to interact with the fMLP-Rs. The cleaved form of suPAR binds and activates the fMLP-Rs and regulates the activity of MCP-1, RANTES and SDF1 receptors. Here, we review the role that shedding and cleavage could play in regulating uPAR structural/functional interaction with other cell-surface receptors and in uPAR-mediated biological and pathological processes.
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PMID:Multiple activities of a multifaceted receptor: roles of cleaved and soluble uPAR. 1927 14


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