Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiogenesis in vivo is distinguished by four stages: subsequent to the transduction of signals to differentiate, stage 1 is defined as an altered proteolytic balance of the cell allowing it to digest through the surrounding matrix. These committed cells then proliferate (stage 2), and migrate (stage 3) to form aligned cords of cells. The final stage is the development of vessel patency (stage 4), generated by a coalescing of intracellular vacuoles. Subsequently, these structures anastamose and the initial flow of blood through the new vessel completes the process. We present and discuss how the available models most closely represent phases of in vivo angiogenesis. The enhancement of angiogenesis by hyaluronic acid fragments, transforming growth factor beta, tumor necrosis factor alpha, angiogenin, okadaic acid, fibroblast growth factor, interleukin 8, vascular endothelial growth factor, haptoglobin, and gangliosides, and the inhibition of the process by hyaluronic acid, estrogen metabolites, genestein, heparin, cyclosporin A, placental RNase inhibitor, steroids, collagen synthesis inhibitors, thrombospondin, fumagellin, and protamine are also discussed.
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PMID:Angiogenesis: models and modulators. 753 24

Endothelial cells activation and proliferation are induced by cytokines and modulated by adhesive molecules of the extracellular matrix. In a previous study, we showed that IL-1beta and TNF-alpha inhibited thrombospondin-1 (TSP) secretion by human umbilical vein endothelial cells. This work was carried on by studying the effects of other cytokines [interleukin 6 (IL-6), IL-8, basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta)] known to modulate endothelial cell proliferation. We show here that TSP incorporation into the subendothelial matrix is inversely proportional to cell density. Proliferative cytokines such as IL-6 and bFGF inhibit TSP secretion, whereas the anti-proliferative TGF-beta enhances it. IL-8 has no effect either on cell proliferation or TSP secretion. Thus, the modulation of TSP secretion by these cytokines is apparently due to changes in cell proliferation. Therefore, when studying the effects of cytokines on TSP secretion, it is important to correlate the concentration of subendothelial matrix TSP to the cell density.
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PMID:Endothelial cell proliferation regulated by cytokines modulates thrombospondin-1 secretion into the subendothelium. 934 5

The cellular phospholipid, lysophosphatidic acid (LPA), released by activated platelets and fibroblasts or, at high levels, from ovarian and cervical carcinomas is a powerful serum mitogen that may modulate several signaling pathways in endothelial cells (EC). Hence, LPA could function in a paracrine manner during EC-platelet interactions at sites of vascular injury. Here, we demonstrate activation of the transcription factor nuclear factor kappa B (NF-kappaB) in EC following exposure to LPA. EC activation was further characterized by increased levels of mRNA transcripts encoding E-selectin, Intercellular Adhesion Molecule-1, Interleukin-8 and Monocyte Chemoattractant Protein-1. These effects were inhibited by preincubating EC either in the presence of mepacrine (to block phospholipase A2) or of pertussis toxin (to increase ADP-ribosylation of Gi proteins). No inhibition was observed in the presence of putative LPA receptor antagonists suramin or thrombospondin. LPA induces a proinflammatory activation of endothelial cells that (i) involves Gi proteins; (ii) depends on phospholipase A2 activity; (iii) is associated with the activation of NF-kappaB and (iv) results in increased expression of proinflammatory genes. We propose that LPA release by activated platelets may directly modulate vascular inflammatory responses.
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PMID:Lysophosphatidic acid activates nuclear factor kappa B and induces proinflammatory gene expression in endothelial cells. 1059 50

Neutrophils undergo constitutive death by apoptosis, leading to safe nonphlogistic phagocytosis and clearance by macrophages. Recent work has shown that before secondary necrosis, neutrophils exhibiting classical features of apoptosis can progress to a morphologically defined late apoptotic state. However, whether such neutrophils could be safely cleared was unknown. We now report that human late apoptotic neutrophils could be purified from cultured neutrophil populations undergoing constitutive death and were subsequently ingested by human monocyte-derived macrophages by serum-independent mechanisms that did not trigger the release of IL-8 or TNF-alpha. Such ingestion was specifically inhibited by Abs to thrombospondin-1 and the alpha(v)beta(3) vitronectin receptor. Murine bone marrow-derived macrophage phagocytosis of late and early apoptotic neutrophils occurred by similar mechanisms, proceeding with the same efficiency as that observed for wild-type controls when macrophages from [alpha(m)](-/-) or [beta(2)](-/-) mice were used. We conclude that specific nonphlogistic, beta(2) integrin-independent mechanisms involving thrombospondin-1 and alpha(v)beta(3) allow macrophages to ingest late apoptotic neutrophils without eliciting inflammatory cytokine secretion.
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PMID:Nonphlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of beta 2 integrins. 1125 36

There is much evidence that rheumatoid arthritis is closely linked to angiogenesis. Important angiogenic mediators have been demonstrated in synovium and tenosynovium of rheumatoid joints. VEGF (Vascular Endothelial Growth Factor), expressed in response to soluble mediators such as cytokines and growth factors and its receptors are the best characterized system in the angiogenesis regulation of rheumatoid joints. Moreover, other angiogenic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-15, IL-18, angiogenin, platelet activating factor (PAF), angiopoietin, soluble adhesion molecules, endothelial mediator (endoglin) play an important role in angiogenesis in rheumatoid arthritis. On the other hand, endostatin, thrombospondin-1 and -2 are angiogenic inhibitors in rheumatoid arthritis. The persistence of inflammation in rheumatoid joints is a consequence of an imbalance between these inducers and inhibitors of angiogenesis.
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PMID:Angiogenesis in rheumatoid arthritis. 1649 85

Cysteinyl leukotrienes (cysLT), i.e., LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT1-R/cysLT2-R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT2-Rs, their role in vascular biology remains to be fully understood. To delineate cysLT2-R actions, we stimulated human umbilical vein EC with LTD4 and determined early induced genes. We also compared LTD4 effects with those induced by thrombin that binds to protease-activated receptor (PAR)-1. Stringent filters yielded 37 cysLT2-R- and 34 PAR-1-up-regulated genes (>2.5-fold stimulation). Most LTD4-regulated genes were also induced by thrombin. Moreover, LTD4 plus thrombin augmented gene expression when compared with each agonist alone. Strongly induced genes were studied in detail: Early growth response (EGR) and nuclear receptor subfamily 4 group A transcription factors; E-selectin; CXC ligand 2; IL-8; a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1 (ADAMTS1); Down syndrome critical region gene 1 (DSCR1); tissue factor (TF); and cyclooxygenase 2. Transcripts peaked at approximately 60 min, were unaffected by a cysLT1-R antagonist, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus; LTD4 up-regulated IL-8 formation and secretion; and LTD4 raised TF protein and TF-dependent EC procoagulant activity. These data show that cysLT2-R activation results in a proinflammatory EC phenotype. Because LTD4 and thrombin are likely to be formed concomitantly in vivo, cysLT2-R and PAR-1 may cooperate to augment vascular injury.
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PMID:Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells. 1660 35

There is an increasing body of evidence that synovitis plays a role in the progression of osteoarthritis and that overproduction of cytokines and growth factors from the inflamed synovium can influence the production of degradative enzymes and the destruction of cartilage. In this study, we investigate the role of synovial macrophages and their main proinflammatory cytokines, interleukin (IL)-1 and tumour necrosis factor-alpha (TNF-alpha), in driving osteoarthritis synovitis and influencing the production of other pro- and anti-inflammatory cytokines, production of matrix metalloproteinases, and expression of aggrecanases in the osteoarthritis synovium. We established a model of cultures of synovial cells from digested osteoarthritis synovium derived from patients undergoing knee or hip arthroplasties. By means of anti-CD14-conjugated magnetic beads, specific depletion of osteoarthritis synovial macrophages from these cultures could be achieved. The CD14+-depleted cultures no longer produced significant amounts of macrophage-derived cytokines like IL-1 and TNF-alpha. Interestingly, there was also significant downregulation of several cytokines, such as IL-6 and IL-8 (p < 0.001) and matrix metalloproteinases 1 and 3 (p < 0.01), produced chiefly by synovial fibroblasts. To investigate the mechanisms involved, we went on to use specific downregulation of IL-1 and/or TNF-alpha in these osteoarthritis cultures of synovial cells. The results indicated that neutralisation of both IL-1 and TNF-alpha was needed to achieve a degree of cytokine (IL-6, IL-8, and monocyte chemoattractant protein-1) and matrix metalloproteinase (1, 3, 9, and 13) inhibition, as assessed by enzyme-linked immunosorbent assay and by reverse transcription-polymerase chain reaction (RT-PCR), similar to that observed in CD14+-depleted cultures. Another interesting observation was that in these osteoarthritis cultures of synovial cells, IL-1beta production was independent of TNF-alpha, in contrast to the situation in rheumatoid arthritis. Using RT-PCR, we also demonstrated that whereas the ADAMTS4 (a disintegrin and metalloprotease with thrombospondin motifs 4) aggrecanase was driven mainly by TNF-alpha, ADAMTS5 was not affected by neutralisation of IL-1 and/or TNF-alpha. These results suggest that, in the osteoarthritis synovium, both inflammatory and destructive responses are dependent largely on macrophages and that these effects are cytokine-driven through a combination of IL-1 and TNF-alpha.
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PMID:The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. 1717 94

The purpose of this article is to present the current state of knowledge regarding the structure and functions of articular cartilage. Articular cartilage is constructed with hyaline cartilage tissue. It is composed of chondrocytes located in lacunae and the extracellular matrix. The chondrial matrix contains water, collagen, proteglycans, non-collagenous matrix proteins, and lipids. Articular cartilage is devided into four zones - superficial, intermediate, deep, and calcified - on the basic of morphology, the orientation of collagen fiber, and the proteoglycan content. The dominant collagen of this tissue is Type II collagen, which, together with smaller quantities of other collagens (i.e. Types IX and XII), forms a network of fibers, with large, aggregating proteoglycans and smaller, non-aggregating proteoglycans. Proteoglycans are proteins that contain covalently attached glycosaminoglycans (GAGs), with water between them. The large aggregating proteoglycans, called "aggrecans", form aggregates that bind hyaluronic acid, and together with collagen they are responsible for the mechanical properties of cartilage. The smallnonaggregating proteoglycans, decorin and fibromodulin, limit the formation of collagen fibres. Other proteins in the cartilage matrix - chondrocalcin and the N-propetide of Type II collagen - participate in fiber formation. Yet other proteins - chondronectin, fibronectin, vitronectin and thrombospondin - take part in the interaction between the chondrocytes and the matrix. Cartilage oligomeric matrix protein (COMP) prevents the vascularization of the cartilage and, perhaps, is responsible for the repair process. The proteins known as Cart-1 and CEP-68 participate in chondrogenesis, while tenascin and Mgp are considered to be cartilage calcification inhibitors. Apart from the structural elements, chondrocytes produce substances that fulfill purely physiological functions: enzymes and cytokines. The enzymes - which include metalloproteinases, adamalysins, serine and cysteine proteases and their inhibitors - participate in cartilage matrix reconstruction. The cytokines - IL-1, TNF-alfa, IL-6, IL-8, and LIF - stimulate the chondrocytes to produce an increased amount of enzymes, while IL-4 inhibits this process. Human articular chondrocytes exibit the constitutive expression of class I molecules of the major histocompatibility complex (MHC), molecules regulating the activation of the complement, and after activation (e.g. under the influence of IFN-alfa, IL-1, TNF-a or in the course of arthritis), also MHC class II and ICAM-1 intracellular adhesion molecules. Numerous studies have shown that chondrocytes also have tissue-specific antigens, which induce the production of antibodies in patients with cartilage grafts, as well as those with rheumatoid arthritis and osteoarthritis. Some of these antibodies react with type II collagen, others are directed against other proteins i.e. anchorin CII and CH65. the role of these diverse molecules, which are present in cartilage cells and separated from the immune system by the matrix, remains unclear.
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PMID:The morphology and selected biological properties of articular cartilage. 1798 77

We compared gene expression in blood neutrophils (polymorphonuclear leukocytes, or PMNs) collected from healthy subjects with those of cystic fibrosis (CF) patients devoid of bacterial colonization. Macroarray analysis of 1050 genes revealed upregulation of 62 genes and downregulation expression of 27 genes in CF blood PMNs. Among upregulated genes were those coding for vitronectin, some chemokines (particularly CCL17 and CCL18), some interleukin (IL) receptors (IL-3, IL-8, IL-10, IL-12), all three colony-stimulating factors (G-, M-, GM-CSF), numerous genes coding for molecules involved in signal transduction, and a few genes under the control of gamma-interferon. In contrast, none of the genes coding for adhesion molecules were modulated. The upregulation of six genes in CF PMNs (coding for thrombospondin-1, G-CSF, CXCL10, CCL17, IKKvarepsilon, IL-10Ra) was further confirmed by qPCR. In addition, the increased presence of G-CSF, CCL17, and CXCL10 was confirmed by ELISA in supernatants of neutrophils from CF patients. When comparison was performed between blood and airway PMNs of CF patients, there was a limited difference in terms of gene expression. Only the mRNA expression of amphiregulin and tumor necrosis factor (TNF) receptor p55 were significantly higher in airway PMNs. The presence of amphiregulin was confirmed by ELISA in the sputum of CF patients, suggesting for the first time a role of amphiregulin in cystic fibrosis. Altogether, this study clearly demonstrates that blood PMNs from CF patients display a profound modification of gene expression profile associated with the disease, suggesting a state of activation of these cells.
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PMID:Neutrophils in cystic fibrosis display a distinct gene expression pattern. 1802 71

Angiogenesis is the growth of new blood vessels. In the two major forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, robust angiogenesis exists, and its blockade may have therapeutic potential, as shown in animal models of experimental intestinal inflammation. While abundant literature is available on the positive regulators of intestinal pathological angiogenesis, e.g. VEGF, b-FGF, IL-8, CD40 and CD40L, almost no data exist on negative regulators. Thrombospondin-1 is a negative regulator of angiogenesis, and it plays a new role in IBD-associated angiogenesis. In addition, recombinant thrombospondin-1 may inhibit pathological angiogenesis and may offer a new therapeutic approach to intestinal inflammation.
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PMID:Negative regulators of angiogenesis in inflammatory bowel disease: thrombospondin in the spotlight. 1833 36


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