UNIPROT:P10145 - FACTA Search

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)

A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation. Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-alpha in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release. Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGF-stimulated IL-8 release. These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.
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PMID:Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium. 1592 44

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has also been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Oxidation of lipoproteins is a hallmark in atherosclerosis. Oxidized low-density lipoprotein induces inflammation as it induces adhesion and influx of monocytes and influences cytokine release by monocytes. A number of proinflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) modulate monocyte adhesion to endothelium. C-reactive protein (CRP), a prototypic marker of inflammation, is a risk marker for CVD and it could contribute to atherosclerosis. Hence, dietary micronutrients having anti-inflammatory and antioxidant properties may have a potential beneficial effect with regard to cardiovascular disease. Vitamin E is a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, alpha-tocopherol (AT) has potential beneficial effects with regard to cardiovascular disease. AT supplementation in human subjects and animal models has been shown to decrease lipid peroxidation, superoxide (O2-) production by impairing the assembly of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase as well as by decreasing the expression of scavenger receptors (SR-A and CD36), particularly important in the formation of foam cells. AT therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, the chemokine IL-8 and plasminogen activator inhibitor-1 (PAI-1) levels as well as decrease adhesion of monocytes to endothelium. In addition, AT has been shown to decrease CRP levels, in patients with CVD and in those with risk factors for CVD. The mechanisms that account for nonantioxidant effects of AT include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine-kinase as well as cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.
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PMID:Vitamin E, oxidative stress, and inflammation. 1601 63

Cigarette smoke may be the main cause of chronic bronchitis. Exposure of cigarette smoke induces the recruitment of inflammatory cells in the airway epithelium, and release of the tumor necrosis factor alpha (TNFalpha) from airways. Previous reports have shown that cigarette smoke induces goblet cell metaplasia by activating an epidermal growth factor receptor (EGFR) cascade, and that this results in mucin production. Rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid, OPC-12759) directly inhibits the production of superoxide (O2-) and inhibits proinflammatory cytokines (such as TNFalpha and IL-8). In the present study, we aimed to analyze the inhibitory effects of rebamipide on TNFalpha and EGFR activation after cigarette smoke treatment in vitro and in vivo. NCl-H292 cells and Sprague-Dawley rats were used for in vitro and in vivo studies. In vitro studies, cigarette smoke solution was found to increase TNFalpha secretion, and EGFR-specific tyrosine phosphorylation, and to elevate MUC5AC production. These effects were inhibited dose-dependently by pretreatment with rebamipide (MUC5AC protein levels were inhibited from 44% to 17%, P<0.05). In vivo studies, cigarette smoke was found to cause inflammatory cell recruitment and to increase the secretion of TNFalpha in bronchoalveolar lavage (BAL) fluids (from 198+/-78 to 2270+/-158 pg/ml, P<0.01). Moreover, the pretreatment of rats with rebamipide inhibited goblet cell metaplasia and TNFalpha secretion, dose-dependently (from 2270+/-158 to 1377+/-112 pg/ml, P<0.05). In conclusion, the exposure of airway epithelium to cigarette smoke-induced TNFalpha production, neutrophil recruitment, activated EGFR, and caused MUC5AC mucin synthesis. Moreover, rebamipide was found to prevent this cigarette smoke-induced TNFalpha release, and mucin production.
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PMID:The inhibitory effects of rebamipide on cigarette smoke-induced airway mucin production. 1603 6

High-throughput genomic technology identified an association between a single nucleotide polymorphism (SNP), a proline (P387) rather than the predominant alanine (A387) at position 387 in thrombospondin-4 (TSP-4) and premature myocardial infarction. The inflammatory hypothesis of atherosclerosis invokes a prominent role of leukocytes and cytokines in pathogenesis. As the expression of TSP-4 by vascular cells permits its exposure to circulating leukocytes, the interactions of human neutrophils (polymorphonuclear leukocytes [PMNs]) with both TSP-4 variants were investigated. Phorbol 12-myristate 13-acetate (PMA)-stimulated PMNs adhered and migrated well and equally on the TSP-4 variants. Integrin alpha(M)beta2 was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)-like domains of TSP-4 harboring the SNPs interacted with the alpha(M)I-domain. Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JNK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant. Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387. H2O2 release and p38MAPK activation were totally inhibited by blockade of alpha(M)beta2. Thus, alpha(M)beta2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant.
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PMID:Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function. 1609 85

HBEpCs (human bronchial epithelial cells) contribute to airway inflammation by secreting a variety of cytokines and chemokines in response to allergens, pathogens, viruses and environmental toxins and pollutants. The potent neutrophil chemoattractant, IL-8 (interleukin-8), is a major cytokine secreted by HBEpCs. We have recently demonstrated that LPA (lysophosphatidic acid) stimulated IL-8 production in HBEpCs via protein kinase C delta dependent signal transduction. However, mechanisms of IL-8 expression and secretion are complex and involve multiple protein kinases and transcriptional factors. The present study was undertaken to investigate MAPK (mitogen-activated protein kinase) signalling in the transcriptional regulation of IL-8 expression and secretion in HBEpCs. Exposure of HBEpCs to LPA (1 microM) enhanced expression and secretion of IL-8 by 5-8-fold and stimulated threonine/tyrosine phosphorylation of ERK (extracellular-signal-regulated kinase), p38 MAPK and JNK (c-Jun N-terminal kinase). The LPA-induced secretion of IL-8 was blocked by the p38 MAPK inhibitor SB203580, by p38 MAPK siRNA (small interfering RNA), and by the JNK inhibitor JNK(i) II, but not by the MEK (MAPK/ERK kinase) inhibitor, PD98059. LPA enhanced the transcriptional activity of the IL-8 gene; that effect relied on activation of the transcriptional factors NF-kappaB (nuclear factor kappaB) and AP-1 (activator protein-1). Furthermore, SB203580 attenuated LPA-dependent phosphorylation of IkappaB (inhibitory kappaB), NF-kappaB and phospho-p38 translocation to the nucleus, NF-kappaB transcription and IL-8 promoter-mediated luciferase reporter activity, without affecting the JNK pathway and AP-1 transcription. Similarly, JNK(i) II only blocked LPA-mediated phosphorylation of JNK and c-Jun, AP-1 transcription and IL-8 promoter-mediated luciferase reporter activity, without blocking p38 MAPK-dependent NF-kappaB transcription. Additionally, siRNA for LPA(1-3) receptors partially blocked LPA-induced IL-8 production and activation of MAPKs. The LPA1 and LPA3 receptors, as compared with LPA2, were most efficient in transducing LPA-mediated IL-8 production. These results show an independent role for p38 MAPK and JNK in LPA-induced IL-8 expression and secretion via NF-kappaB and AP-1 transcription respectively in HBEpCs.
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PMID:Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells. 1619 69

Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.
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PMID:Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. 1620 90

Cot is one of the MAP kinase kinase kinases that regulates the ERK1/ERK2 pathway under physiological conditions. Cot is activated by LPS, by inducing its dissociation from the inactive p105 NFkappaB-Cot complex in macrophages. Here, we show that IL-1 promotes a 10-fold increase in endogenous Cot activity and that Cot is the only MAP kinase kinase kinase that activates ERK1/ERK2 in response to this cytokine. Moreover, in cells where the expression of Cot is blocked, IL-1 fails to induce an increase in IL-8 and MIP-1betamRNA levels. The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6. Most important, IL-1-induced ERK1/ERK2 activation is inhibited by PP1, a known inhibitor of Src tyrosine kinases, but this tyrosine kinase activity is not required for IL-1 to activate other MAP kinases such as p38 and JNK. This Src kinases inhibitor does not block the dissociation and subsequently degradation of Cot in response to IL-1, indicating that other events besides Cot dissociation are required to activate Cot. All these data highlight the specific requirements for activation of the Cot-MKK1-ERK1/ERK2 pathway and provide evidence that Cot controls the functions of IL-1 that are mediated by ERK1/ERK2.
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PMID:TRAF6 and Src kinase activity regulates Cot activation by IL-1. 1637 Dec 47

Exposure to zinc-laden particulate matter in ambient and occupational settings has been associated with proinflammatory responses in the lung. IL-8 is an important proinflammatory cytokine in the human lung and is induced in human airway epithelial cells exposed to zinc. In this study, we examined the cellular mechanisms responsible for Zn(2+)-induced IL-8 expression. Zn(2+) stimulation resulted in pronounced increases in both IL-8 mRNA and protein expression in the human airway epithelial cell line (BEAS-2B). IL-8 promoter activity was significantly increased by Zn(2+) exposure in BEAS-2B cells, indicating that Zn(2+)-induced IL-8 expression is transcriptionally mediated. Mutation of the activating protein (AP)-1 response element in an IL-8 promoter-enhanced green fluorescent protein construct reduced Zn(2+)-induced IL-8 promoter activity. Moreover, Zn(2+) exposure of BEAS-2B cells induced the phosphorylation of the AP-1 proteins c-Fos and c-Jun. We observed that Zn(2+) exposure induced the phosphorylation of ERK, JNK, and p38 MAPKs, whereas inhibition of ERK or JNK activity blocked IL-8 mRNA and protein expression in BEAS-2B cells treated with Zn(2+). In addition, we investigated the role of protein tyrosine phosphatases in the activation of signaling by Zn(2+). Zn(2+) treatment inhibited ERK- and JNK-directed phosphatase activities in BEAS-2B cells. These results suggested that Zn(2+)-induced inhibition of phosphatase activity is an initiating event in MAPK and AP-1 activation that leads to enhanced IL-8 expression by human airway epithelial cells.
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PMID:Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells. 1637 69

Aggregation of the type 1 Fc-epsilon receptors (Fc-epsilon-RI) on mast cells initiates a network of biochemical processes culminating in secretion of both granule-stored and de novo-synthesized inflammatory mediators. A strict control of this response is obviously a necessity; nevertheless, this regulation is hardly characterized. Here we report that a prototype inhibitory receptor, the mast cell function-associated antigen (MAFA), selectively regulates the Fc-epsilon-RI stimulus-response coupling network and the subsequent de novo production and secretion of inflammatory mediators. Specifically, MAFA suppresses the PLC-gamma2-[Ca2+]i, Raf-1-Erk1/2, and PKC-p38 coupling pathways, while the Fyn-Gab2-mediated activation of PKB and Jnk is essentially unaffected. Hence, the activities of several transcription/nuclear factors for inflammatory mediators (NF-kappaB, NFAT) are markedly reduced, while those of others (Jun, Fos, Fra, p90rsk) are unaltered. This results in a selective inhibition of gene transcription of cytokines including IL-1beta, IL-4, IL-8, and IL-10, while that of TNF-alpha, MCP-1, IL-3, IL-5, or IL-13 remains unaffected. Taken together, these results illustrate the capacity of an immunoreceptor tyrosine-based inhibitory motif-containing receptor to cause tight and specific control of the production and secretion of inflammatory mediators by mast cells.
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PMID:Selective inhibition of the Fc epsilon RI-induced de novo synthesis of mediators by an inhibitory receptor. 3070 14

Tumor necrosis factor-alpha (TNF-alpha) is a potent multifunctional cytokine that plays a central role in the pathogenesis of many inflammatory diseases. Interleukin-8 (IL-8) is a principle neutrophil chemoattractant and activator in humans. The alveolar macrophage-derived TNF-alpha initiates lung inflammation through its ability to stimulate IL-8 synthesis in airway epithelial cells. Since recent studies demonstrated that the stimulation of epidermal growth factor receptor (EGFR) could induce IL-8 secretion, the involvement of EGFR in TNF-alpha-induced IL-8 secretion in airway epithelium-like NCI-H292 cells was investigated in this study. TNF-alpha and epidermal growth factor (EGF) stimulated IL-8 secretion in a time- and concentration-dependent manner. Inhibition of the EGFR by either an anti-EGFR neutralizing antibody or by its specific inhibitor AG1478 (1 microM) blocked TNF-alpha-induced IL-8 secretion. In addition, TNF-alpha stimulated tyrosine phosphorylation of the EGFR within 5 min after stimulation. Further, TNF-alpha-induced IL-8 secretion was completely inhibited by the neutralizing antibody against amphiregulin (AR), an EGFR ligand, suggesting that TNF-alpha-induced IL-8 secretion was mediated by the AR-EGFR pathway. Furthermore, TNF-alpha stimulated the release of AR in a concentration-dependent manner. Finally, both AR and IL-8 release-induced by TNF-alpha were eliminated by pretreatment with either GM6001, a broad-spectrum inhibitor for metalloprotease, or TAPI-1, relatively selective inhibitor for TNF-alpha converting enzyme (TACE). These findings indicate that metalloprotease-mediated AR shedding and subsequent activation of EGFR play a critical role in TNF-alpha-induced IL-8 secretion from the human airway epithelium-like NCI-H292 cells, and that TACE is one of the most possible candidates for metalloprotease responsible for TNF-alpha-induced AR shedding.
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PMID:Metalloprotease-dependent amphiregulin release mediates tumor necrosis factor-alpha-induced IL-8 secretion in the human airway epithelial cell line NCI-H292. 1642 93

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