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)

Although X chromosome transfer experiments indicated that tumor suppressor genes are present on the X chromosome, they have not been previously identified. In this report, we show that the ETS transcription factor MEF (ELF4), which is located on chromosome Xq26.1, possesses tumor suppressive capability. MEF expression was up-regulated by 5-azacytidine in some cancer cell lines. MEF overexpression induced morphological changes, such as the conversion of normally loose cell-cell contacts to strong interactions similar to those seen in the presence of matrix metalloproteinase (MMP) inhibitor BB94. In the colony formation assay, A549 cells, but not MEF-overexpressing cells, formed colonies in soft agar culture. Furthermore, MEF-overexpressing cells s.c. injected in the nude mice did not grow, whereas the control cells did. The A549 tumors were poorly differentiated, whereas the MEF-overexpressing tumors were well differentiated. By immunostaining with CD31, a marker on vascular endothelial cells, we found that tumor angiogenesis was significantly suppressed in the tumors formed from MEF-overexpressing cells. In addition, the conditioned media from A549 cell cultures stimulated the migration of human umbilical vein endothelial cells, whereas conditioned media from MEF-overexpressing cell cultures had less of an effect. By gelatin zymography, Western blotting analysis, and immunohistochemistry, we found that the expression levels of MMP-9 and MMP-2 were significantly reduced in MEF-overexpressing tumors. Immunohistochemical analyses showed that interleukin (IL)-8 expression was reduced in the MEF-overexpressing tumors in nude mice. Furthermore, IL-8 mRNA expression in vitro was significantly down-regulated in MEF-overexpressing cells, compared with A549 cells. MEF suppressed the transcription and promoter activities of the genes encoding MMP-9 and IL-8, whereas ETS-2 up-regulated these activities. Therefore, we propose that MEF is a candidate tumor suppressor gene on the X chromosome with activities that are opposite to those of ETS-2.
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PMID:The ETS transcription factor MEF is a candidate tumor suppressor gene on the X chromosome. 1243 53

IL-8, a member of the chemokine family, has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to determine the mechanism of IL-8-mediated angiogenesis. We examined the direct role of IL-8 in angiogenesis by examining IL-8 receptor expression on endothelial cells and their proliferation, survival, and matrix metalloproteinases (MMPs) production. We demonstrate that HUVEC and human dermal microvascular endothelial cells constitutively express CXCR1 and CXCR2 mRNA and protein. Recombinant human IL-8 induced endothelial cell proliferation and capillary tube organization while neutralization of IL-8 by anti-IL-8 Ab blocks IL-8-mediated capillary tube organization. Incubation of endothelial cells with IL-8 inhibited endothelial cell apoptosis and enhanced antiapoptotic gene expression. Endothelial cells incubated with IL-8 had higher levels of Bcl-x(L):Bcl-x(S) and Bcl-2:Bax ratios. Furthermore, incubation of endothelial cells with IL-8 up-regulated MMP-2 and MMP-9 production and mRNA expression. Our data suggest that IL-8 directly enhanced endothelial cell proliferation, survival, and MMP expression in CXCR1- and CXCR2-expressing endothelial cells and regulated angiogenesis.
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PMID:IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. 1262 97

The purpose of the present study was to examine the expression of interleukin (IL)-8 and IL-8 receptors and to evaluate the effects of IL-8 on human pancreatic cancer. We examined the expression of IL-8 and its two receptors (CXCR1 and CXCR2) in 40 surgically resected human pancreatic cancer tissues and in three different human pancreatic cancer cell lines (PANC-1, MIAPaCa-2 and Capan-2). The immunohistochemical analysis using specific antibodies demonstrated that positive staining for IL-8, CXCR1 and CXCR2 in surgically resected human pancreatic cancer was 50, 55 and 65%, respectively. Moreover, 40% of these cases were positive for both IL-8 and IL-8 receptors. In contrast, immunoreactive signals for those proteins were extremely suppressed in normal pancreatic tissues. All of the pancreatic cancer cell lines expressed IL-8 and IL-8 receptors at the RNA and protein levels. Receptor binding experiments using 125I-labeled IL-8 showed that PANC-1 cells had specific binding sites for IL-8. The cell proliferation assay demonstrated that IL-8 did not affect the growth of the three cell lines. However, treatment with IL-8 enhanced the invasiveness into Matrigel and increased the activity of matrix metalloproteinase (MMP)-2 in supernatants of the PANC-1 cells. These results demonstrate that IL-8 and IL-8 receptors are over-expressed in pancreatic cancer, and suggest that IL-8 regulates MMP-2 activity and plays an important role in the invasiveness of human pancreatic cancer.
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PMID:Potential involvement of IL-8 and its receptors in the invasiveness of pancreatic cancer cells. 1263 66

Lysophosphatidic acid (LPA) is a lipid mediator with diverse effects on various cells. Here, we investigated the effects of LPA on human colon carcinoma DLD1 cells. Northern blot analysis revealed that DLD1 highly expressed LPA1/Edg-2 but showed only low expression of LPA2/Edg-4 and no expression of LPA3/Edg-7 at the mRNA level. Western blot analysis revealed that DLD1 cells highly expressed LPA1 at the protein level. Using the Boyden chamber assay, LPA markedly increased DLD1 cell migration at concentrations as low as 10 nM, with maximum stimulation at 100 nM (3.6-fold increase). Checkerboard analysis indicated that LPA stimulated both the chemotactic and chemokinetic migration of DLD1 cells. LPA induced a dose-dependent increase in the proliferation of DLD1 cells (3.2-fold increase at 20 microM). Furthermore, LPA stimulated DLD1 cell adhesion to collagen type I (2.0-fold increase at 10 microM) and also stimulated the secretion of both vascular endothelial growth factor (1.4-fold increase at 20 microM) and interleukin 8 (19-fold increase at 20 microM) by ELISA. In contrast, as for matrix metalloproteinase, LPA had no significant effect on pro-matrix metalloproteinase-2 secretion and its activation, as measured by Western blot analysis. Thus, LPA, at concentrations that are present physiologically, enhanced DLD1 cell migration, proliferation, adhesion, and secretion of angiogenic factors, all of which are crucial for cancer metastasis. In comparison, other human colon carcinoma cells (HT29 and WiDR) exclusively expressed LPA2. LPA enhanced their proliferation and secretion of angiogenic factors, whereas LPA did not enhance migration or adhesion. Our results suggest that LPA acts as a potent stimulator of colon cancer progression, although the binding to LPA1 and LPA2 induces slightly different responses.
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PMID:Lysophosphatidic acid (LPA) enhances the metastatic potential of human colon carcinoma DLD1 cells through LPA1. 1267 Sep 25

Chemotactic chemokines can be released from lung fibroblasts in response to interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. An imbalance between proteases and antiproteases has been observed at inflammatory sites, and, therefore, protease inhibitors might modulate fibroblast release of chemotactic cytokines. To test this hypothesis, serine protease inhibitors (FK-706, alpha(1)-antitrypsin, or N(alpha)-p-tosyl-L-lysine chloromethyl ketone) were evaluated for their capacity to attenuate the release of neutrophil chemotactic activity (NCA) or monocyte chemotactic activity (MCA) from human fetal lung fibroblasts (HFL-1). Similarly, the release of the chemoattractants IL-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, macrophage colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor, from HFL-1, were evaluated in response to IL-1beta and TNF-alpha. NCA, MCA, and chemotactic cytokines were attenuated by FK-706. However, matrix metalloproteinase inhibitors were without effect, and cysteine protease inhibitors only slightly attenuated chemotactic or cytokine release. These data suggest that IL-1beta and TNF-alpha may stimulate lung fibroblasts to release NCA and MCA by a protease-dependent mechanism and that serine protease inhibitors may attenuate the release.
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PMID:Serine protease inhibitors modulate chemotactic cytokine production by human lung fibroblasts in vitro. 1267 71

The production of reactive oxygen species (ROS), prostaglandins (PGs), proinflammatory cytokines, and proteases has been implicated in the pathogenesis of term and preterm labor. The nuclear factor-kappaB (NF-kappaB) transcription pathway is activated by ROS and is a key regulator of PGs, proinflammatory cytokine release, and protease activity. N-Acetyl-cysteine (NAC) is an antioxidant that through its ability to scavenger ROS suppresses NF-kappaB DNA-binding activity and resultant gene expression. The aim of this study was to elucidate the effect of NAC on NF-kappaB DNA-binding activity, phospholipid metabolism, cytokine release, and protease activity from human fetal membranes. Human amnion and choriodecidua (n = 9 separate placentas) were treated with 0 (control), 5, 10, or 15 mM NAC in the presence of 10 micro g/ml lipopolysaccharide. After 6-h incubation, the tissues were collected, NF-kappaB DNA binding activity was assessed by gel shift binding assays, and matrix metalloproteinase-9 and urokinase-type plasminogen activator activity were determined by zymography. The incubation medium was collected and assayed for type II phospholipase A(2) tissue content, IL-6, IL-8, TNFalpha, and 8-isoprostane release by ELISA. The release of PGF(2alpha) was measured by RIA. Treatment of fetal membranes with NAC significantly suppressed lipopolysaccharide-stimulated type II phospholipase A(2) release and content; PGF(2alpha), IL-6, IL-8, TNFalpha, and 8-isoprostane release; and matrix metalloproteinase-9 and urokinase-type plasminogen activator enzyme activity and suppressed NF-kappaB DNA-binding activity (by ANOVA, P < 0.05). The data presented in this study demonstrate that NAC inhibits an NF-kappaB-activated pathway and subsequent phospholipid metabolism, proinflammatory cytokine release, and protease activity in human fetal membranes.
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PMID:N-Acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-kappaB deoxyribonucleic acid-binding activity in human fetal membranes in vitro. 1267 64

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus, causing severe asthma that may progress to bronchiectasis. Sputum neutrophilia can occur in association with sputum eosinophilia and correlates with the degree of bronchiectasis. The mechanisms of sputum neutrophilia in ABPA are not known. The aim of this study was to investigate the role of the chemokine interleukin (IL)-8 in sputum neutrophilia in ABPA. Induced sputum was obtained from subjects with ABPA (n=29), and compared to nonsensitised asthma (n=9) and healthy controls (n=21). Semiquantitative polymerase chain reaction was used to assess IL-8 gene expression in induced sputum and IL-8 protein was measured by enzyme-linked immunosorbent assay. Sputum IL-8 protein was significantly higher in ABPA compared to asthma and controls. IL-8 messenger ribonucleic acid/glyceraldehyde-3-phosphate dehydrogenase ratio was elevated in ABPA compared to asthma and controls. Sputum IL-8 correlated with sputum neutrophils, matrix metalloproteinase-9 levels and forced expiratory volume in one second. Interleukin-8 gene expression and protein release were increased in allergic bronchopulmonary aspergillosis and correlated with airway neutrophilia and airway obstruction. The interleukin-8-mediated neutrophil influx in allergic bronchopulmonary aspergillosis may induce lung damage via release of matrix metalloproteinase-9, potentially leading to bronchiectasis.
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PMID:Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis. 1276 39

We examined whether interleukin-1 (IL-1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL-1beta enhanced expression of various cytokines (IL-6, IL-8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule-1 (ICAM-1) by A549, PC14, RERF-LC-AI, and SBC-3 cells expressing IL-1 receptors. A549 cells transduced with human IL-1beta-gene with the growth-hormone signaling-peptide sequence (A549/IL-1beta) secreted a large amount of IL-1beta protein. Overexpression of IL-1beta resulted in augmentation of expression of the cytokines, ICAM-1, and matrix metalloproteinase-2 (MMP-2). A549/IL-1beta cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti-IL-1beta antibody inhibited formation of lung metastasis by A549/IL-1beta cells. Moreover, A549/IL-1beta cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL-1beta cells. Histological analyses showed that more host-cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL-1beta cells, compared with tumors derived from control A549 cells. These findings suggest that IL-1beta facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis.
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PMID:Multifunctional interleukin-1beta promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules. 1282 17

Recombinant growth factors (GFs) are used to mobilize hematopoietic stem cells (HSCs) for autologous and allogeneic transplantation; however, little is known about the mechanism(s) critical to this process. Increased levels of serum matrix metalloproteinase (MMP)-9 are detected during mobilization by G-CSF in humans or interleukin (IL)-8 in primates and mice, suggesting a role for this molecule in mobilization. Further, antibodies to MMP-9 block IL-8-induced mobilization. To investigate the role of MMP-9, we compared G-CSF and Flt-3 ligand (Flt-3L)-induced mobilization in wild-type (WT) and MMP-9 knockout (KO) mice. The absence of MMP-9 in the KO mice was confirmed by zymography, which also revealed that serum MMP-9 levels were elevated in WT mice following G-CSF administration. We report that MMP-9 KO mice did not have impaired G-CSF- or Flt-3L-induced hematopoietic progenitor mobilization, suggesting that MMP-9 is not an absolute requirement for this process. In addition, MMPs produced by HSCs have been demonstrated to be important for their transmigration; however, we demonstrate that the engraftment of MMP-9-deficient bone marrow HSCs was not impaired in sublethally irradiated WT recipients. We conclude that while MMP-9 may play an important role in GF-induced hematopoietic progenitor mobilization and engraftment in WT animals, compensatory upregulation of enzymes with a similar activity profile to MMP-9 may obscure the impact of MMP-9 deficiency in the KO model.
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PMID:Use of matrix metalloproteinase (MMP)-9 knockout mice demonstrates that MMP-9 activity is not absolutely required for G-CSF or Flt-3 ligand-induced hematopoietic progenitor cell mobilization or engraftment. 1283 95

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


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