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)

Symptoms originating from the central nervous system (CNS) occur frequently in patients with systemic lupus erythematosus (SLE), and CNS involvement in lupus is associated with increased morbidity and mortality. We recently showed that neurones and astrocytes are continuously damaged during the course of CNS lupus. The matrix metalloproteinases (MMPs) are a group of tissue degrading enzymes that may be involved in this ongoing brain destruction. The aim of this study was to examine endogenous levels of free, enzymatically active MMP-2 and MMP-9 in cerebrospinal fluid from patients with SLE. A total of 123 patients with SLE were evaluated clinically, with magnetic resonance imaging of brain and cerebrospinal fluid (CSF) analyses. Levels of free MMP-2 and MMP-9 were determined in CSF using an enzymatic activity assay. CSF samples from another 22 cerebrally healthy individuals were used as a control. Intrathecal MMP-9 levels were significantly increased in patients with neuropsychiatric SLE as compared with SLE patients without CNS involvement (P < 0.05) and healthy control individuals (P = 0.0012). Interestingly, significant correlations between MMP-9 and intrathecal levels of neuronal and glial degradation products were noted, indicating ongoing intrathecal degeneration in the brains of lupus patients expressing MMP-9. In addition, intrathecal levels of IL-6 and IL-8--two cytokines that are known to upregulate MMP-9--both exhibited significant correlation with MMP-9 levels in CSF (P < 0.0001), suggesting a potential MMP-9 activation pathway. Our findings suggest that proinflammatory cytokine induced MMP-9 production leads to brain damage in patients with CNS lupus.
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PMID:Intrathecal levels of matrix metalloproteinases in systemic lupus erythematosus with central nervous system engagement. 1553 33

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

The small GTPases of the Rho family are key intermediates in cellular signalling triggered by activated cell-adhesion receptors. In this study, we took advantage of RNA interference (RNAi) using small interfering RNAs (siRNAs) to define the roles of the best-characterized members of the RhoGTPase family, RhoA, Rac1 and Cdc42, in the control of MMP-1, MMP-2 and type-I-collagen expression in normal human skin fibroblasts (HSFs). A specific and long-lasting repression, up to 7 days after transfection, of the three GTPases was achieved by transient transfection of specific siRNA. The silencing of Cdc42, but not that of RhoA or Rac1, induced a 15-fold increase in MMP-1 secretion. This upregulation was confirmed at the mRNA level and observed with two different siRNAs targeting Cdc42. Such a regulation was also observed in various human cell lines and was rescued by re-expressing wild-type Cdc42 encoded by a construct bearing silent mutations impeding its recognition by the siRNA. By contrast, MMP-2 and type-I-collagen expression was not affected by the individual silencing of each Rho GTPase. Cytokine protein array, enzyme-linked immunosorbent assays and reverse-transcription PCR measurements revealed that ablation of Cdc42 induced an overexpression of interleukin 8 and MCP-1. Although these cytokines are known to induce the expression of MMP-1, we showed that they were not involved in the Cdc42-mediated upregulation of MMP-1. Silencing of Cdc42 also induced an increased phosphorylation of ERK1/2 and p38 MAP kinase. The use of chemical inhibitors on Cdc42-ablated cells revealed that the upregulation of MMP-1 is dependent on the ERK1/2 pathways, whereas the p38 MAP kinase pathway displayed an inhibitory role. Simultaneous knock-down of two or three Rho GTPases allowed us to demonstrate that the RhoA-ROCK pathway was not involved in this regulation but that the silencing of Rac1 reduced the effect of Cdc42 suppression. These data suggest that, in vivo, when cell/extracellular-matrix interactions via integrins induce cytoskeleton organization, MMP-1 expression is maintained at a low level by Cdc42 via a repression of the Rac1 and ERK1/2 pathways. Therefore, Cdc42 contributes to ECM homeostasis and connective tissue integrity.
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PMID:Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway. 1572 53

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

Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA) and is regarded as a major destructive element of articular bone and cartilage. This pathological process is accompanied by the production of proinflammatory cytokines, prostaglandin E(2) (PGE(2)), and matrix metalloproteinases (MMPs) in synoviocytes. We studied the spontaneous production of these substances in RA synoviocytes in spheroid culture. Synovial sarcoma cell line SW 982 formed a single spheroid in non-adherent culture plates. It produced interleukin (IL)-1beta, IL-6, IL-8, PGE(2), MMP-2 and MMP-13. Neither the addition of integrin antagonizing oligopeptide (GRGDSP) nor that of vitronectin receptor inhibitor SB-265123 to the culture inhibited any production. Phosphorylation of p38 mitogen-activated protein (MAP) kinase was observed during the culture. A novel p38 MAP kinase inhibitor, R-130823, inhibited the release of IL-6, IL-8 and MMP-13 in a concentration-dependent manner, but not that of IL-1beta or MMP-2. Real-time RT-PCR analysis demonstrated that IL-6, IL-8 and MMP-13 were inhibited at the transcriptional level. R-130823 did not affect the production of PGE(2) in spheroid culture, while the addition of R-130823 suppressed IL-1beta-induced PGE(2) synthesis in monolayer culture of SW 982 cells. The results suggest that spheroid culture induced proinflammatory factors and MMPs in signaling pathways both dependent and independent of p38 MAP kinase.
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PMID:Novel p38 MAP kinase inhibitor R-130823 suppresses IL-6, IL-8 and MMP-13 production in spheroid culture of human synovial sarcoma cell line SW 982. 1588 46

Interleukin-8 (IL-8/CXCL8), a paracrine angiogenic factor, modulates multiple biologic functions in CXCR1 and CXCR2 expressing endothelial cells. Several reports suggest that inflammation, infection, cellular stress and tumor presence regulate IL-8 production in endothelial cells. In the present study, we test the hypothesis that IL-8 regulates multiple biological effects in endothelial cells in an autocrine manner. We examined the autocrine role of IL-8 in regulating angiogenesis by using a neutralizing antibody to IL-8, CXCR1 or CXCR2 in human vein umbilical endothelial cell (HUVEC) and human dermal microvascular endothelial cell (HMEC). Neutralizing antibody to IL-8, CXCR1 or CXCR2 inhibited endothelial cell proliferation, and MMP-2 production as compared to cells cultured with medium alone or control antibody. In addition, we observed that the number of apoptotic cells was significantly higher in anti-IL-8, anti-CXCR1 and anti-CXCR2 treated endothelial cells, which coincided with decreased survival-associated gene expression. We observed reduced migration of endothelial cells treated with anti-IL-8 and anti-CXCR2 antibody, but not anti-CXCR1 antibody as compared to controls. Further, we observed an inhibition of capillary tube formation and neovascularization following treatment with anti-IL-8, anti-CXCR1 and anti-CXCR2 antibodies. Together these data suggest that IL-8 functions as an important autocrine growth and angiogenic factor in regulating multiple biological activities in endothelial cells.
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PMID:Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. 1613 19

We hypothesized that resuscitation with 100% O2 compared with 21% O2 is detrimental to pulmonary tissue. The pulmonary injury was assessed by matrix metalloproteinase (MMP) activity, oxidative stress, IL-8, and histology 2.5 h after resuscitation from a hypoxic state. In pulmonary tissue extracts, MMP activity was analyzed by broad matrix-degrading capacity (total MMP) and zymography. MMP-2 mRNA expression was evaluated by quantitative real-time PCR. Total endogenous antioxidant capacity was measured by the oxygen radical absorbance capacity (ORAC) assay, and IL-8 was analyzed by ELISA technique. In bronchoalveolar lavage (BAL) fluid, MMPs were analyzed by zymography. In pulmonary tissue, pro- and active MMP-2 levels were increased in piglets that were resuscitated with 100% O2 compared with 21% O2. Pro-MMP-9, total MMP activity, and MMP-2 mRNA levels were significantly increased in resuscitated piglets compared with baseline. Net gelatinolytic activity increased in submucosa and blood vessels after 100% O2 and only in the blood vessels after 21% O2. Compared with baseline, ORAC values were considerably lowered in the resuscitated piglets and significantly reduced in the 100% O2 versus 21% O2 group. In BAL fluid, both pro-MMP-9 and pro-MMP-2 increased 2-fold in the 100% O2 group compared with 21% O2. Moreover, IL-8 concentration increased significantly in piglets that were resuscitated with 100% O2 compared with 21% O2, suggesting a marked proinflammatory response in the pulmonary tissue. Altogether, these data strongly suggest that caution must be taken when applying pure O2 to the newborn infant.
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PMID:Resuscitation of hypoxic piglets with 100% O2 increases pulmonary metalloproteinases and IL-8. 1614 71

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.
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PMID:Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. 1620 20

Phenoxodiol (2H-1-benzopyran-7-0,1, 3-[4-hydroxyphenyl], PXD) is a synthetic analogue of the naturally-occurring plant isoflavone and anticancer agent, genistein. PXD directly induces mitotic arrest and apoptosis in most cancer cells and is currently undergoing clinical trials, as a chemotherapeutic in ovarian and prostate cancers. We show here that PXD also exhibits potent antiangiogenic properties. Thus, it inhibited endothelial cell proliferation, migration and capillary tube formation and inhibited expression of the matrix metalloproteinase MMP-2, a major matrix degrading enzyme. Importantly, we demonstrate that PXD is functional in vivo since it inhibited the extent of capillary tube invasion in an in vivo model of angiogenesis. We show that phenoxodiol inhibits hallmarks of endothelial cell activation, namely TNF or IL-1 induced E-selectin and VCAM-1 expression and IL-8 secretion. However, PXD had no effect on unstimulated endothelial cells. We also describe that PXD inhibits the lipid kinase sphingosine kinase, which recently has been implicated in endothelial cell activation and angiogenesis as well as oncogenesis. Thus, our results suggest that PXD may be an effective anticancer drug targeting the two drivers of tumour growth--the proliferation of the tumour cells themselves and the angiogenic and inflammatory stimulation of the vasculature.
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PMID:Phenoxodiol, an experimental anticancer drug, shows potent antiangiogenic properties in addition to its antitumour effects. 1635 57

IL-20 belongs to the IL-10 family and is involved in the pathogenesis of keratinocyte hyperproliferation in vivo. Endothelial cells express IL-20 receptors. To explore the function of IL-20 on endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMECs) with human IL-20 and analyzed its effect on endothelial cells. IL-20 induced proliferation of endothelial cells and the activity was specifically blocked by anti-human-IL-20 monoclonal antibody and soluble (s)IL-20 receptor (R)1 and sIL-20R2. An alternatively spliced variant of IL-20 was isolated and also was shown to induce proliferation of HUVECs and HMECs. Treatment of HUVECs with both IL-10 and IL-20 demonstrated that IL-10 antagonized the activity of IL-20 because it diminished IL-20-induced proliferation of HUVECs. IL-20 significantly induced HUVECs migration and vascular tube formation on Matrigel in vitro. In vivo, IL-20 also enhanced tumor angiogenesis. Incubation of IL-20 with HUVECs induced transcripts of bFGF, VEGF, MMP-2, MMP-9, and IL-8. Furthermore, incubation of HUVECs with IL-20 induced phosphorylation of ERK1/2, p38, and JNK. Thus, IL-20 is a pleiotropic cytokine and promotes angiogenesis.
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PMID:Interleukin-20 promotes angiogenesis in a direct and indirect manner. 1651 54


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