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)

Overstretching the airways during positive pressure mechanical ventilation or attacks of acute severe asthma is associated with important biologic responses. Interleukin (IL)-8-dependent neutrophil recruitment seems to play a critical role in the process of mechanical stress-induced airway inflammation. Herein, we show that human bronchial epithelial BEAS-2B cells submitted to cyclic stretch in vitro produce IL-8, at both the mRNA and protein levels. This cellular stress "turns on" activator protein (AP)-1 and cyclic AMP (cAMP)-responding elements. The mitogen-activated protein (MAP) kinases (MAPK) p44/42, SAPK/JNK, and p38 were all rapidly activated (phosphorylated) after the initiation of the cyclic strain (5-10 min). The blockade of p38 with the pharmacologic inhibitor SB203580 abrogated IL-8 production by cell stretching, and an inhibitor of the p44/42 pathway, PD98059, partially inhibited the IL-8 response. A nonspecific tyrosine kinase inhibitor, genistein, also blocked the stretch-induced IL-8 production. This suggests that MAPK, and p38 in particular, are proximal and key intracellular signaling molecules mediating cell activation in response to cyclic stretch, a mechanical strain similar to that applied to lung epithelial cells during mechanical ventilation. Pharmacologic inhibition of the p38 pathway holds promise as a new therapeutic avenue in ventilated patients.
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PMID:Role of MAP kinase activation in interleukin-8 production by human BEAS-2B bronchial epithelial cells submitted to cyclic stretch. 1209 Dec 53

Interaction of the neuropeptide substance P (SP) and its neurokinin-1 receptor (NK-1R) plays an important role in the pathophysiology of intestinal inflammation. SP is known to stimulate production of interleukin (IL)-6 and IL-8 in the U-373-MG human astrocytoma cell line via activation of p38 MAPK (mitogen-activated protein kinase) and nuclear factor (NF)-kappaB, respectively. However, the signalling mechanisms by which SP-NK-1R interaction induces NF-kappaB activation and IL-8 expression are still not clear. In this study we demonstrate that SP stimulates IL-8 secretion and IL-8 promoter activity in the NCM460 non-transformed human colonic epithelial cell line transfected with NK-1R cDNA. Our results indicate that inhibition of endogenous Rho family proteins (RhoA, Rac1 and Cdc42) by their respective dominant negative mutants significantly decreases SP-induced IL-8 secretion and IL-8 promoter activity. We also demonstrate that SP rapidly activates RhoA, Rac1 and Cdc42 and that co-expression of the dominant negative mutants of RhoA, Rac1 and Cdc42 in NK-1R cDNA-transfected NCM460 cells significantly inhibits SP-induced NF-kappaB-dependent gene expression. These results demonstrate that Rho family small GTPases RhoA, Rac1 and Cdc42 are novel signal transducers for SP-stimulated IL-8 expression.
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PMID:Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves Rho family small GTPases. 1216 92

The human lymphotoxin beta receptor (LTbetaR), a member of the tumor necrosis factor (TNF) receptor superfamily, is essential for not only the development and organization of secondary lymphoid tissues, but also for chemokine release. Even though LTbetaR was shown to recruit TNF-receptor-associated factor (TRAF) 2, 3, and 5, and to induce cell apoptosis or NF-kappaB activation, however, the downstream signaling leading to chemokine expression is not illustrated yet. In this study, we find that overexpression of LTbetaR in HEK293 cells increases IL-8 promoter activity and leads to IL-8 release. LTbetaR-induced IL-8 gene expression requires NF-kappaB (-80 to -71) and AP-1 (-126 to -12) binding sites located in IL-8 promoter, and NF-kappaB is more crucial than AP-1 for IL-8 gene expression. Reporter assay with dominant-negative mutants of TRAFs reveals that TRAF2, 3, and 5, as well as the downstream signal molecules NIK, IKKalpha, and IKKbeta, are involved in IL-8 gene expression. LTbetaR-mediated IL-8 response was inhibited by the dominant-negative mutants of ASK1, MKK4, MKK7, and JNK, but not by those of MEKK1, TAK1, MEK, ERK, and p38 MAPK. This suggests that IL-8 induction by LTbetaR is via TRAFs-elicited signaling pathways, including NIK/IKK-dependent NF-kappaB activation and ASK/MKK/JNK-dependent AP-1 activation.
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PMID:Lymphotoxin beta receptor induces interleukin 8 gene expression via NF-kappaB and AP-1 activation. 1216 72

We have previously shown that mast cells enhance eosinophil survival and activation. In this study we further characterized mast cell activity toward eosinophils. Sonicate of both rat peritoneal mast cells and the human mast cell line 1 (HMC-1) induced a concentration-dependent IL-6 and IL-8 release from human peripheral blood eosinophils (ELISA). HMC-1-induced IL-8 release was significantly reduced by the tryptase inhibitors GW-45 and GW-58 (90 and 87%, respectively, at an optimal concentration) but not by anti-stem cell factor, anti-TNF-alpha, or anti-IFN-gamma neutralizing Abs or by the antihistamine drugs pyrilamine and cimetidine. In a manner similar to HMC-1, human recombinant tryptase induced the expression of mRNA for IL-8 (RT-PCR) and caused IL-8 release from the eosinophils. Addition of cycloheximide, actinomycin D, dexamethasone, PD 98059, curcumin, or SB 202190 completely inhibited the tryptase-induced IL-6 and IL-8 release. In contrast, cyclosporin A had no effect on tryptase-induced IL-8 release. Tryptase caused phosphorylation of extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases 1 and 2, and p38 (Western blot). Tryptase also induced the translocation of c-Jun from the cytosol to the nucleus (confocal microscopy) and enhanced AP-1 binding activity to the DNA (EMSA). Eosinophils were found to express proteinase-activated receptor 2 (FACS). When eosinophils were incubated with tryptase in the presence of anti-proteinase-activated receptor 2 antagonist Abs a significant decrease in the IL-6 and IL-8 release occurred. In summary, we have demonstrated that the preformed mast cell mediator tryptase induces cytokine production and release in human peripheral blood eosinophils by the mitogen-activated protein kinase/AP-1 pathway.
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PMID:Tryptase activates the mitogen-activated protein kinase/activator protein-1 pathway in human peripheral blood eosinophils, causing cytokine production and release. 1219 39

Inflammatory bowel disease of the colon is associated with a high osmolarity of colonic contents. We hypothesized that this hyperosmolarity may contribute to colonic inflammation by stimulating the proinflammatory activity of intestinal epithelial cells (IECs). The human IEC lines HT-29 and Caco-2 were used to study the effect of hyperosmolarity on the IEC inflammatory response. Exposure of IECs to hyperosmolarity triggered expression of the proinflammatory chemokine interleukin (IL)-8 both at the secreted protein and mRNA levels. In addition, hyperosmotic stimulation induced the release of another chemokine, GRO-alpha. These effects were because of activation of the transcription factor, nuclear factor (NF)-kappaB, because hyperosmolarity stimulated both NF-kappaB DNA binding and NF-kappaB-dependent transcriptional activity. Hyperosmolarity activated both p38 and p42/44 mitogen-activated protein kinases, which effect contributed to hyperosmolarity-stimulated IL-8 production, because p38 and p42/44 inhibition prevented the hyperosmolarity-induced increase in IL-8 production. In addition, the proinflammatory effects of hyperosmolarity were, in a large part, mediated by activation of Na(+)/H(+) exchangers, because selective blockade of Na(+)/H(+) exchangers prevented the hyperosmolarity-induced IEC inflammatory response. In summary, hyperosmolarity stimulates IEC IL-8 production, which effect may contribute to the maintenance of inflammation in inflammatory bowel disease.
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PMID:Hyperosmotic stress induces nuclear factor-kappaB activation and interleukin-8 production in human intestinal epithelial cells. 1221 27

Recent studies indicate that maximal IL-8 protein expression requires activation of NF-kappaB as well as activation of the MAP kinases ERK, JNK, and p38. However, the precise relationship between NF-kappaB transactivation and MAP kinase activation remains unclear. We examined the requirements of NF-kappaB, ERK, JNK, and p38 for TNF-alpha-induced transcription from the IL-8 promoter in a human bronchial epithelial cell line. Treatment with TNF-alpha induced activation of all three MAP kinases. Using a combination of chemical and dominant-negative inhibitors, we found that inhibition of NF-kappaB, ERK, and JNK, but not p38, each decreased TNF-alpha-induced transcription from the IL-8 promoter. Inhibition of JNK signaling also substantially reduced TNF-alpha-induced NF-kappaB transactivation, whereas inhibition of ERK and p38 had no effect. On the other hand, ERK was required and sufficient for TNF-alpha-induced activation of activator protein (AP)-1 promoter sequences, which together function as a basal level enhancer. JNK activation was also required for AP-1 transactivation. Finally, inhibition of p38 attenuated IL-8 protein abundance, suggesting that p38 regulates IL-8 expression in a posttranscriptional manner. We conclude that, in human airway epithelial cells, MAP kinases may regulate IL-8 promoter activity by NF-kappaB-dependent (in the case of JNK) and -independent (ERK) processes, as well as by posttranscriptional mechanisms (p38).
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PMID:Regulation of human airway epithelial cell IL-8 expression by MAP kinases. 1222 44

Enterohaemorrhagic Escherichia coli O157:H7 (EHEC) is a gastrointestinal pathogen that is generally non-invasive for intestinal epithelial cells, yet causes acute intestinal inflammation, diarrhoea, haemorrhagic colitis and haemolytic uraemic syndrome. To study signal transduction pathways activated in human intestinal epithelial cells by EHEC, we took advantage of EHEC O157:H7 and isogenic mutants deficient in the major EHEC virulence factors, intimin (eae-) and Shiga toxin (stx-). Infection with wild-type EHEC activated p38 and ERK MAP kinases and the nuclear translocation of the transcription factor NF-kappaB. Downstream, this was accompanied by increased expression of mRNA and protein for the neutrophil chemoattractant IL-8. Isogenic eae- and stx- mutants also activated p38 and ERK MAP kinases, and NF-kappaB and stimulated increases in IL-8 protein secretion similar to those of wild-type EHEC. Further, inhibition of either p38, ERK or NF-kappaB activation abrogated the IL-8 response induced by wild-type EHEC and the mutants. Epithelial cell MAP kinase and NF-kappaB pathways leading to IL-8 secretion were also activated by isolated EHEC H7 flagellin, which was active when added to either the apical or basolateral surface of polarized human intestinal epithelial cells. We conclude that EHEC interacting with intestinal epithelial cells activates intracellular signalling pathways and an epithelial cell proinflammatory response independent of either Shiga toxin or intimin, two of the major known virulence factors of EHEC. The activation of proinflammatory signals in human colon epithelial cells in response to this non-invasive pathogen appears to depend to a significant extent on H7 flagellin.
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PMID:Role of EHEC O157:H7 virulence factors in the activation of intestinal epithelial cell NF-kappaB and MAP kinase pathways and the upregulated expression of interleukin 8. 1236 1

Neutrophils must follow both endogenous and bacterial chemoattractant signals out of the vasculature and through the interstitium to arrive at a site of infection. By necessity, in the setting of multiple chemoattractants, the neutrophils must prioritize, favoring end target chemoattractants (e.g., fMLP and C5a) emanating from the site of infection over intermediary endogenous chemoattractants (e.g., IL-8 and LTB4) encountered en route to sites of infection. In this study, we propose a hierarchical model of two signaling pathways mediating the decision-making process of the neutrophils, which allows end target molecules to dominate over intermediary chemoattractants. In an under agarose assay, neutrophils predominantly migrated toward end target chemoattractants via p38 MAPK, whereas intermediary chemoattractant-induced migration was phosphoinositide 3-kinase (PI3K)/Akt dependent. When faced with competing gradients of end target and intermediary chemoattractants, Akt activation was significantly reduced within neutrophils, and the cells migrated preferentially toward end target chemoattractants even at 1/1,000th that of intermediary chemoattractants. End target molecules did not require chemotactic properties, since the p38 MAPK activator, LPS, also inhibited Akt and prevented migration to intermediary chemoattractants. p38 MAPK inhibitors not only reversed this hierarchy, such that neutrophils migrated preferentially toward intermediary chemoattractants, but also allowed neutrophils to be drawn out of a local end target chemoattractant environment and toward intermediary chemoattractants unexpectedly in an exaggerated (two- to fivefold) fashion. This was entirely related to significantly increased magnitude and duration of Akt activation. Finally, end target chemoattractant responses were predominantly Mac-1 dependent, whereas nondominant chemoattractants used primarily LFA-1. These data provide support for a two pathway signaling model wherein the end target chemoattractants activate p38 MAPK, which inhibits intermediary chemoattractant-induced PI3K/Akt pathway, establishing an intracellular signaling hierarchy.
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PMID:An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. 1237 Feb 41

The p38 mitogen-activated protein kinase (MAPK) signaling pathway regulates a wide range of inflammatory responses in many different cells. Inhibition of p38 MAPK before exposing a cell to stress stimuli has profound anti-inflammatory effects, but little is known about the effects of p38 MAPK inhibition on ongoing inflammatory responses. LPS-induced activation of p38 MAPK in human neutrophils was inhibited by poststimulation exposure to a p38 MAPK inhibitor (M39). Release of TNF-alpha, macrophage-inflammatory protein (MIP)-2 (MIP-1beta), and IL-8 by LPS-stimulated neutrophils was also reduced by poststimulation p38 MAPK inhibition. In contrast, release of monocyte chemoattractant protein-1 was found to be p38 MAPK independent. Ongoing chemotaxis toward IL-8 was eliminated by p38 MAPK inhibition, although the rate of nondirectional movement was not reduced. A murine model of acute LPS-induced lung inflammation was used to study the effect of p38 MAPK inhibition in ongoing pulmonary inflammation. Initial pulmonary cell responses occur within 4 h of stimulation in this model, so M39 was administered 4 h or 12 h after exposure of the animals to aerosolized LPS to avoid inhibition of cytokine release. Quantities of TNF-alpha, MIP-2, KC, or monocyte chemoattractant protein-1 recovered from bronchial alveolar lavage or serum were not changed. Recruitment of neutrophils, but not other leukocytes, to the airspaces was significantly reduced. Together, these data demonstrate the selective reduction of LPS-induced neutrophil recruitment to the airspaces, independent of suppression of other inflammatory responses. These findings support the feasibility of p38 MAPK inhibition as a selective intervention to reduce neutrophilic inflammation.
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PMID:Selective suppression of neutrophil accumulation in ongoing pulmonary inflammation by systemic inhibition of p38 mitogen-activated protein kinase. 1239 Dec 45

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

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