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

Lipoxins are a novel class of endogenous eicosanoid mediators that potently inhibit inflammatory events by signaling via specific receptors expressed on phagocytic cells. Animal models have shown that lipoxin A4 (LXA4) down-regulates inflammation in vivo. Here we demonstrate, for the first time, the expression of LXA4 receptors, and their up-regulation by IL-1 beta, in normal human synovial fibroblasts (SF). We examined whether exogenous LXA4 abrogated IL-1 beta stimulation of SF in vitro. IL-1 beta induced the synthesis of IL-6, IL-8, and matrix metalloproteinases (MMP)-1 and -3. At nanomolar concentrations, LXA4 inhibited these IL-1 beta responses with reduction of IL-6 and IL-8 synthesis, by 45 +/- 7% and 75 +/- 11%, respectively, and prevented IL-1 beta-induced MMP-3 synthesis without significantly affecting MMP-1 levels. Furthermore, LXA4 induced a 2-fold increase of tissue inhibitor of metalloproteinase (TIMP)-1 and a approximately 3-fold increase of TIMP-2 protein levels. LXA4 inhibitory responses were dose dependent and were abrogated by pretreatment with LXA4 receptor antiserum. LXA4-induced changes of IL-6 and TIMP were accompanied by parallel changes in mRNA levels. These results indicate that LXA4 in activated SF inhibits the synthesis of inflammatory cytokines and MMP and stimulates TIMP production in vitro. These findings suggest that LXA4 may be involved in a negative feedback loop opposing inflammatory cytokine-induced activation of SF.
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PMID:Lipoxin A4 inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. 1067 6

Three canine cell lines, K1, K6 and DH82, derived from canine malignant neoplasms, were characterised. They were examined for expression of surface antigens, cytokines, neuropeptide receptors, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The growth characteristics of the cell lines were established and bioassays used to detect production of TNF-alpha, IL-1 and IL-6. In the DH82 cell line, production of TNF-alpha and IL-6 was readily detected. Neither K1 or K6 cell lines produced any measurable amounts of TNF-alpha, IL-1 or IL-6. At a molecular level, using reverse transcription-polymerase chain reaction (RT-PCR) to detect specific mRNA, the DH82 cell line expressed TNF-alpha, IL-1 and IL-6, whereas the K1 and K6 cell lines expressed TNF-alpha. Canine IL-5, IL-8 and IL-10 mRNA were detected in the DH82 cell line but only IL-5 and IL-8 mRNA were detected in the K1 and K6 cell lines. Gelatin zymography was used for the detection of MMP-2 and MMP-9 and all three cell lines produced MMP-2 but only the DH82 cell line produced MMP-9. Reverse zymography was used to detect TIMP-1 and TIMP-2 and all three cell lines produced both proteins. The presence of these MMPs and TIMPs was confirmed at a molecular level using RT-PCR. Canine MMP-14 mRNA was detected in all three cell lines. For this investigation several genes for canine inflammatory molecules were cloned and sequenced for molecular detection; these included IL-1, IL-6, IL-8, TNF-alpha, MMP-9, MMP-14, TIMP-1, TIMP-2 and beta-actin. Of all the cell surface antigens tested, only CD14 was expressed on the DH82 cell line although CD5 and CD45 was partially expressed. The K1 and K6 cell lines were negative for all of the CD markers tested. K1 and K6 were negative for Neurokinin 1 receptor (NK1-R) but positive for Calcitonin gene related peptide receptor type 1 (CGRP-1R) and Calcitonin gene related peptide receptor component protein (CGRP-RCP). The DH82 cell line expressed neither NK1-R or CGRP-1R; however, it did express CGRP-RCP. Generally the DH82 cell line exhibited considerable similarity to canine monocytes, but all three cell lines will be useful as standards and for the purification of various immunological and inflammatory mediators in the dog.
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PMID:Immunological and inflammatory characterisation of three canine cell lines: K1, K6 and DH82. 1088 96

Rheumatoid arthritis is a chronic inflammatory disease characterized by destruction of cartilage and bone that is mediated by synovial fibroblasts. To determine the mechanisms by which these cells are activated to produce matrix metalloproteinases (MMPs), the effects of microparticles were investigated. Microparticles are small membrane-bound vesicles whose release from immune cells is increased during activation and apoptosis. Because microparticles occur abundantly in the synovial fluid in rheumatoid arthritis, they could represent novel stimulatory agents. Microparticles derived from T cells and monocytes strongly induced the synthesis of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblasts. The induction was time-dependent, with effects primarily observed after 36 h; under these conditions, MMP-2, MMP-14, and tissue inhibitor of MMP-1 (TIMP-1), TIMP-2, and TIMP-3 were not induced. Microparticles also increased the synthesis of inflammatory mediators including IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), and MCP-2. In Ikappa-B-transfected synovial fibroblasts, MMPs were less inducible by microparticles compared with wild-type fibroblasts. Blocking of TNFalpha and IL-1beta with antibodies against TNFalpha and with IL-1 receptor antagonist did not abrogate stimulation by microparticles. These data provide evidence for a novel mechanism by which vesicles derived from activated or apoptotic immune cells can promote the destructive activity of synovial fibroblasts in rheumatoid arthritis.
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PMID:The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. 1570 93

Persistent, poorly healing wounds are a significant clinical problem in patients who have had previous irradiation. The pathology of chronic dermal ulcers is characterised by excessive proteolytic activity which degrades the extracellular matrix (required for cell migration) and growth factors and their receptors. Interestingly, the molecular basis of radiation-induced dermal wounds is poorly understood. The aim of this study was to investigate, by immunohistochemistry, the expression of the endothelial marker vWF, of angiogenic bFGF, VEGF and IL-8, of collagenases MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2, in tissue samples from radiation-induced chronic dermal wounds and healthy control skin. Performing immunohistochemical detection of microvessels, an equivalent density of microvessels was observed within tissue samples from normal healthy skin and from radiation-induced non-healing cutaneous wounds. Investigation of angiogenic bFGF and VEGF demonstrated a decreased expression of both factors in the radiation-induced dermal wounds. The expression of angiogenic IL-8 was weak in both the healthy skin samples and the radiation-induced wounds. In addition, an increased expression of collagenases MMP-2 and MMP-9 protein within the radiation-induced wounds was demonstrated. While the expression of TIMP-1 showed no difference of expression between normal control skin and tissue samples from radiation-induced wounds, TIMP-2 expression was slightly increased compared to healthy controls. Our data suggest that radiation-induced dermal injuries often fail to heal because of decreased angiogenesis and persistently high concentrations of MMPs with an imbalance of their tissue inhibitors. The basic mechanisms of wound healing in radiation-induced dermal wounds at the molecular level need to be understood further for the development of innovative treatment strategies.
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PMID:Immunohistochemical analysis of radiation-induced non-healing dermal wounds of the head and neck. 1579 96

The establishment of metastatic bone lesions in prostate cancer (CaP) is a process partially dependent on angiogenesis. Previously we demonstrated that the stromal-derived factor-1 (SDF-1 or CXCL12)/CXCR4 chemokine axis is critical for CaP cell metastasis. In this investigation, cell lines were established in which CXCR4 expression was knocked down using siRNA technology. When CaP cells were co-transplanted with human vascular endothelial cells into SCID mice, significantly fewer human blood vessels were observed paralleling the reductions in CXCR4 levels. Likewise, the invasive behaviors of the CaP cells were inhibited in vitro. From these functional observations we explored angiogenic and signaling mechanisms generated following SDF-1 binding to CXCR4. Differential activation of the MEK/ERK and PI3K/AKT pathways that result in differential secretion IL-6, IL-8, TIMP-2 and VEGF were seen contingent on the cell type examined; VEGF and TIMP-2 expression in PC3 cells are dependent on AKT activation and ERK activation in LNCaP and LNCaP C4-2B cells leads to IL-6 or IL-8 secretion. At the same time, expression of angiostatin levels were inversely related to CXCR4 levels, and inhibited by SDF-1 stimulation. These data link the SDF-1/CXCR4 pathway to changes in angiogenic cytokines by different signaling mechanisms and, suggest that the delicate equilibrium between proangiogenic and antiangiogenic factors may be achieved by different signal transduction pathways to regulate the angiogenic phenotype of prostate cancers. Taken together, our results provide new information regarding expression of functional CXCR4 receptor-an essential role and potential mechanism of angiogenesis upon SDF-1 stimulation.
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PMID:Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. 1600 85

We used cytokine protein array to analyze the expression of cytokines from human cord blood-derived mesenchymal stem cells (CB-MSCs). Several cytokines, interleukins (IL), and growth factors, including ENA-78, GM-CSF, GRO, IL-1beta, IL-6, IL-8, MCP-1, OSM, VEGF, FGF-4, FGF-7, FGF-9, GCP-2, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IP-10, LIF, MIF, MIP-3alpha, osteoprotegerin, PARC, PIGF, TGF-beta2, TGF-beta3, TIMP-1, as well as TIMP-2, were secreted by CB-MSCs, while IL-4, IL-5, IL-7, IL-13, TGF-beta1, TNF-alpha, and TNF-beta were not expressed under normal growth conditions. IL-6, IL-8, TIMP-1, and TIMP-2 were the most abundant interleukins expressed by CB-MSCs. A set of growth factors were selected to evaluate their stimulatory effects on the IL6 secretion for CB-MSCs. IL-1beta was the most important factor inducing CB-MSC to secret IL-6. The mechanism by which IL-1beta promoted IL-6 expression in CB-MSCs was studied. By using various inhibitors of signal transduction, we found that activation of p38 mitogen-activated protein kinases (MAPK) and MAPK kinase (MEK) is essential in the IL-1beta stimulated signaling cascade which leads to the increase in IL-6 synthesis. Additionally, continuous supplement of IL-1beta in the CB-MSCs culture will facilitate adipogenic maturation of CB-MSCs as evidenced by the presence of oil drops in the CB-MSCs and secretion of leptin, a molecule marker of adipocytes. These results strongly suggest that cytokine induction and signal transduction are important for the differentiation of CB-MSCs.
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PMID:Cytokine interactions in mesenchymal stem cells from cord blood. 1637 3

The involvement of inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) has been investigated using samples from relatively central airways such as airway biopsies, but there have been fewer studies in the peripheral lung, which is thought to be the main site of the disease process. To determine the molecules that relate to the mechanisms underlying the pathogenesis of COPD, we evaluated the mRNA expression of inflammatory cytokines, chemokines, oxidant enzymes, antioxidant enzymes, proteinases and antiproteinases in peripheral lung tissues from 33 COPD and non-COPD subjects who were undergoing lung resection for lung cancer using an RT-PCR technique. Among the 42 studied candidate genes, the expressions of mRNA for catalase, glutathion S-transferase P1 (GSTP1), glutathion S-transferase M1 (GSTM1), microsomal epoxide hydrolase (mEPHX) and tissue inhibitor of metalloproteinase 2 (TIMP2) were significantly decreased in COPD lung tissues compared with those in non-COPD tissues, and most of these decreases were significantly correlated with the degree of airflow limitation. On the other hand, the expressions of mRNA for interleukin 1beta (IL-1beta), interleukin 8 (IL-8), growth-related oncogene-alpha (Gro-alpha) and monocyte chemotactic protein-1 (MCP-1) were significantly increased in COPD lungs. Most of these changes were also associated with cigarette smoking. These data suggest that an impairment of protective mechanisms against oxidants and xenobiotics, in addition to the upregulation of CXC- and CC-chemokines, may be associated with cigarette smoking and involved in the inflammatory process of COPD.
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PMID:Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung. 1691 84

Lymphocytes have been shown to be involved in modulating monocyte and macrophage behavior in the foreign body reaction. Lymphocyte effects on biomaterial-adherent macrophage and foreign body giant cell (FBGC) behavior were further investigated by culturing monocytes alone or together with lymphocytes, either in direct co-cultures or indirectly in transwells, on a series of polyethylene terephthalate-based photograft co-polymerized material surfaces displaying distinct hydrophobic, hydrophilic/neutral, hydrophilic/anionic, and hydrophilic/ cationic chemistries. After periods of 3, 7, and 10 days, cytokine production was quantified by enzyme-linked immunosorbent assay and normalized to adherent macrophage/FBGC density to yield a measure of adherent macrophage/FBGC activation. Interactions with lymphocytes enhanced adherent macrophage and FBGC production of pro-inflammatory IL-1beta, TNF-alpha, IL-6, IL-8, and MIP-1beta on the hydrophobic and hydrophilic/cationic surfaces but had no effect on anti-inflammatory IL-10 production indicating lymphocytes promote a pro-inflammatory response to biomaterials. Lymphocytes also did not significantly influence MMP-9, TIMP-1, and TIMP-2 production. Interactions through indirect (paracrine) signaling showed a significant effect in enhancing adherent macrophage/FBGC activation at early time points whereas interactions via direct (juxtacrine) mechanisms dominated at later time points. Biomaterial surface chemistries differentially affected the observed responses as hydrophilic/neutral and hydrophilic/anionic surfaces, evoked the highest levels of activation relative to the other surfaces but did not facilitate lymphocyte enhancement of adherent macrophage/FBGC activation.
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PMID:Paracrine and juxtacrine lymphocyte enhancement of adherent macrophage and foreign body giant cell activation. 1843 95

We previously reported an increase in signal transducer and activator of transcription 3 (Stat3) activation in keloid fibroblasts, which contributes to collagen production, cell proliferation, and migration. We further investigated the effect of epithelial-mesenchymal interaction on Stat3 in normal and keloid fibroblasts in noncoculture and coculture conditions. pY705 Stat3 was higher in keloid fibroblasts compared to normal fibroblasts in noncoculture. However, a more drastic decrease in pY705 Stat3 was observed in keloid fibroblasts compared to normal fibroblasts when cocultured with their respective keratinocytes over 5 days. To explore this paracrine effect, we examined the secretion of cytokines by cytokine arrays. Altered cytokine production was detected in keloid fibroblasts and keratinocytes, either in noncoculture or coculture conditions. IL-6, IL-8, monocyte chemoattractant protein-1, tissue inhibitor of metalloproteinases (TIMPs)-1, and TIMP-2 were major cytokines detected. Angiogenin, oncostatin M (OSM), vascular endothelial cell growth factor, IGF-binding protein-1, osteoprotegerin, and transforming growth factor-beta2 were present in keloid keratinocyte-fibroblast coculture, but absent in normal keratinocyte-fibroblast coculture. Only IL-6 and OSM stimulated strong pY705 Stat3 and cell proliferation in both normal and keloid fibroblasts. Other cytokines increased proliferation of keloid fibroblasts, but not normal fibroblasts, suggesting an altered state in keloid fibroblasts. Multiple cytokines likely contribute to keloid pathogenesis and a combinatorial neutralizing antibody/cytokine therapy may be effective in ameliorating keloid scars.
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PMID:Cytokine profiling and Stat3 phosphorylation in epithelial-mesenchymal interactions between keloid keratinocytes and fibroblasts. 1903 37

The aim of this study was to assess sputum levels of the metalloproteinases MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2, as well as MMPs/TIMPs ratios in relation to exhaled NO (eNO) and sputum NOs (nitrates and nitrites) and IL8 obtained from chronic obstructive pulmonery disease (COPD) patients, healthy non-smokers, and healthy smokers. We found higher levels of TIMP-1 (118.9 ng/ml) and TIMP-2 (3.75 ng/ml) in COPD patients than in healthy smokers (17.7 ng/ml, P<0.03; 0.51 ng/ml, P>0.05, respectively) and healthy non-smokers (84.6 ng/ml, P>0.05; 1.61 ng/ml, P>0.05, respectively). We also observed significant positive correlations between concentrations of NOs and MMP-1, MMP-2, MMP-3, and TIMP-2 (r=0.37, P<0.02; r=0.60, P<0.0001; r=0.56, P<0.0004 and r=0.47 P<0.004, respectively) in COPD patients. IL8, MMP-2, MMP-3, and TIMP-2 levels in induced sputum were negatively correlated with airway obstruction, i.e., FEV(1)/FVC (r=-0.61, P<0.00009; r=-0.41, P<0.01; r=-0.38, P<0.02; r=-0.49, P<0.002). Our study points to a potentially pathogenic role of stromelysin-1 (MMP-3) in COPD.
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PMID:Induced sputum metalloproteinases and their inhibitors in relation to exhaled nitrogen oxide and sputum nitric oxides and other inflammatory cytokines in patients with chronic obstructive pulmonary disease. 1921 8


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