Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enteropathogenic Escherichia coli (EPEC) alters many functions of the host intestinal epithelia. Inflammation is initiated by activation of nuclear factor (NF)-kappaB, and paracellular permeability is enhanced via a Ca2+- and myosin light-chain kinase (MLCK)-dependent pathway. The aims of this study were to identify signaling pathways by which EPEC triggers inflammation and to determine whether these pathways parallel or diverge from those that alter permeability. EPEC-induced phosphorylation and degradation of the primary inhibitor of NF-kappaB (IkappaBalpha) were tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta independent. In contrast to Salmonella typhimurium, EPEC-stimulated IkappaBalpha degradation and IL-8 expression did not require Ca2+. Instead, extracellular signal-regulated kinase (ERK)-1/2 was significantly and rapidly activated. ERK1/2 inhibitors attenuated IkappaBalpha degradation and IL-8 expression. Although ERK1/2 can activate MLCK, its inhibition had no impact on EPEC disruption of the tight junction barrier. In conclusion, EPEC-induced inflammation 1) is TNF-alpha and IL-1beta receptor independent, 2) utilizes pathways differently from S. typhimurium, 3) requires ERK1/2, and 4) employs signals that are distinct from those that alter permeability. This is the first time that EPEC-activated signaling cascades have been linked to independent functional consequences.
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PMID:EPEC-activated ERK1/2 participate in inflammatory response but not tight junction barrier disruption. 1155 8

Neutrophil-dependent inflammation dependent on monosodium urate (MSU) crystal-induced IL-8 expression occurs in gout. MSU crystals activate phagocyte Src family tyrosine kinases and the serine/threonine kinase p70s6k. Thus, using monocytic THP-1 cells, we assessed the potential for Src family kinases and p70s6k to mediate MSU-induced IL-8 expression. MSU crystals induced phosphorylation of p70s6k and the Src kinases c-Src, Lyn, Hck, and Fyn. IL-8 expression was attenuated more by the Src kinase inhibitor PP1 than by the p70s6k inhibitor rapamycin. PP1 inhibited crystal-induced phosphorylation of ERK1/2 and IkappaBalpha and suppressed IkappaB kinase (IKK) activation and NF-kappaB binding to the IL-8 promoter, signals that mediate MSU-induced IL-8 expression. Transfection of the native Src inhibitor, C-terminal Src kinase (Csk), also suppressed crystal-induced c-Src, ERK1/2, and IkappaBalpha phosphorylation and IL-8 expression. We conclude that Src family tyrosine kinase signaling plays a significant role in MSU crystal-induced IL-8 expression via stimulation of ERK1/2 pathway and NF-kappaB activation.
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PMID:Src family protein tyrosine kinase signaling mediates monosodium urate crystal-induced IL-8 expression by monocytic THP-1 cells. 1173 59

TFF-peptides (formerly P-domain peptides, trefoil factors) are typical secretory products of many mucous epithelia and are aberrantly secreted during chronic inflammatory diseases. They are known to enhance the migration of intestinal, corneal, and bronchial epithelial cells. Using the human bronchial epithelial cell line BEAS-2B as a model, it is shown here for the first time that TFF-peptides are capable of modulating the inflammatory response in vitro by regulating tumor necrosis factor-alpha-induced secretion of interleukin (IL)-6 and IL-8. In contrast, TFF2 itself does not change IL-6 and IL-8 secretion but triggers sustained activation of the extracellular signal-regulated kinases (ERK1/2) as well as phosphorylation of c-Jun N-terminal kinase (JNK). A complex differential regulation of tumor necrosis factor-alpha-induced IL-6 and IL-8 secretion by TFF2 is observed that involves signaling via protein kinase C and ERK1/2. Furthermore, the motogenic effect of TFF2 on BEAS-2B cells is analyzed using a modified Boyden chamber assay. This migratory effect is shown to be dependent not only on protein kinase C and ERK1/2 but also on the activation of the Src family of tyrosine kinases. Taken together, the data presented indicate an important physiological role of TFF-peptides during inflammatory conditions of mucous epithelia.
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PMID:Protein kinase C and ERK activation are required for TFF-peptide-stimulated bronchial epithelial cell migration and tumor necrosis factor-alpha-induced interleukin-6 (IL-6) and IL-8 secretion. 1188 1

A novel cytokine, ML-1, was recently discovered, which shares a similar sequence homology with, but is functionally distinct from, IL-17 (Kawaguchi, M., Onuchic, L., Li, X. D., Essayan, D. M., Schroeder, J., Xiao, H. Q., Liu, M. C., Krishnaswamy, G., Germino, G., and Huang, S. K. (2001) J. Immunol. 167, 4430-4435). To determine the signaling mechanisms of ML-1, we investigated activation of mitogen-activated protein (MAP) kinases induced by ML-1. Results show that ML-1 induces in a time-dependent fashion the expression of IL-6 and IL-8 in both primary bronchial epithelial cells (PBECs) and human umbilical vein endothelial cells (HUVECs). ML-1 activated a MAP kinase and an extracellular signal-regulated kinase (ERK)1/2 but not p38 or the c-Jun N-terminal kinase (JNK) in both cell types. Selective MAP kinase kinase (MEK)1/2 inhibitors, PD98059 and U0126, inhibited, in a dose-dependent manner, ML-1-induced expression of IL-6 and IL-8. These findings suggest that ML-1-induced IL-6 and IL-8 production is mediated through the activation of ERK1/2 in both cell types.
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PMID:Activation of extracellular signal-regulated kinase (ERK)1/2, but not p38 and c-Jun N-terminal kinase, is involved in signaling of a novel cytokine, ML-1. 1189 Dec 14

Host response to injury and infection is accompanied by a rapid rise in the blood of acute-phase proteins such as serum amyloid A (SAA). Although SAA has been used as a marker for inflammatory diseases, its role in the modulation of inflammation and immunity has not been defined. Human neutrophils respond to SAA with secretion of the proinflammatory cytokines interleukin 8 (IL-8) and, to a lesser extent, tumor necrosis factor alpha (TNF-alpha). The induction of IL-8 secretion by SAA involves both transcription and translation and correlates with activation of nuclear factor kappaB (NF-kappaB). The proximal signaling events induced by SAA include mobilization of intracellular Ca(2+) and activation of the mitogen-activated protein kinases ERK1/2 and p38, both required for the induced IL-8 secretion. Pertussis toxin effectively blocks SAA-induced IL-8 secretion indicating involvement of a Gi-coupled receptor. Overexpression of FPRL1/LXA4R in HeLa cells results in a significant increase of the expression of NF-kappaB and IL-8 luciferase reporters by SAA, and an antibody against the N-terminal domain of FPRL1/LXA4R inhibits IL-8 secretion. Lipoxin A4, which binds to FPRL1/LXA4R specifically, decreases SAA-induced IL-8 secretion significantly. Collectively, these results indicate that the cytokine-like property of SAA is manifested through activation of the Gi-coupled FPRL1/LXA4R, which has been known to mediate the anti-inflammatory effects of lipoxin A4. The ability of FPRL1/LXA4R to mediate 2 drastically different and opposite functions suggests that it plays a role in the modulation of inflammatory and immune responses.
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PMID:Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. 1239 91

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

Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (PlGF) activated monocytes and increased mRNA levels of cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) and chemokines (monocyte chemotactic protein-1 [MCP-1], IL-8, and macrophage inflammatory protein-1beta [MIP-1beta]) in both normal monocytes and in the THP-1 monocytic cell line. This increase in mRNA expression of cytochemokines was also reflected in monocytes derived from subjects with SCD. We studied the PlGF-mediated downstream cellular signaling events that caused increased transcription of inflammatory cytochemokines and chemotaxis of THP-1 monocytes. PlGF-mediated cytochemokine mRNA and protein expression was inhibited by PD98059 and wortmannin, inhibitors of mitogen-activated protein kinase kinase (MAPK/MEK) kinase and phosphatidylinositol-3 (PI3) kinase, respectively, but not by SB203580, a p38 kinase inhibitor. PlGF caused a time-dependent transient increase in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK-1/2), which was completely inhibited by wortmannin, indicating that activation of PI3 kinase preceded MEK activation. PlGF also induced transient phosphorylation of AKT. MEK and PI3 kinase inhibitors and antibody to Flt-1 abrogated PlGF-induced chemotaxis of THP-1 monocytes. Overexpression of a dominant-negative AKT or a dominant-negative PI3 kinase p85 subunit in THP-1 monocytes attenuated the PlGF-mediated phosphorylation of ERK-1/2, cytochemokine secretion, and chemotaxis. Taken together, these data show that activation of monocytes by PlGF occurs via activation of Flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. Therefore, we propose that increased levels of PlGF in circulation play an important role in the inflammation observed in SCD via its effects on monocytes.
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PMID:Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. 1268 30

Cell-cell contact between human retinal pigment epithelium (hRPE) cells and monocytes occurs in many retinal diseases involving blood-retinal barrier breakdown. This study investigates chemokine secretion induced by co-culture of hRPE cells and monocytes and illustrates the roles of p38 kinase, ERK, JNK/SAPK and NF-kappaB-inducing kinase signaling pathways for hRPE IL-8 and MCP-1 secretion induced in hRPE by co-culture with monocytes. Co-culture of hRPE cells with monocytes increased steady-state IL-8 and MCP-1 mRNA and protein secretion. Stimulation of hRPE cells by monocytes resulted in prominent increases in p38, ERK1/2 and JNK/SAPK phosphorolation, IkappaBalpha degradation, and NF-kappaB nuclear translocation. The induced IL-8 and MCP-1 proteins were almost completely supporessed by U0126, a specific mitogen-activated protein kinase kinase (MEK) inhibitor, or by SB203580, a selective p38 inhibitor. Chemokine secretion was completely blocked by simultaneous administration of U0126 and SB203580. Induction of IL-8 and MCP-1 was abrogated by Ro318220, an inhibitor of PKC, as well as by genistein or herbimycin A, inhibitors of PTK. In addition, anti-inflammatory drugs dexamethasone (DEX) and cyclosporin A (CSA) both blocked activation of JNKS/SAPK and the cell-cell contact induced production of hRPE IL-8 and MCP-1, while activation of p38 and ERK was only inhibited by DEX, but not by CSA. These results suggest that activation of DEX-sensitive, CSA-resistant MEK/ERK and p38 pathways, and activation of NF-kappaB, PKC, and PTK are essential for IL-8 and MCP-1 expression by hRPE cells.
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PMID:Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade. 1269 21

Toll-like receptors (TLRs) activate antimicrobial gene expression in response to detection of specific bacterial products. Relatively little is known about TLR5, the only TLR thought to be preferentially expressed by epithelial cells, beyond that it confers activation of the transcription factor NF-kappaB in a MyD-88 dependent manner in response to flagellin. Because TLRs, in general, are also thought to signal through members of the MAPK family, we examined flagellin-induced MAPK activation (via examining its phosphorylation status) and its subsequent role in expression of the chemokine IL-8 in polarized intestinal epithelia. Flagellin, like other proinflammatory stimuli (TNF-alpha, Salmonella typhimurium), activated p38 MAPK in a TLR5-dependent manner, whereas aflagellate bacteria or EGF did not activate this kinase. Although ERK1 and -2 were also observed to be activated in response to flagellin, their activation was not restricted to proinflammatory stimuli because they were also potently activated by aflagellate bacteria (S. typhimurium or Escherichia coli) and EGF (neither of which activate NF-kappaB in these cells). Pharmacological inhibition of p38 MAPK (by SB-203580) potently (IC50 = 10 nM) reduced expression of IL-8 protein (maximal inhibition, 75%) but had no effect on NF-kappaB activation, only slightly attenuated upregulation of IL-8 mRNA levels in response to flagellin, and did not effect IL-8 mRNA stability. Together, these results indicate that epithelial TLR5 mediates p38 activation and subsequently regulates flagellin-induced IL-8 expression independently of NF-kappaB, probably by influencing IL-8 mRNA translation.
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PMID:TLR5-mediated activation of p38 MAPK regulates epithelial IL-8 expression via posttranscriptional mechanism. 1270 97

Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including interleukin (IL)-8. The mechanisms regulating lung stretch-induced cytokine production are unclear. We hypothesized that stretch-induced IL-8 production is dependent on the activation of the mitogen-activated protein kinases, c-Jun NH2-terminal kinases (JNK), p38, and/or extracellular signal-regulated kinase (ERK) 1/2. We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/min for 5 min-2 h. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression, and JNK activation, but only transient activation of p38 and ERK1/2. Inhibition of stretch-induced JNK activation by adenovirus-mediated gene transfer of stress-activated protein kinase (SEK-1), a dominant-negative mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP-600125 blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation NF-kappaB and activator protein (AP)-1 was blocked by NF-kappaB inhibitor and JNK inhibitor, respectively. An NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-kappaB-inducing kinase (NIK) activation, and inhibition of NF-kappaB attenuated IL-8 mRNA expression and IL-8 production. We conclude that stretch-induced transcriptional regulation of IL-8 mRNA and IL-8 production was via activation of AP-1 and NF-kappaB and was dependent on JNK and NIK activation, respectively.
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PMID:Stretch-induced IL-8 depends on c-Jun NH2-terminal and nuclear factor-kappaB-inducing kinases. 1271 52


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