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)

Lipopolysaccharide (LPS) is a key inflammatory mediator. It has been proposed to function as an important molecule that alerts the host of potential bacterial infection. Although highly conserved, LPS contains important structural differences among different bacterial species that can significantly alter host responses. For example, LPS obtained from Porphyromonas gingivalis, an etiologic agent for periodontitis, evokes a highly unusual host cell response. Human monocytes respond to this LPS by the secretion of a variety of different inflammatory mediators, while endothelial cells do not. In addition, P. gingivalis LPS inhibits endothelial cell expression of E-selectin and interleukin 8 (IL-8) induced by other bacteria. In this report the ability of P. gingivalis LPS to activate p38 mitogen-activated protein (MAP) kinase was investigated. It was found that p38 MAP kinase activation occurred in response to P. gingivalis LPS in human monocytes. In contrast, no p38 MAP kinase activation was observed in response to P. gingivalis LPS in human endothelial cells or CHO cells transfected with human Toll-like receptor 4 (TLR-4). In addition, P. gingivalis LPS was an effective inhibitor of Escherichia coli-induced p38 MAP kinase phosphorylation in both endothelial cells and CHO cells transfected with human TLR-4. These data demonstrate that P. gingivalis LPS activates the LPS-associated p38 MAP kinase in monocytes and that it can be an antagonist for E. coli LPS activation of p38 MAP kinase in endothelial and CHO cells. These data also suggest that although LPS is generally considered a bacterial component that alerts the host to infection, LPS from P. gingivalis may selectively modify the host response as a means to facilitate colonization.
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PMID:Porphyromonas gingivalis lipopolysaccharide is both agonist and antagonist for p38 mitogen-activated protein kinase activation. 1189 49

Although Fas (APO-1/CD95) is expressed ubiquitously and induces cell death, it is also known to mediate other responses such as inflammation and angiogenesis in vivo. Previously, we have reported that Fas ligation induces selective expression of chemokines (IL-8 and MCP-1) in human astroglioma cells in vitro. In this study, we investigated whether Fas ligation can induce expression of other cytokines. Expression of IL-1alpha, IL-1beta, IL-6, IL-10, IL-12, IFN-beta, IFN-gamma, LT-beta, TGF-beta, TNF-a and TNF-beta mRNA levels in CRT-MG human astroglioma cells upon Fas ligation was investigated using RNase protection assay (RPA). We found that IL-6 mRNA is selectively induced upon Fas ligation, and IL-6 mRNA and protein expression was further investigated using single probe RPA and ELISA. To investigate the in vivo expression of IL-6, human brain specimens were homogenized and ELISA was performed for IL-6 expression. Herein, we demonstrate that: (1) Among these cytokines, only IL-6 was induced upon Fas ligation in a dose- and time-dependent manner; (2) A selective p38 MAP kinase inhibitor, SB202190, and a MEK inhibitor, U0126, suppressed induction of IL-6 mRNA and protein expression by Fas ligation; and (3) Glioblastoma multiforme samples (n = 11) contain significantly higher levels of IL-6 compared to those of control brains (n = 5), which correlate with increased levels of Fas. These results suggest that the Fas-FasL system may play a role in the regulation of tumor growth and survival by inducing the pleiotropic cytokine IL-6.
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PMID:Fas engagement increases expression of interleukin-6 in human glioma cells. 1194 22

Some of the most important pathobiology in cystic fibrosis occurs not as a direct result of impaired chloride transport, but the downstream consequences of defective CFTR function, particularly the lung infection and inflammation that ultimately takes the lives of most patients. Interrupting the vicious cycle of infection and inflammation is effective in slowing the course of the disease, and antibiotics have long been the staple of pulmonary therapy. However, limiting the inflammatory response in the CF lung is also effective. High dose ibuprofen clearly retards progression of lung disease, but also entrains adverse events that mar its therapeutic utility, so alternative anti-inflammatory agents are necessary. Because of the remarkable therapeutic success of ibuprofen, consideration should be given to finding less toxic alternatives. However, it is also appropriate to consider the mechanisms by which the inflammatory response occurs in the CF lung, and identify sites to interrupt it. Sites at which therapeutic intervention is possible are the neutralization of cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, or IL-8 with specific antibodies or receptor antagonists, inhibition of the intracellular signaling cascades that result in cytokine production (for example, at the level of p38 MAP kinase), application of cytokines such as Il-10 that are themselves anti-inflammatory, or modulating the arachidonic acid cascade with inhibitors directed at leukotriene B(4). In addition, interventions designed to limit the consequences of the inflammatory response, such as protease inhibitors and reagents to limit the ill effects of DNA accumulation in airways, are in use. To limit adverse effect and concentrate the therapeutic effect, there may be value in targeting delivery of the therapeutic reagents to the inflamed site, either by specifically directing systemic delivery or by exploitation of the aerosol route. Treating the inflammatory response is important, for the data from the ibuprofen study show that the effects of anti-inflammatory therapy are additive or even synergistic with intensive conventional therapy and alter the rate of decline of pulmonary function, and therefore benefits for survival of patients with CF are to be expected.
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PMID:Pharmacological approaches for the discovery and development of new anti-inflammatory agents for the treatment of cystic fibrosis. 1245 52

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

Although tremendous effort has been put towards identifying the surface molecules of nontypeable Haemophilus influenzae (NTHi) for vaccine development over the past decades, it is only recently that we have begun to appreciate the intricate host epithelial signaling networks activated by NTHi, an important human pathogen causing respiratory infections. From what has been reported, it is evident that NTHi activates multiple signaling pathways in host epithelial cells that, in turn, inadvertently contribute to the pathogenesis. Among those signaling pathways, activation of NF-kappaB leads to up-regulation of IL-1beta, IL-8 and TNF-alpha, mucin MUC2 and Toll-like receptor 2 (TLR2), whereas activation of p38 MAP kinase mediates not only up-regulation of inflammatory mediators and mucin MUC5AC but also down-regulation of TLR2. Interestingly, NTHi-induced activation of the PI3K-Akt pathway, however, leads to inhibition of p38 mitogen-activated protein (MAP) kinase. Moreover, the TGF-beta-Smad signaling pathway cooperates with NF-kappaB to mediate up-regulation of mucin MUC2. Finally, glucocorticoids synergistically enhance NTHi-induced TLR2 expression via specific up-regulation of the MAP kinase phosphatase-1 that, in turn, leads to inactivation of p38 MAP kinase, the negative regulator for TLR2 expression. These studies may bring new insights into the molecular pathogenesis of NTHi-induced infections and open up novel therapeutic targets for these diseases.
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PMID:Exploitation of host epithelial signaling networks by respiratory bacterial pathogens. 1268 24

Hepatitis C virus (HCV) infects approximately 40% of human immunodeficiency virus (HIV) patients, and the resulting hepatic dysfunction that occurs is the primary cause of death in patients with co-infection. We hypothesized that hepatocytes exposed to HCV and HIV proteins might be susceptible to injury via an "innocent bystander" mechanism. To assess this, we studied the effects of envelope proteins, E2 of HCV and gp120 of HIV, in model HepG2 cells. Upon co-stimulation with HCV-E2 and HIV-gp120, we observed a potent proinflammatory response with the induction of IL-8. Furthermore, our studies revealed that HCV-E2 and HIV-gp120 act collaboratively to trigger a specific set of downstream signaling pathways that include activation of p38 mitogen-activated protein (MAP) kinase and the tyrosine phosphatase, SHP2. Both specific inhibitors of p38 MAP kinase and sodium vanadate, a potent protein-tyrosine phosphatase inhibitor, blocked IL-8 production in a dose-dependent manner. The role of p38 MAP kinase and SHP2 was further defined by transiently overexpressing dominant negative mutants of these proteins into HepG2 cells. These studies revealed that overexpression of an inactive p38 MAP kinase or SHP2 mutant partially abrogated HCV-E2- and HIV-gp120-induced IL-8 production. Further studies revealed that IL-8 induction was not mediated through activation of the NF-kappa B pathway. However, HCV-E2 plus HIV-gp120 was shown to increase the DNA binding activity of AP-1. These results emphasize that expression of the proinflammatory chemokine IL-8, induced by HCV-E2 and HIV-gp120, may be mediated through p38 MAP kinase and SHP2 in an NF-kappa B-independent manner, albeit through AP-1-driven processes.
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PMID:Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes. 1282 91

Interleukin-1 (IL-1) plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). IL-1 action is regulated in part by its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1Ra). Four splice variants of IL-1Ra gene product have been described, one secreted (sIL-1Ra) and three intracellular (icIL-1Ra1, 2, 3). Although sIL-1Ra and icIL-1Ra1 bind to type I IL-1 receptor with equal affinity, icIL-1Ra1 may carry out unique functions inside cells. The goal of this study was to determine the role of icIL-1Ra1 in regulation of cytokine-induced IL-6 and IL-8 production in Caco-2 intestinal epithelial cells. icIL-1Ra1 inhibited IL-1-induced IL-6 and IL-8 production. IL-1 activated all three mitogen-activated protein (MAP) kinase family members: p38 MAP kinase, extracellular-regulated kinases (ERK), and c-Jun amino-terminal kinases (JNK). Specific inhibitors of each MAP kinase pathway decreased IL-1-induced IL-6 and IL-8 production. Overexpression of icIL-1Ra1 inhibited p38 MAP kinase phosphorylation, but had no effect on ERK and JNK phosphorylation. In addition, icIL-1Ra1 inhibited nuclear translocation of NF-kappaB after IL-1 stimulation. In conclusion, these data indicate that icIL-1Ra1, acting in the cytoplasm of Caco-2 cells, decreased IL-1-induced IL-6 and IL-8 production. This intracellular anti-inflammatory activity of icIL-1Ra1 was mediated through inhibition of p38 MAP kinase and NF-kappaB signal transduction pathways.
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PMID:Intracellular IL-1Ra type 1 inhibits IL-1-induced IL-6 and IL-8 production in Caco-2 intestinal epithelial cells through inhibition of p38 mitogen-activated protein kinase and NF-kappaB pathways. 1290 52

The role of lysophosphatidylcholine (LPC) in the induction of MCP-1, IL-8 and RANTES, which are chemotactic factors to monocytes, neutrophils and lymphocytes, respectively, by human vascular endothelial cells (EC), was examined. LPC induced the expression of MCP-1 and IL-8 in a concentration- and time-dependent manner in microvascular EC (MVEC) and in large vessel EC from aorta, pulmonary artery and umbilical vein. LPC also induced RANTES in MVEC but not in large vessel EC. Signaling pathways responsible for LPC induction of chemokines were examined in MVEC. LPC and TNFalpha, a cytokine secreted in sites of inflammation, additively stimulated RANTES expression. LPC did not augment TNFalpha induction of MCP-1 or IL-8. A platelet-activating factor receptor antagonist (BN52021) failed to block LPC induction of MVEC chemokines, but the G(i)-protein inhibitor pertussis toxin partially blocked LPC induction of RANTES and IL-8. LPC activated multiple kinases in MVEC; it increased the phosphorylation of ERK1/2, AKT and p38 MAP kinase in a time-dependent manner. An inhibitor of the MAPK/ERK pathway, PD98059, blocked the phosphorylation of ERK1/2 and RANTES induction by LPC, but augmented IL-8 induction. LY294002, a specific inhibitor of phosphoinositide 3 kinase (PI3 kinase), blunted the phosphorylation of AKT and inhibited LPC induction of RANTES more strongly than IL-8. Inhibition of p38 MAP kinase pathway by SB202190 also blocked LPC-induced expression of IL-8 and RANTES. Our results suggest that LPC induction of chemokines in MVEC is distinct from that in large vessel EC, and required the activities of MAP kinases and PI3 kinase for the induction of RANTES and IL-8. We speculate that the presence of LPC, a bioactive lipid product of phospholipase A(2) (PLA(2)) and a constituent of oxidized low-density lipoprotein, can differentially influence the chemotaxis of particular leukocyte subpopulations during inflammation.
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PMID:Lysophosphatidylcholine regulates human microvascular endothelial cell expression of chemokines. 1459 94

Lipopolysaccharide (LPS) and porins of Gram-negative outer membranes are the main pathogenic factors implicated in the clinical syndrome of septic shock. The biological activity of porins and LPS are similar, but they occur by different mechanisms. It seems that porins act through different intracellular pathways with respect to LPS. In this study we analyzed the role of several inhibitors of the MEK/ERK signal pathway on the induction of proinflammatory and immunological cytokines in U937 cell line stimulated by Salmonella typhimurium porins and compared it to the cytokine induction after LPS stimulation. We investigated the effects of p38 MAP kinase inhibitor SB-203580, MEK/ERK kinase inhibitor PD-098059 and Raf-1 inhibitor forskolin, and demonstrated that they modulate cytokine mRNA expression in a different manner as a consequence of the use of porins or LPS as stimuli. TNF-alpha and IL-1beta mRNA expression is decreased by PD-098059 after stimulation with LPS but not with porins in differentiated U937 cells. IL-10 mRNA expression is inhibited by SB-203580 and PD-098059 after stimulation with porins in U937 cells. IL-6 and IL-8 mRNA expression is not changed by PD-098059 or SB-203580, after stimulation either with porins or LPS. Furthermore, mRNA expression of the studied cytokines, except for GM-CSF, is not changed using forskolin.
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PMID:Induction of cytokine mRNA expression in U937 cells by Salmonella typhimurium porins is regulated by different phosphorylation pathways. 1462 44

The human bronchial epithelial cells are the primary sites of influenza virus infection. In this study, the effect of indirubin on the expression of the chemokine regulated on activation, normal T cell expressed and secreted (RANTES) by the influenza virus-infected H292 human epithelial cell line was examined. The expression of RANTES mRNA was analyzed using reverse transcription polymerase chain reaction and the concentration of RANTES production was determined by the enzyme-linked immunosorbent assay. At the non-cytotoxic concentrations, indirubin was found to reduce both the expression and production of RANTES in influenza A/NWS/33-infected H292 cells. Inhibition was also observed in influenza virus B/Lee-infected cells. Significant reduction of the expression of IL-8 was not observed after the infection. Indirubin-3'-oxime, a recently developed derivative with kinase inhibitory activity, also mediates a potent inhibitory effect on the expression of RANTES. The influenza virus infection-induced phosphorylation of the nuclear transcription NF-kB regulatory molecule IkBalpha and the p38 MAP kinase were also found to be inhibited by indirubin-3'-oxime. This finding suggests that indirubin is one of the components in the Chinese medicinal herbs Isatis indigotica and Strobilanthes cusia with immunomodulatory activity on the expression of RANTES.
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PMID:Inhibition of RANTES expression by indirubin in influenza virus-infected human bronchial epithelial cells. 1466 39

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