UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour necrosis factor alpha (TNF-alpha) inflammatory activity is mediated, at least in part, by prostaglandin E(2)(PGE(2)). In osteoarthritis (OA), other cytokines are believed to play a role by interacting with TNF-alpha. Using OA synovial fibroblasts, we investigated the effects of interleukin 8 (IL-8), leukaemia inhibitory factor (LIF) and IL-11 on the level of TNF-alpha-induced PGE(2), and their impact on the TNF-alpha-induced cellular signalling cascades including the TNF-receptor (TNF-R), soluble TNF-R (TNF-sR), cytoplasmic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX-2), and the transcription factors NF-kappaB, C/EBP, CREB and AP-1.IL-8 increased in a synergistic manner (282% at 5 ng/ml) and LIF in an additive fashion (69% at 50 ng/ml) the TNF-alpha-induced PGE(2)release, while IL-11 reduced it (52% at 5 ng/ml). IL-8 (5 ng/ml) and LIF (50 ng/ml) alone upregulated (30%) the TNF-R binding level, but significantly downregulated the TNF-alpha-induced levels (P<0.007 and P<0.004, respectively) and the TNF-sR55 level. In contrast, IL-11 reduced the basal level by 18% (P<0.005) and the TNF-alpha-induced level of TNF-R by 51% (P<0.01) as well as decreasing both TNF-sR55 and TNF-sR75. The COX-2 synthesis level was increased by IL-8 and LIF under TNF-alpha treatment but downregulated by IL-11. IL-8 and LIF either alone or under TNF-alpha treatment increased the cPLA2 synthesis, while IL-11 decreased the level under both conditions. Interestingly, IL-8 induced in a synergistic manner and LIF in an additive fashion, the level of cPLA2 activity. IL-8 and LIF had no effect on the TNF-alpha-induced NF-kappaB accumulation, while IL-11 significantly decreased it (P<0. 02). All three cytokines inhibited TNF-alpha-induced C/EBP, but no true effect was noted for AP-1 and CREB in the presence of TNF-alpha. These results indicate that IL-8 synergizes and LIF potentiates the TNF-alpha PGE(2)effect which appears to be mediated mostly by increasing cPLA2 activity level. On the other hand, IL-11 alone had no effect on the PGE(2)release, but in conjunction with TNF-alpha, this cytokine showed anti-inflammatory properties. This study provides a rational foundation to develop therapeutic strategies for the treatment of OA by shedding light on the mechanisms of action of three prominent cytokines at work in articular joint tissues.
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PMID:Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-alpha-induced PGE(2)release and on signalling pathways in human OA synovial fibroblasts. 1062 27

Interleukin-8 (IL-8) is a cytokine which recruits and activates neutrophils into tissue stroma. It is present in uterine tissues and its concentration increases in the third trimester and with labour. The promoter region of the IL-8 gene contains binding sites for the transcription factors, nuclear factor-kappa B (NF-kappaB), activator protein-1 (AP-1) and CCAAT/enhancer-binding protein (C/EBP). These are in close proximity to each other and to the coding region of the gene. This study used site-directed mutagenesis of each of these sites to examine the relative importance of each site in IL-8 gene expression in a cervical cell line and in amnion cells obtained before and after labour. We found that the NF-kappaB site was essential for basal and IL-1beta-stimulated gene expression in all cell types. Neither of the other binding sites was consistently essential for gene expression but may have an additive role in promoter activity. We conclude that the NF-kappaB binding site is essential for up-regulation of IL-8 gene expression in these uterine cell types. An increase in IL-8 expression has been shown to occur in the uterus in association with parturition and NF-kappaB binding to the promoter may be of importance at this time.
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PMID:Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells. 1147 Aug 67

Neurotensin (NT), a neuropeptide released in the gastrointestinal tract in response to several stimuli, is involved in the pathophysiology of colonic inflammation. However, the molecular mechanism(s) mediating this proinflammatory response remains unclear. We found that NCM460, non-transformed human colonocytes, express a functional high affinity NT receptor that mediates NT-induced Erk activation. By using NCM460 cells stably transfected with NTR1, we show that NTR1 activation leads to interleukin (IL)-8 secretion that is mediated via both NF-kappaB- and Erk-dependent pathways. In addition, NT-stimulated NF-kappaB activation is dependent on intracellular calcium release. NT-stimulated Erk activity requires Ras activation because overexpression of the dominant negative Ras mutant Ras-17N almost completely inhibits the Erk activation. Furthermore, NT directly stimulates Ras-GTP formation as shown by a Ras-GTP pull-down assay. By using reporter gene constructs containing targeted substitutions in the IL-8 promoter, we show that the NF-kappaB, AP-1, and to a lesser degree the C/EBP sites in the IL-8 promoter region are required for IL-8 gene expression induced by NT. In summary, our results demonstrate that NT stimulates calcium-dependent NF-kappaB and Ras-dependent Erk pathways that mediate the release of IL-8 from non-transformed human colonocytes. We speculate that these NT-related proinflammatory pathways are important in the pathophysiology of colonic inflammation.
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PMID:Signal transduction pathways mediating neurotensin-stimulated interleukin-8 expression in human colonocytes. 1157 37

Nacystelyn (NAL), a recently developed lysine salt of N-acetyl-L-cytokine (NAC) has mucolytic and antioxidant properties. In this study, we investigated the effect of NAL upon oxidant-mediated interleukin (IL)-8 release and the activation of the redox-sensitive transcription factors AP-1, NF-kappaB, and C/EBP in a human alveolar epithelial cell line (A549). NAL (5 mM) enhanced intracellular glutathione (GSH) after 4 h and abolished H(2)O(2)-induced IL-8 release from A549 cells. This was associated with inhibition of NF-kappaB and C/EBP DNA-binding, measured by the Electrophoretic Mobility Shift Assay (EMSA). NAL also abolished the transcriptional activation of IL-8 in an IL-8-chloramphenicol acetyl transferase (CAT) reporter system, transfected into A549 cells. Supernatants obtained from H(2)O(2)-treated A549 cells induced chemotaxis of polymorphonuclear neutrophils, which could be inhibited by co-incubation with NAL. These data indicate that NAL may be used to modulate pro-inflammatory process by inhibiting cytokine release in the lungs and thus has therapeutic potential in inflammatory lung diseases.
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PMID:Nacystelyn inhibits oxidant-mediated interleukin-8 expression and NF-kappaB nuclear binding in alveolar epithelial cells. 1195 50

Interleukin-8 (IL-8), which is a member of C-X-C chemokine subfamily, is an important activator and chemoattractant for neutrophils and has been implicated in a variety of inflammatory diseases. Numerous reports show that various cells express IL-8 mRNA and produce IL-8 protein rapidly, including monocytes, T lymphocytes, neutrophils, fibroblasts, endothelial cells and epithelial cells. The human IL-8 gene has a length of 5191 bp and contains four exons separated by three introns. It maps to human chromosome 4q12-q21. The mRNA consists of a 101 bases 5' untranslated region, an open reading frame of 297 bases, and a long 3' untranslated region of 1.2 kb. The 5' flanking region of the IL-8 gene contains potential binding sites for several nuclear factors including activated protein-1 (AP-1), activated protein-2 (AP-2), nuclear factor-gene binding (NF-kappa B), nuclear factor-interleukin-6 (NF-IL-6, also calls CAAT/enhancer-binding proteins, C/EBP), IFN regulatory factor-1 (IRF-1), hepatocyte nuclear factor-1 (HNF-1), and so on. IL-8 gene expression is regulated initially at the level of gene transcription. The rapid induction of IL-8 gene expression is likely mediated by latent transcription factors that bind the IL-8 promoter. AP-1 and NF-IL-6 physically interact with NF-kappa B, and functional cooperativity among these factors appears to be critical for optimal IL-8 promoter activity in different cell types. The IL-8 receptor (IL-8R) is a dimeric glycoprotein consisting of a 59 KDa and a 67 KDa subunit. It has been given the name CDw128. It is expressed in many different cell types including those not responding to IL-8. The receptor density is approximately 20,000/cell in neutrophils, 1,040/cell in monocytes, and 300/cell in T-lymphocytes. The IL-8R is a member of the family of G-protein-coupled receptors. There are at least two different IL-8 receptor types (CXCR1 and CXCR2). The activities of IL-8 are not species-specific. IL-8 affects the adhesion of neutrophils to the endothelium and induces the transendothelial migration of neutrophils. IL-8 also exhibits in vitro chemotactic activities against of T-lymphocytes and basophils. IL-8 gene expression can be regulated by fluid shear stress, which may play an important role in the genesis and development of both inflammation and arterosclerosis.
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PMID:[The study on the interleukin-8 (IL-8)]. 1256 82

Here we investigated the mechanisms by which mechanical stretch regulates the production of IL-8 in primary human airway smooth muscle cells (HASMC). Bronchial HASMC were subjected to cyclic mechanical stretch (12%, 1 Hz) using the computer-controlled Flexcell Strain system. Mechanical stretch increased IL-8 mRNA expression and protein production. Cyclic stretch of HASMC also increased the kinase activities of ERK1/2, JNK1, p38, and the DNA binding activities of AP-1 and C/EBP transcription factors with little effect on NF-kappa B. The inhibition of AP-1 and C/EBP transcriptional activities blocked the production of IL-8 in culture supernatants. Furthermore, the inhibition of ERK1/2 and p38 but not JNK1 caused a significant down-regulation in the expression and production of IL-8 in response to cyclic stretch. Although protein tyrosine kinases were required for the activation of both ERK1/2 and p38 kinase, stretch-activated channels, small GTPase proteins, and extracellular Ca2+ influx were required only for the activation of p38 kinase whereas phosphoinositide 3-kinase was needed for ERK1/2 activation. In addition, the phosphorylation of ERK1/2 was essential for the activation of AP-1 whereas p38 MAP kinase was needed for the activation of C/EBP. Our data demonstrate that the cyclic stretch of HASMC causes the increased production of IL-8 by activating the AP-1 and C/EBP transcription factors through the activation of ERK1/2 and p38 kinase signaling pathways.
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PMID:CCAAT/enhancer-binding protein and activator protein-1 transcription factors regulate the expression of interleukin-8 through the mitogen-activated protein kinase pathways in response to mechanical stretch of human airway smooth muscle cells. 1263 25

Pretreatment of HT29-D4 epithelial adenocarcinoma colic cells with des-IGF-1 upregulated TNF alpha-mediated activation of IL-8 expression at different levels (protein, mRNA, and hnRNA). RNA transcription but not RNA stabilization was found to be involved. In this cell line, cooperation of NF-kappa B with other factors appeared essential for IL-8 expression. Indeed, TNF alpha-induced NF-kappa B translocation was not sufficient to support enhancement of the transcription and des-IGF-1 did not promote but partly inhibited both the TNF alpha-induced NF-kappa B activation and I kappa B alpha degradation through a PI-3K-dependent pathway. A CCAAT/enhancer binding protein (C/EBP) site located on the IL-8 gene enhancer cooperated with a NF-kappa B binding site and led to the upregulation of IL-8 expression. Binding of C/EBP alpha to this sequence disappeared in IGF-1 treated cells. This event may be important for the cross-talk between IGF-1- and TNF alpha-mediated pathways leading to the control of inflammatory processes and the decision concerning apoptosis or cell survival.
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PMID:Insulin-like growth factor-1 downregulates nuclear factor kappa B activation and upregulates interleukin-8 gene expression induced by tumor necrosis factor alpha. 1276 6

Increased levels of proinflammatory cytokines are present in bronchoalveolar lavage fluid in various lung diseases. Redox-sensitive transcription factors such as NF-kappaB regulate gene transcription for these cytokines. We therefore studied the effect of a new thiol antioxidant compound, Nacystelyn (NAL), on IL-8 regulation in a human macrophage-derived cell line (THP-1). LPS (10 microg/ml) increased IL-8 release compared with control levels. This LPS activation was inhibited by coincubation with NAL (1 and 5 mM). Pretreatment with cycloheximide or okadaic acid, protein synthesis, and serine/threonine phosphatase inhibitors, respectively, did not modify inhibition of IL-8 release caused by NAL. NF-kappaB and C/EBP DNA binding were increased after LPS treatment compared with control, an effect inhibited by cotreatment with NAL. Activator protein (AP)-1 DNA binding was unaffected. The enhanced neutrophil chemotaxis produced by conditioned media from LPS-treated cells was inhibited when cells were cotreated with NAL. The selectivity of NAL inhibition upon IL-8 expression was studied. LPS-treated THP-1 cells also had higher levels of TNF-alpha, transforming growth factor (TGF)-beta1 and -3, MIP-1alpha and -beta, and RANTES gene expression. However, only LPS-induced IL-8 and TGF-beta1 expressions were inhibited by NAL. An anti-inflammatory effect of NAL was confirmed in vivo as shown by a reduction in LPS-induced neutrophil recruitment to the lungs following instillation of NAL into the lungs. Our studies demonstrate that NAL has anti-inflammatory properties in vitro and in vivo, may therefore have a therapeutic role in lung inflammation, and has the advantage over other antioxidant agents in that it may be administrated by inhalation.
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PMID:Regulation of LPS-mediated inflammation in vivo and in vitro by the thiol antioxidant Nacystelyn. 1513 98

Respiratory viruses induce and potentiate airway inflammation, which is related to the induction of proinflammatory mediators such as interleukin (IL)-8 and IL-6. Here we report on mechanisms implicated in IL-8 and IL-6 production by airway epithelium-like NCI-H292 cells exposed to parainfluenza virus type 4a (PIV-4). PIV-4 readily infected NCI-H292 cells as reflected by intracellular PIV-4 antigen expression. PIV-4 infection triggered a biphasic IL-8 and IL-6 mRNA response. Transient transfection with truncated and mutated promoter constructs identified NF-kappaB and activator protein (AP)-1, and CCAAT-enhancer binding protein (C/EBP) as the relevant transcription factors for PIV-4-induced IL-8 and IL-6 gene transcription, respectively. An increase of DNA-binding activities for NF-kappaB and C/EBP paralleled the induction of the first and second IL-8 and IL-6 mRNA peaks, whereas the onset of AP-1 paralleled the first IL-8 mRNA peak only. The second mRNA peak, apparently dependent on viral replication, coincided also with a marked reduction of IL-8 and IL-6 mRNA degradation. Importantly, cells at the time of the reduced mRNA degradation displayed an exaggerated IL-8 and IL-6 protein production to a secondary stimulus, as exemplified by steeper dose-response curves to TNF-alpha. Thus PIV-4 infection enhances epithelial IL-8 and IL-6 production by transcriptional and posttranscriptional mechanisms. The previously unrecognized phase of reduced IL-8 and IL-6 mRNA degradation and the concurrent amplified epithelial IL-8 and IL-6 responses may play an important role in virus-induced potentiation of airway inflammation.
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PMID:Exaggerated IL-8 and IL-6 responses to TNF-alpha by parainfluenza virus type 4-infected NCI-H292 cells. 1527 81

Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity, is now known to possess tumorigenic and proangiogenic properties as well. In human gliomas, IL-8 is expressed and secreted at high levels both in vitro and in vivo, and recent experiments suggest it is critical to glial tumor neovascularity and progression. Levels of IL-8 correlate with histologic grade in glial neoplasms, and the most malignant form, glioblastoma, shows the highest expression in pseudopalisading cells around necrosis, suggesting that hypoxia/anoxia may stimulate expression. In addition to hypoxia/anoxia stimulation, increased IL-8 in gliomas occurs in response to Fas ligation, death receptor activation, cytosolic Ca(2+), TNF-alpha, IL-1, and other cytokines and various cellular stresses. The IL-8 promoter contains binding sites for the transcription factors NF-kappaB, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has been shown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-kappaB-mediated IL-8 transcription and subsequent angiogenesis in gliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenic and angiogenic responses include CXCR1 and CXCR2, both of which are G-protein coupled, and the Duffy antigen receptor for cytokines, which has no defined intracellular signaling capabilities. The proangiogenic activity of IL-8 occurs predominantly following binding to CXCR2, but CXCR1 appears to contribute as well through independent, small-GTPase activity. A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies.
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PMID:The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. 1583 Dec 31

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