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)

CP-64131 (CP), an aminobenzazepine with cytokine-like, physiologic effects similar to granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF, increases the number of neutrophils and stimulates marrow recovery after doxirubicin ablation. CP can also function as a neutrophil agonist, like formyl-Met-leu-Phe (fMLP). In these studies, we show that CP is unique in that it stimulates the p38-mitogen-activated protein kinase (MAPK) pathway but not extracellular signal-regulated kinase (ERK)1/2 or c-jun N-terminal kinase MAPKs in human neutrophils from peripheral blood. This is in contrast to other neutrophil agonists such as fMLP, interleukin (IL)-8, or GM-CSF, which stimulate multiple MAPK pathways. Like fMLP and IL-8, CP is capable of stimulating superoxide (O2-) production, CD11b expression, and cell polarization in human neutrophils. CP-stimulated O2- production is completely dependent on p38-MAPK activation, as determined by sensitivity to the p38-MAPK inhibitor SB203580. In contrast, SB203580 only partially inhibits expression of CD11b and has no effect on cell polarization stimulated by CP. Therefore, CP treatment of neutrophils activates p38-MAPK but has effects independent of p38-MAPK activation. In human embryonic kidney 293 cells, a human kidney epithelial cell line CP stimulates p38-MAPK and modestly activates ERK1/2. The findings define CP as a novel, small molecule, which has little cellular toxicity in vitro. CP has the ability to activate specific MAPK pathways in different cell types and should prove to be an effective agonist in combination with inhibitors to study biological responses regulated by MAPKs.
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PMID:CP-64131, an aminobenzazepine with cytokine-like properties, stimulates human neutrophil functions through the p38-MAPK pathway. 1515 76

The capacity of cytokines to modulate neutrophil apoptosis is thought to be a major factor influencing the resolution of granulocytic inflammation. We have previously shown that the late survival effect of TNF-alpha in human neutrophils involves activation of both NF-kappa B and phosphoinositide 3-kinase (PI3-kinase) pathways. In this study, we address how these pathways integrate to prevent cell death. In human neutrophils, TNF-alpha (200 U/ml) induced rapid I kappa B-alpha degradation, NF-kappa B activation and IL-8 release (31.8+/-5.4 pg/10(5) cells/2 h), whereas GM-CSF (10 ng/ml) stimulated an equivalent IL-8 release (26.5+/-4.5 pg/10(5) cells/2 h) without enhanced I kappa B-alpha degradation or NF-kappa B activation compared to control. Importantly, inhibition of PI3-kinase did not modify TNF-alpha -induced I kappa B-alpha degradation, yet fully inhibited the survival effect of both cytokines. Inhibition of I kappa B-alpha phosphorylation, PI3-kinase or ERK1/2 activation blocked IL-8 release by both cytokines. Blocking IL-8 activity by inhibiting its synthesis or by using a neutralizing antibody enhanced the early pro-apoptotic effect of TNF-alpha and inhibited its late survival effect without affecting GM-CSF-induced survival. These data suggest that cross-talk between NF-kappa B and PI3-kinase pathways in TNF-alpha -stimulated neutrophils results from NF-kappa B/ERK1/2-dependent IL-8 production which acts in an autocrine manner to drive PI3-kinase-dependent survival. In contrast, GM-CSF-mediated survival does not involve NF-kappa B activation or IL-8 release.
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PMID:The survival effect of TNF-alpha in human neutrophils is mediated via NF-kappa B-dependent IL-8 release. 1516 44

Chemokines are important mediators of inflammation. It has been demonstrated that there is an increase in chemokine expression in both the sera and brain of individuals infected with human immunodeficiency virus type 1 (HIV-1). The HIV-1 viral protein, Tat, a transcriptional regulator, has been detected in the central nervous system (CNS) of infected individuals, and has been demonstrated to induce chemokines from various cells within the brain. The authors now show that the interaction of human microglia, the resident phagocytes of the brain, with Tat leads to dramatic increases in the secretion of the chemokines CCL2, CXCL8, CXCL10, CCL3, CCL4, and CCL5. Treatment of microglia with Tat plus specific inhibitors of signal transduction pathways demonstrated that the induction of each chemokine is regulated differently. Tat-induced expression of CCL2 and CCL4 was mediated by the activation of the extracellular regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K) pathway, whereas the induction of CXCL8 and CCL3 was mediated only by the p38 MAPK pathway. Tat-induced CXCL10 expression was mediated, to some extent, by activation of the ERK1/2 MAPK pathway, phosphatidylinositol 3-kinase pathway, and the p38 MAPK pathway, whereas CCL5 expression was not mediated by any pathway tested. Western blot analysis demonstrated phosphorylation of ERK 1/2 and Akt upon stimulation of microglia with Tat. These data suggest that a soluble HIV-1 viral protein can alter the chemokine balance in the brain, which can then lead to an influx of inflammatory cells and contribute to the neuropathogenesis of HIV-1 infection.
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PMID:Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. 1520 27

Interleukin-8 (IL-8) is released in response to inflammatory stimuli, such as bacterial products. Either porins or lipopolysaccharide (LPS) stimulated THP-1 cells to release IL-8 after 24 h. We have previously reported that stimulation of monocytic cells with Salmonella enterica serovar Typhimurium porins led to the activation of mitogen-activated protein kinase cascades and of protein tyrosine kinases (PTKs). In this report, we demonstrate, using two potent and selective inhibitors of MEK activation by Raf-1 (PD-098059) and p38 (SB-203580), that both ERK1/2 and p38 pathways play a key role in the production of IL-8 by porins and LPS. Porin-stimulated expression of activating protein 1 (AP-1) and correlated IL-8 release is also inhibited by PD-098059 or SB-203580 indicating that the Raf-1/MEK1-MEK2/MAPK cascade is required for their activation. Also PTKs modulate the pathway that control IL-8 gene expression, in fact its expression is abolished by tyrphostin. By using N-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN) an inhibitor of nuclear factor-kappaB (NF-kappaB) activity, we also observed IL-8 release modulation. Our results elucidate some of the molecular mechanisms by which AP-1 and NF-kappaB regulate IL-8 release and open new strategies for the design of specific molecules that will modulate IL-8 effects in various infectious diseases.
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PMID:Interleukin-8 production by THP-1 cells stimulated by Salmonella enterica serovar Typhimurium porins is mediated by AP-1, NF-kappaB and MAPK pathways. 1520 47

Inflammatory cytokine production by alveolar macrophages (AMs) is regulated by transcriptional activation and may be increased by cigarette smoking. The smoking-induced regulation of interleukin (IL)-8 by extracellular signal-regulated kinase (ERK)-1 and -2, p38 mitogen-activated protein kinase (MAPK) and the transcription factor nuclear factor-kappaB (NF-kappaB) in lipopolysaccharide-stimulated AMs was assessed in nine smokers compared with nine healthy nonsmokers. IL-8 production was dependent on phosphorylation of ERK-1 and -2 and p38 MAPK, as examined by PD 098059 (10 microM), an inhibitor of the upstream activator of MAPK kinase (MKK)-1, and SB 203580 (10 microM), an inhibitor of p38 MAPK. IL-8 release and the inhibitory effect of PD 098059 were increased in AMs from smokers. Moreover, ERK-2 messenger ribonucleic acid expression, as examined by reverse transcriptase polymerase chain reaction and phosphorylation of ERK-2 using Western blots, were increased in AMs from smokers, indicating a smoking-induced modulatory role of ERK-1 and -2. Lipopolysaccharide-induced IL-8 production was dependent on activation of NF-kappaB, as examined by SN 50 (100 microM), an inhibitor of NF-kappaB translocation, and the specific NF-kappaB inhibitor kinase-2 inhibitor, AS 602868 (10 microM), with no differences in AMs from smokers and nonsmokers. SN 50 but not PD 098059 and SB 203580 blocked NF-kappaB deoxyribonucleic acid-binding, and this occurred to the same extent in AMs from smokers and nonsmokers, as examined by electromobility shift assay. It is concluded that cigarette smoking enhances mitogen-activated protein kinase activation more than nuclear factor-kappaB activation to increase lipopolysaccharide-induced interleukin-8 production in alveolar macrophages.
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PMID:Effect of smoking on MAP kinase-induced modulation of IL-8 in human alveolar macrophages. 1521 90

Helicobacter pylori infection leads to significant inflammations in the gastric mucosa, which is closely associated with development of gastric cancer. Heat shock protein 90 (HSP 90) has been revealed to be critical for intracellular signaling that participates in inflammatory response as well as carcinogenesis. In this study, we investigated a regulatory role of HSP 90 in H. pylori-induced IL-8 production. Our results showed that H. pylori stimulated significant phosphorylation of HSP 90 and the phosphorylation was diminished by administration of HSP 90 inhibitor, geldanamycin (GA). Treatment of GA completely inhibited H. pylori-induced IL-8 production due to deactivation of ERK1/2 and NF-kappaB. These results subsequently lead to inactivation of AP-1 and NF-kappaB, which are known to be major transcriptional factors of IL-8. Our data provide important insights that HSP 90 is involved as a crucial regulator in H. pylori-induced IL-8 production and its inhibitor could be potentially used for the inhibition of H. pylori-provoked inflammation.
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PMID:Blockage of HSP 90 modulates Helicobacter pylori-induced IL-8 productions through the inactivation of transcriptional factors of AP-1 and NF-kappaB. 1524 Jan 21

Crystalline silica has been shown to trigger pulmonary inflammation both in vivo and in vitro, but the underlying molecular mechanisms remain unclear. In the present study we focus on the intracellular signaling pathways regulating chemokine release from lung epithelial cells after crystalline silica exposure. Our results show that silica particles induced a concentration- and time-dependent increase in interleukin (IL)-8 release from the human epithelial lung cell line A549. The IL-8 induction was significantly attenuated by inhibitors of the mitogen-activated protein kinases (MAPKs), p38 (SB202190) and extracellular signal-regulated kinase (ERK)-1 and -2 (PD98059), as well as a general protein tyrosine kinase (PTK) inhibitor (genistein). However, IL-8 induction was most efficiently inhibited by the Src family kinase (SFK) inhibitor, PP2, suggesting a crucial role of SFKs in regulating silica-induced IL-8 release from A549 cells. Silica exposure induced phosphorylation of the MAPKs p38 and ERK1/2, but not JNK or ERK5. Silica also induced a significant phosphorylation of SFKs. Moreover, PP2 inhibited silica-induced phospho-ERK1/2 to near-control levels, whereas phospho-p38 was not significantly reduced by the SFK inhibitor. Our results suggest the presence of two separate signaling pathways which are important in the regulation of silica-induced IL-8 release from A549 cells; one involving SFK-dependent activation of ERK1/2, and the other activation of p38, at least partly independent of SFKs. Experiments with primary type 2 (T2) cells from rat lungs suggest that crystalline silica-induced release of macrophage inflammatory protein (MIP)-2 is regulated through similar mechanisms.
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PMID:p38 and Src-ERK1/2 pathways regulate crystalline silica-induced chemokine release in pulmonary epithelial cells. 1524 Aug 96

Lung overstretch involves mechanical factors, including large tidal volumes (VT), which induce inflammatory responses. The current authors hypothesised that inspiratory flow contributes to ventilator-induced inflammation. Buffer-perfused rabbit lungs were ventilated for 2 h with 21%, O2+5%, CO2, positive end-expiratory pressure of 2-3 cmH2O and randomly assigned to either: 1) normal VT (6 mL x kg(-1)) at respiratory rate (RR) 30, inspiration:expiration time ratio (I:E) 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1); 2) large VT (12 mL x kg(-1)) at RR 30, I:E 1:1, high inspiratory flow 12 mL x kg(-1) x s(-1) (HRHF); 3) large VT at RR 15, I:E 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1) (LRLF); or 4) large VT at RR 15, I:E 1:2.3, high inspiratory flow 10 mL x kg(-1) x s(-1) (LRHF). Physiological parameters, tumour necrosis factor (TNF)-alpha, interleukin (IL)-8 and activation of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK)1/2, p38 and stress-activated protein kinase (SAPK)/ c-Jun N-terminal kinase (JNK)) were measured. HRHF increased weight gain, perfusate IL-8 and phosphorylation of ERK1/2, p38 and SAPK/JNK. These responses were absent during LRLF but present during LRHF. Changes in TNF-alpha were small. Tissue IL-8 and phospho-ERK1/2 staining was localised primarily to smooth muscle, adventitia and bronchial epithelium within larger bronchioles and arterioles. These results indicate that mild overstretch of perfused lungs during high inspiratory flow enhances inflammatory signalling by cells in lung regions most affected by strong turbulent airflow.
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PMID:Reduced inspiratory flow attenuates IL-8 release and MAPK activation of lung overstretch. 1533 91

Activation of CXCR2 IL-8 receptor leads to activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and rapid receptor endocytosis. Co-immunoprecipitation and co-localization experiments showed that arrestin and CXCR2 form complexes with components of the ERK1/2 cascade following ligand stimulation. However, in contrast to the activation of the beta2-adrenergic receptor, arrestin was not necessary for ERK1/2 phosphorylation or receptor endocytosis. In contrast, beta-arrestin 1/2 double knockout cells showed greatly enhanced phosphorylation of ERK1/2, as well as phosphorylation of the stress kinases p38 and c-Jun N-terminal protein kinase. The stimulation of stress kinases in arrestin double knockout cells could be attenuated in the presence of diphenylene iodonium (DPI), an inhibitor of the NADPH oxidase, suggesting that reactive oxidant species (ROS) participated in mitogen-activated protein kinase (MAPK) activation. ROS could indeed be detected in IL-8-stimulated beta-arrestin 1/2 knockout cells, and cytoplasmic Rac was translocated to the membrane fraction, which is a prerequisite for oxidant formation. The oxidative burst induced cell death within 6 h of IL-8 stimulation of these cells, which could be prevented in the presence of DPI. These results indicate a novel function for arrestin, which is protection from an excessive oxidative burst, resulting from the sustained stimulation of G-protein-coupled receptors that cause Rac translocation.
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PMID:Arrestin regulates MAPK activation and prevents NADPH oxidase-dependent death of cells expressing CXCR2. 1536 49

Lung inflammation resulting from bacterial infection of the respiratory mucosal surface in diseases such as cystic fibrosis and pneumonia contributes significantly to the pathology. A major consequence of the inflammatory response is the recruitment and accumulation of polymorphonuclear cells (PMNs) at the infection site. It is currently unclear what bacterial factors trigger this response and exactly how PMNs are directed across the epithelial barrier to the airway lumen. An in vitro model consisting of human PMNs and alveolar epithelial cells (A549) grown on inverted Transwell filters was used to determine whether bacteria are capable of inducing PMN migration across these epithelial barriers. A variety of lung pathogenic bacteria, including Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa are indeed capable of inducing PMN migration across A549 monolayers. This phenomenon is not mediated by LPS, but requires live bacteria infecting the apical surface. Bacterial interaction with the apical surface of A549 monolayers results in activation of epithelial responses, including the phosphorylation of ERK1/2 and secretion of the PMN chemokine IL-8. However, secretion of IL-8 in response to bacterial infection is neither necessary nor sufficient to mediate PMN transepithelial migration. Instead, PMN transepithelial migration is mediated by the eicosanoid hepoxilin A3, which is a PMN chemoattractant secreted by A549 cells in response to bacterial infection in a protein kinase C-dependent manner. These data suggest that bacterial-induced hepoxilin A3 secretion may represent a previously unrecognized inflammatory mechanism occurring within the lung epithelium during bacterial infections.
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PMID:Polymorphonuclear cell transmigration induced by Pseudomonas aeruginosa requires the eicosanoid hepoxilin A3. 1549 23


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