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

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

IL-8 is an important mediator of leukocyte trafficking and activation, participating in tumor angiogenesis, inflammatory processes and coronary atherosclerosis. Under flow conditions IL-8, in conjunction with MCP-1, triggers the firm adhesion of monocytes to the vascular endothelium. While previous studies have suggested the requirement of NF-kappaB for IL-8 secretion by endothelial cells, we investigated the possibility of IL-8 transactivation under conditions of NF-kappaB suppression. Inhibition of the proteasome by MG-132 or lactacystin completely blocked TNF-alpha-induced IkappaBalpha degradation as well as NF-kappaB activity in human arterial endothelial cells. Surprisingly, basal secretion of IL-8 protein was eight- to tenfold induced by proteasome inhibitors, while MCP-1 expression was, as expected, completely down-regulated. IL-8 was up-regulated at the transcriptional level, and promoter studies proved a more than ninefold induction of transcription factor AP-1 activity to be the cause of increased IL-8 transcription. Mutation of the AP-1 binding site in an IL-8 promoter construct completely abrogated this effect, while mutation of the NF-kappaB motif did not influence IL-8 transactivation by proteasome inhibitors. With DNA binding assays we found a seven- to eightfold induction of phosphorylated c-Jun and hence JNK kinase activity under MG-132 treatment. Induction of JNK kinase appeared independent of the cell type, even in tumor cell lines not responding to proteasome inhibitors. Since neither inactivation of p53 in wild-type p53 cells nor reintroduction of functional p53 into p53(-/-) cells affected MG-132-inducible IL-8 secretion, a direct influence of p53 on IL-8 regulation could be excluded. These results show that proteasome inhibitors can not only lead to functional AP-1 induction by enhanced c-Jun phosphorylation, but also transactivate the IL-8 gene in human endothelial cells despite complete suppression of NF-kappaB activity.
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PMID:Proteasome inhibition leads to NF-kappaB-independent IL-8 transactivation in human endothelial cells through induction of AP-1. 1220 33

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

Leukocyte-derived proteases have long been considered simply degradative. However, emerging data raise possibilities of a complex and specific biologic role for these proteases in substrate processing and in signaling pathways within cells. This study reports that the release of neutrophilic and monocytic proteases, such as proteinase 3 (PR3) and human neutrophil elastase (HNE), can result in their entry into endothelial cells coincident with the activation of proapoptotic-signaling events through ERK, JNK, and p38 MAPK. Inhibition of JNK blocked PR3-induced apoptosis, and inhibition of p38 MAPK blocked PR3- and HNE-induced apoptosis, indicating that these pathways are required for activation of apoptosis. It is here shown that protease entry results in direct cleavage of p65 NF-kappaB in the N-terminal region by PR3 and in the C-terminal region by HNE. This cleavage results in diminished transcriptional activity by NF-kappaB as demonstrated by diminished levels of TNF-alpha-induced IL-8 message in the presence of PR3 or HNE. Inhibition of caspases did not block the cleavage of p65 NF-kappaB, and sequence analysis showed that the PR3 and HNE cleavage sites are unique with respect to reported caspase sites. The data demonstrate that PR3 and HNE have specific, fundamental roles in endothelial responses during inflammation. Upon entry, they can usurp the cell's control of its own fate by directly intervening into caspase cascades. This provides a unique mechanism of crosstalk between leukocytes and endothelial cells at sites of inflammation that impacts both cytokine networks and cell viability.
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PMID:Novel effects of neutrophil-derived proteinase 3 and elastase on the vascular endothelium involve in vivo cleavage of NF-kappaB and proapoptotic changes in JNK, ERK, and p38 MAPK signaling pathways. 1244 2

Type III secretion systems are used by several pathogens to translocate effector proteins into host cells. Yersinia pseudotuberculosis delivers several Yop effectors (e.g. YopH, YopE and YopJ) to counteract signalling responses during infection. YopB, YopD and LcrV are components of the translocation machinery. Here, we demonstrate that a type III translocation protein stimulates proinflammatory signalling in host cells, and that multiple effector Yops counteract this response. To examine proinflammatory signalling by the type III translocation machinery, HeLa cells infected with wild-type or Yop-Y. pseudotuberculosis strains were assayed for interleukin (IL)-8 production. HeLa cells infected with a YopEHJ- triple mutant released significantly more IL-8 than HeLa cells infected with isogenic wild-type, YopE-, YopH- or YopJ- bacteria. Complementation analysis demonstrated that YopE, YopH or YopJ are sufficient to counteract IL-8 production. IL-8 production required YopB, but did not require YopD, pore formation or invasin-mediated adhesion. In addition, YopB was required for activation of nuclear factor kappa B, the mitogen-activated protein kinases ERK and JNK and the small GTPase Ras in HeLa cells infected with the YopEHJ- mutant. We conclude that interaction of the Yersinia type III translocator factor YopB with the host cell triggers a proinflammatory signalling response that is counteracted by multiple effectors in host cells.
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PMID:Proinflammatory signalling stimulated by the type III translocation factor YopB is counteracted by multiple effectors in epithelial cells infected with Yersinia pseudotuberculosis. 1260 36

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

Gastroesophageal reflux disease is the most common malady of the esophagus, affecting 7% of the United States population. Histological assessment demonstrates classic inflammatory mechanisms including selective leukocyte recruitment and hemorrhage, suggesting a prominent role for the microvasculature. We isolated and characterized human esophageal microvascular endothelial cells (EC) (HEMEC), examined inflammatory activation in response to cytokines, LPS, and acidic pH exposure, and identified signaling pathways that underlie activation. HEMEC displayed characteristic morphological and phenotypic features including acetylated LDL uptake. TNF-alpha/LPS activation of HEMEC resulted in upregulation of the cell adhesion molecules (CAM) ICAM-1, VCAM-1, E-selectin, and mucosal addressin CAM-1 (MAdCAM-1), increased IL-8 production, and enhanced leukocyte binding. Both acid and TNF-alpha/LPS activation lead to activation of SAPK/JNK in HEMEC that was linked to VCAM-1 expression and U-937 leukocyte adhesion. Expression of constitutive inducible nitric oxide synthase in HEMEC was in marked contrast to intestinal microvascular endothelial cells. In this study, we demonstrate that HEMECs are phenotypically and functionally distinct from lower gut-derived endothelial cells and will facilitate understanding of inflammatory mechanisms in esophageal inflammation.
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PMID:Isolation and characterization of human esophageal microvascular endothelial cells: mechanisms of inflammatory activation. 1291 42

Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. We here show that human subcutaneous adipose cells, like 3T3-L1 cells, are target cells for IL-6. To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor alpha (TNF-alpha). IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. However, IL-6, like TNF-alpha exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor gamma. This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-alpha, IL-6 does not increase pS-307 (or pS-612) of IRS-1. The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-alpha and IL-8, was markedly increased ( approximately 15-fold) in human fat cells from insulin-resistant individuals. We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance.
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PMID:Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. 1295 69

The role of caveolae in CD40/CD154 activation of proinflammatory chemokines and their potential role in renal inflammatory disease were explored in primary cultures of human renal proximal tubule epithelial cells. With the use of a cell fractionation assay, caveolin-1 (Cav-1), the defining structural protein of caveolae, was detected exclusively in the cell membrane (detergent insoluble) component of resting and CD40-activated cells. In the unstimulated condition, CD40 was associated with Cav-1, and with activation of the receptor by its cognate ligand CD154, CD40 disassociated from Cav-1. Other previously identified components of the CD40 signaling pathway, namely, SAPK/JNK, p38, and ERK1/2 MAPKs, but not tumor necrosis factor receptor-associated factor 6 (TRAF-6), were also present within caveolae and dissociated from this structure with ligation of the CD40 receptor. Disruption of caveolae with filipin diminished CD40-mediated MAPK activation and blunted downstream monocyte chemoattractant protein-1 (MCP-1) and IL-8 production. Similarly, dislodgment of signaling proteins from their scaffolding with a peptide targeted to the Cav-1 scaffolding domain (CSD) resulted in blunted MAPK activation and augmented IL-8 and MCP-1 production. In contrast, epidermal growth factor (EGF)-mediated tyrosine phosphorylation of the EGF receptor and activation of ERK1/2 were not interrupted by the peptide. We conclude that in human renal proximal tubule epithelial cells, CD40 and its downstream MAPK signaling proteins are located in membrane rafts and that disruption of caveolae or dislodgment of signaling proteins from the CSD diminishes MAPK activation and IL-8 and MCP-1 production in these cells.
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PMID:Functional caveolae are a prerequisite for CD40 signaling in human renal proximal tubule cells. 1466 33

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