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)

The mechanisms which soften the cervix and allow it to dilate at birth are not well known. This is a crucial element in labour and current pharmacological approaches, largely the use of prostaglandins (PG), are only semi-selective for the cervix and can cause inappropriate myometrial contractions. Cervical ripening is accompanied by the influx of neutrophils, the neutrophil is a ready source of collagenase, and the cervix is dependent on collagen for its rigidity. Thus it is important to study factors controlling neutrophil influx into the cervix at term. PGE and interleukin-8 (IL-8, or neutrophil chemotactic factor) work synergistically in inducing neutrophil influx into tissue. Activating this type of synergy, between a vasoactive and a chemotactic agent is likely to be the physiological mechanism for inducing cervical ripening. Future approaches to control the cervix are likely to exploit these pathways and lead to more effective and acceptable methods for inducing labour.
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PMID:Inflammatory mediators and cervical ripening. 1238 44

Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.
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PMID:Determinants of human B cell migration across brain endothelial cells. 1270 26

To gain insight into the transformation of epidermal cells into squamous carcinoma cells (SCC), we compared the response to ultraviolet B radiation (UVB) of normal human epidermal keratinocytes (NHEK) versus their transformed counterpart, SCC, using biological and molecular profiling. DNA microarray analyses (Affymetrix), approximately 12000 genes) indicated that the major group of upregulated genes in keratinocytes fall into three categories: (i). antiapoptotic and cell survival factors, including chemokines of the CXC/CC subfamilies (e.g. IL-8, GRO-1, -2, -3, SCYA20), growth factors (e.g. HB-EGF, CTGF, INSL-4), and proinflammatory mediators (e.g. COX-2, S100A9), (ii). DNA repair-related genes (e.g. GADD45, ERCC, BTG-1, Histones), and (iii). ECM proteases (MMP-1, -10). The major downregulated genes are DeltaNp63 and PUMILIO, two potential markers for the maintenance of keratinocyte stem cells. NHEK were found to be more resistant than SCC to UVB-induced apoptosis and this resistance was mainly because of the protection from cell death by secreted survival factors, since it can be transferred from NHEK to SCC cultures by the conditioned medium. Whereas the response of keratinocytes to UVB involved regulation of key checkpoint genes (p53, MDM2, p21(Cip1), DeltaNp63), as well as antiapoptotic and DNA repair-related genes - no or little regulation of these genes was observed in SCC. The effect of UVB on NHEK and SCC resulted in upregulation of 251 and 127 genes, respectively, and downregulation of 322 genes in NHEK and 117 genes in SCC. To further analyse these changes, we used a novel unsupervised coupled two-way clustering method that allowed the identification of groups of genes that clearly partitioned keratinocytes from SCC, including a group of genes whose constitutive expression levels were similar before UVB. This allowed the identification of discriminating genes not otherwise revealed by simple static comparison in the absence of UVB irradiation. The implication of the changes in gene profile in keratinocytes for epithelial cancer is discussed.
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PMID:Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer. 1277 51

On chemokine stimulation, leucocytes produce and secrete proteolytic enzymes for innate immune defence mechanisms. Some of these proteases modify the biological activity of the chemokines. For instance, neutrophils secrete gelatinase B (matrix metalloproteinase-9, MMP-9) and neutrophil collagenase (MMP-8) after stimulation with interleukin-8/CXCL8 (IL-8). Gelatinase B cleaves and potentiates IL-8, generating a positive feedback. Here, we extend these findings and compare the processing of the CXC chemokines human and mouse granulocyte chemotactic protein-2/CXCL6 (GCP-2) and the closely related human epithelial-cell derived neutrophil activating peptide-78/CXCL5 (ENA-78) with that of human IL-8. Human GCP-2 and ENA-78 are cleaved by gelatinase B at similar rates to IL-8. In addition, GCP-2 is cleaved by neutrophil collagenase, but at a lower rate. The cleavage of GCP-2 is exclusively N-terminal and does not result in any change in biological activity. In contrast, ENA-78 is cleaved by gelatinase B at eight positions at various rates, finally generating inactive fragments. Physiologically, sequential cleavage of ENA-78 may result in early potentiation and later in inactivation of the chemokine. Remarkably, in the mouse, which lacks IL-8 which is replaced by GCP-2/LIX as the most potent neutrophil activating chemokine, N-terminal clipping and twofold potentiation by gelatinase B was also observed. In addition to the similarities in the potentiation of IL-8 in humans and GCP-2 in mice, the conversion of mouse GCP-2/LIX by mouse gelatinase B is the fastest for any combination of chemokines and MMPs so far reported. This rapid conversion was also performed by crude neutrophil granule secretion under physiological conditions, extending the relevance of this proteolytic cleavage to the in vivo situation.
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PMID:Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities. 1295 Feb 57

Recent clinical studies suggest that some of the beneficial effects of 3-hydroxy-3-metylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the incidence of myocardial infarctions and ischemic strokes may be through their non-cholesterol-lowering "direct" effects on atherosclerotic vessels. We designed this study to test the hypothesis that fluvastatin inhibits atheroma formation and increase plaque stability independent of cholesterol-lowering effects. Rabbits were fed 0.5% high-cholesterol diet for 12 weeks (progression phase) and then fed the high-cholesterol diet either containing or not containing fluvastatin 2mg/kg per day for additional 8 weeks (treatment phase). Rabbits fed normal diet were used as control. Plasma total and LDL-cholesterol concentrations did not differ during the treatment phase of the experiment. Atherosclerotic changes (plaque formation, lipid- and macrophage-rich intimal thickening, the increase in MCP-1, IL-8, TNF-alpha, IL-1beta, M-CSF, MMP-1, MMP-9, MMP-12, and ACE mRNA expression, and the increase in plasma MCP-1 levels) were observed in the high-cholesterol diet group (HC). All of these changes were less in the fluvastatin-treated group (HC+Flu) than in HC. There was no significant difference in aortic collagen (type I and type IV) mRNA expression between groups. Furthermore, fluvastatin increased the extracellular matrix content (collagen) and vascular smooth muscle cell composition in the atherosclerotic lesion, leading to the increase in plaque stability score (collagen+smooth muscle cell area)/(macrophage+lipid deposition area) in HC+Flu. Fluvastatin not only reduced atherogenesis but also to stabilized vulnerable atheromatous plaques in atherosclerotic rabbits, presumably through the macrophage recruitment and activation in the aortic lesion, at a low dose without cholesterol-lowering effects.
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PMID:HMG-CoA reductase inhibitor, fluvastatin, has cholesterol-lowering independent "direct" effects on atherosclerotic vessels in high cholesterol diet-fed rabbits. 1296 85

Proteolytic processing is an important regulatory mechanism for chemokines. Matrix metalloproteinases (MMPs), such as gelatinase A/MMP-2 and gelatinase B/MMP-9, are known to process the aminoterminal end of various chemokines, including interleukin-8 (IL-8/CXCL-8) and monocyte chemotactic protein-3 (MCP-3/CXCL-7). In the present study, two proteases, gelatinase B and neutrophil collagenase/MMP-8, are shown for the first time to process the carboxyterminal end of two chemokines, monokine induced by interferon (IFN)-gamma (MIG/CXCL-9) and IFN-inducible protein-10 (IP-10/CXCL-10). Neutrophil collagenase degrades MIG into small fragments and cleaves IP-10 behind positions 71 and 73. Gelatinase B degrades IP-10 and cleaves MIG at three different sites in its extended carboxyterminal region. This results in the formation of MIG(1-94), MIG(1-93), and MIG(1-90). In general, gelatinase B was more efficient than neutrophil collagenase in processing these chemokines. Alignment of the CXC chemokines with the respective cleavage sites by both MMPs identified the ELR motif as a possible determinant for amino terminal cleavage by these MMPs.
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PMID:Carboxyterminal cleavage of the chemokines MIG and IP-10 by gelatinase B and neutrophil collagenase. 1455 Feb 88

Tuberculosis is characterized by granuloma formation and caseous necrosis, but the factors causing tissue destruction are poorly understood. Matrix metalloproteinase (MMP)-9 (92-kDa gelatinase) secretion from monocytes is stimulated by Mycobacterium tuberculosis (M. tb) and associated with local tissue injury in tuberculosis patients. We demonstrate strong immunohistochemical MMP-9 staining in monocytic cells at the center of granuloma and adjacent to caseous necrosis in M. tb-infected patient lymph nodes. Minimal tissue inhibitor of MMPs-1 staining indicated that MMP-9 activity is unopposed. Because granulomas characteristically contain few mycobacteria, we investigated whether monocyte-monocyte cytokine networks amplify MMP-9 secretion. Conditioned medium from M. tb-infected primary human monocytes or THP-1 cells (CoMTB) stimulated MMP-9 gene expression and a >10-fold increase in MMP-9 secretion by monocytes at 3-4 days (p < 0.009, vs controls). Although CoMTB stimulated dose-dependent MMP-9 secretion, MMP-1 (52-kDa collagenase) was not induced. Anti-TNF-alpha Ab but not IL-1R antagonist pretreatment decreased CoMTB-induced MMP-9 secretion by 50% (p = 0.0001). Anti-TNF-alpha Ab also inhibited MMP-9 secretion from monocytic cells by 50%, 24 h after direct M. tb infection (p = 0.0002). Conversely, TNF-alpha directly stimulated dose-dependent MMP-9 secretion. Pertussis toxin inhibited CoMTB-induced MMP-9 secretion and enhanced the inhibitory effect of anti-TNF-alpha Ab (p = 0.05). Although chemokines bind to G protein-linked receptors, CXCL8, CXCL10, CCL2, and CCL5 did not stimulate monocyte MMP-9 secretion. However, the response to cholera toxin confirmed that G protein signaling pathways were intact. In summary, MMP-9 within tuberculous granuloma is associated with tissue destruction, and TNF-alpha, critical for antimycobacterial granuloma formation, is a key autocrine and paracrine regulator of MMP-9 secretion.
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PMID:Unopposed matrix metalloproteinase-9 expression in human tuberculous granuloma and the role of TNF-alpha-dependent monocyte networks. 1460 66

Human airway smooth muscle cells (HASMC) contribute to the process of airway wall remodelling in asthma by virtue of their secretory functions. This study was performed to investigate the effectiveness of the commonly used steroids beclomethasone, budesonide and fluticasone in downregulating HASMC production of RANTES and IL-8. HASMC (n=5) were cultured from dissected bronchi using collagenase digestion. Confluent HASMC were exposed to TNFalpha and IL-1beta (10 ng/ml) for 24 h. All stimulations were set with and without pre-treatment with beclomethasone, budesonide or fluticasone for 2 h at concentrations of 10(-9)-10(-6)M. IL-8 and RANTES mRNA expression was assessed by RT-PCR and protein secretion was determined by ELISA. Pre-treatment with beclomethasone, budesonide or fluticasone reduced TNFalpha- and IL-1beta-stimulated IL-8 and RANTES release from HASMC in a dose dependent manner. However, beclomethasone was 22-28% less effective than fluticasone and budesonide in inhibiting chemokine production. TNFalpha- and IL-1beta-induced RANTES and IL-8 expression was reduced on the transcriptional level by pre-treatment with fluticasone and budesonide. The results suggest that the topical steroids fluticasone, budesonide and to a lesser extent beclomethasone may have beneficial effects on airway inflammation in asthma by reducing RANTES and IL-8-induced leukocyte infiltration into the airway wall.
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PMID:Inhibition of chemokine production from human airway smooth muscle cells by fluticasone, budesonide and beclomethasone. 1464 70

The pro-inflammatory cytokine interleukin-1beta (IL-1) induces articular chondrocytes to produce reactive oxygen species (ROS), including hydrogen peroxide (H2O2), which mediate some IL-1-induced responses. This study aimed at elucidating the role of ROS, particularly H2O2, in mediating IL-1-induced activation of the transcription factor activator protein-1 (AP-1) in primary cultures of articular chondrocytes. AP-1 may function either as an inducer or as a repressor of the inducible nitric oxide synthase (iNOS) gene promoter. Since we observed that AP-1 is not required for iNOS expression in chondrocytes, we also investigated whether it is a repressor of this gene. The results of electrophoretic mobility shift assays showed that both IL-1 and H2O2 activated AP-1 and that inhibition of IL-1-induced ROS production abrogated AP-1 activation. The AP-1 complexes, induced by either IL-1 or H2O2, contained c-Fos/c-Jun and c-Fos/JunD heterodimers, but IL-1 activated AP-1 with a kinetics slower than that observed with H2O2. Pre-activation of AP-1, before stimulation of the cells with IL-1, did not inhibit iNOS mRNA and protein synthesis, relative to cells treated with IL-1 alone. These results indicate that H2O2 is a major mediator of IL-1-induced AP-1 activation in articular chondrocytes and that inhibition of ROS production is an effective strategy to block this IL-1-induced response. This study also identifies c-Fos/c-Jun and c-Fos/JunD heterodimers as the AP-1 transcription factors induced by IL-1, which, although not involved in the transcriptional regulation of the iNOS gene, may be important for the regulation of other genes also relevant in arthritic diseases, namely the collagenase-1 and IL-8 genes.
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PMID:Hydrogen peroxide mediates interleukin-1beta-induced AP-1 activation in articular chondrocytes: implications for the regulation of iNOS expression. 1468 13

The purpose of this study was to examine the source of adipokines released by the visceral and sc adipose tissues of obese humans. Human adipose tissue incubated in primary culture for 48 h released more prostaglandin E(2), IL-8, and IL-6 than adiponectin, whereas the release of plasminogen activator inhibitor 1 and hepatocyte growth factor was less than that of adiponectin but greater than that of leptin. IL-10 and TNFalpha were released in amounts less than those of leptin, whereas vascular endothelial growth factor and IL1-beta were released in much lower amounts. The accumulation of adipokines was also examined in the three fractions (adipose tissue matrix, isolated stromovascular cells, and adipocytes) obtained by collagenase digestion of adipose tissue. Over 90% of the adipokine release by adipose tissue, except for adiponectin and leptin, could be attributed to nonfat cells. Visceral adipose tissue released greater amounts of vascular endothelial growth factor, IL-6, and plasminogen activator inhibitor 1 compared with abdominal sc tissue. The greatly enhanced total release of TNFalpha, IL-8, and IL-10 by adipose tissue from individuals with a body mass index of 45 compared with 32 was due to nonfat cells. Furthermore, most of the adipokine release by the nonfat cells of adipose tissue was due to cells retained in the tissue matrix after collagenase digestion.
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PMID:Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. 1472 44


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