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)

Interleukin-8 (IL-8) mRNA was rapidly, but not permanently, induced at high levels by phorbol-12myristate-13acetate (PMA) in HL60 cells. Ongoing protein synthase does not seem to be required for the initial induction of IL-8 gene expression. However, the rate of transient induction kinetics was modulated by cycloheximide (CHX) indicating that secondary response genes are involved in the regulation of IL-8 RNA levels. Repression of the induced IL8 mRNA by 21 h PMA-treatment was due to reduced transcriptional activity of the gene. In HL60 cells stimulated for 1.5 and 21 h the half-lives of the lL-8 transcripts were markedly increased, suggesting the presence of negatively-acting transcriptional regulator(s).
 ...
PMID:The induction kinetics of Il-8 messenger RNA in HL60 cells demonstrate the participation of negative-acting gene(s). 763 90

Thioredoxin (TRX) is a cellular reducing catalyst induced by oxidative stress and is involved in the redox regulation of transcription factors such as NF-kappaB. We found that the serum TRX concentration was elevated in patients with rheumatoid arthritis (RA) as compared with values from healthy individuals and patients with osteoarthritis (33.6 +/- 35.1 vs 11.8 +/- 6.6 ng/ml, p < 0.01). Moreover, the TRX concentration in the synovial fluid (SF) was much more elevated in RA patients than in osteoarthritis patients (103.4 +/- 53.3 vs 24.6 +/- 17.4 ng/ml, p < 0.001). Multiple regression analysis revealed that the serum C-reactive protein value was better correlated with the linear combination of SF TNF-alpha and SF TRX values than with SF TNF-alpha alone, suggesting that TRX might play a subsidiary role in the rheumatoid inflammation. We thus examined the effect of TRX on the TNF-alpha-induced IL-6 and IL-8 production using rheumatoid synovial fibroblast cultures. The extents of IL-6 and IL-8 production in response to TNF-alpha were greatly augmented by TRX as compared with TNF-alpha alone. TRX alone did not have such effects. We also found that TRX appeared to accelerate the nuclear translocation of NF-kappaB, a major transcriptional regulator for production of IL-6 and IL-8 on stimulation with TNF-alpha. Consistent with these findings, the IkappaBalpha phosphorylation at Ser32 and its subsequent degradation in response to TNF-alpha was facilitated by TRX. These findings indicate that the elevated TRX concentration in SF of RA patients might be involved in the aggravation of rheumatoid inflammation by augmenting the NF-kappaB activation pathway.
 ...
PMID:Involvement of thioredoxin in rheumatoid arthritis: its costimulatory roles in the TNF-alpha-induced production of IL-6 and IL-8 from cultured synovial fibroblasts. 1038 35

The pathogenesis of Shigella flexneri infection centers on the ability of this organism to invade epithelial cells and initiate an intense inflammatory reaction. Because NF-kappa B is an important transcriptional regulator of genes involved in inflammation, we investigated the role of this transcription factor during S. flexneri infection of epithelial cells. Infection of HeLa cells with invasive S. flexneri induced NF-kappa B DNA-binding activity; noninvasive S. flexneri strains did not lead to this activation. The pathway leading to NF-kappa B activation by invasive S. flexneri involved the kinases, NF-kappa B-inducing kinase, I kappa B kinase-1, and I kappa B kinase-2. NF-kappa B activation was linked to inflammation, because invasive S. flexneri activated an IL-8 promoter-driven reporter gene, and the kappa B site within this promoter was indispensable for its induction. Microinjection of bacterial culture supernatants into HeLa cells suggested that LPS is responsible for NF-kappa B activation by S. flexneri infection. In conclusion, the eukaryotic transcription factor NF-kappa B was activated during S. flexneri infection of epithelial cells, which suggests a role for this transcriptional regulator in modulating the immune response during infection in vivo.
 ...
PMID:Invasive Shigella flexneri activates NF-kappa B through a lipopolysaccharide-dependent innate intracellular response and leads to IL-8 expression in epithelial cells. 1087 65

Twitching motility is a form of bacterial translocation over firm surfaces that requires retractile type IV pili. Microscopic colonies of Ralstonia solanacearum strains AW1, K60 and GMI1000 growing on the surface of a rich medium solidified with 1.6% agar appeared to exhibit twitching motility, because early on they divided into motile 'rafts' of cells and later developed protruding 'spearheads' at their margins. Individual motile bacteria were observed only when they were embedded within masses of other cells. Varying degrees of motility were observed for 33 of 35 strains of R. solanacearum in a selected, diverse collection. Timing was more important than culture conditions for observing motility, because by the time wild-type colonies were easily visible by eye (about 48 h) this activity ceased and the spearheads were obscured by continued bacterial multiplication. In contrast, inactivation of PhcA, a transcriptional regulator that is essential for R. solanacearum to cause plant disease, resulted in colonies that continued to expand for at least several additional days. Multiple strains with mutations in regulatory genes important for virulence were tested, but all exhibited wild-type motility. Many of the genes required for production of functional type IV pili, and hence for twitching motility, are conserved among unrelated bacteria, and pilD, pilQ and pilT orthologues were identified in R. solanacearum. Colonies of R. solanacearum pilQ and pilT mutants did not develop spearheads or rafts, confirming that the movement of cells that had been observed was due to twitching motility. Compared to the wild-type parents, both pilQ and pilT mutants caused slower and less severe wilting on susceptible tomato plants. This is the first report of twitching motility by a phytopathogenic bacterium, and the first example where type IV pili appear to contribute significantly to plant pathogenesis.
 ...
PMID:Twitching motility of Ralstonia solanacearum requires a type IV pilus system. 1173 54

As reported previously for Ralstonia solanacearum strain GMI1000, wild-type strains AW1 and K60 were shown to produce Hrp pili. AW1 and K60 mutants lacking Hrp pili still exhibited twitching motility, which requires type 4 pili (Tfp), and electron microscopy revealed that they still made flexuous polar pili. Twitching-positive cells had an extracellular 17 kDa protein that was associated with piliation, and an internal 43-amino-acid sequence of this protein was typical of type 4 pilins. This amino acid sequence is encoded by an open reading frame, designated pilA, in the genomic sequence of GMI1000. PilA is 46% identical to a Pseudomonas aeruginosa type 4 pilin over its entire length and has all the conserved residues and motifs characteristic of type 4 group A pilins. pilA mutants did not make the 17 kDa PilA protein and did not exhibit twitching motility. When compared with its parent, an AW1 pilA mutant was reduced in virulence on tomato plants and in autoaggregation and biofilm formation in broth culture. Unlike AW1, a pilA mutant did not exhibit polar attachment to tobacco suspension culture cells or to tomato roots; it was also not naturally competent for transformation. We reported previously that twitching motility ceases in maturing AW1 colonies and that inactivation of PhcA, a global transcriptional regulator, results in colonies that continue to exhibit twitching motility. Similarly, in broth culture, expression of a pilA::lacZ fusion in AW1 decreased 10-fold at high cell density, but expression remained high in a phcA mutant. In addition, pilA::lacZ expression was positively regulated 10-fold by PehR, a response regulator that is known to be repressed by PhcA. This signal cascade is sufficient to explain why pilA expression, and thus twitching motility, decreases at high cell densities.
 ...
PMID:Ralstonia solanacearum requires type 4 pili to adhere to multiple surfaces and for natural transformation and virulence. 1240 19

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.
 ...
PMID:Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. 1520 27

Chemokines, or chemotactic cytokines, are major regulators of the inflammatory response and have been identified as pathogenic factors in the periprosthetic soft tissue. Particulate wear debris induced NF-kappaB activation, the major transcriptional regulator of IL-8 and MCP-1 pro-inflammatory genes and, indeed, both IL-8 and MCP-1 chemokine gene expressions were upregulated in titanium particulate-stimulated human osteoblasts. Here, we demonstrate that phagocytosed particles activate the IL-8 gene promoter via a NF-kappaB-mediated mechanism. Transfection of a dominant negative mutant IkappaBalpha protein that cannot be serine phosphorylated led to suppression of IL-8 promoter activity. The p65/RelA NF-kappaB subunit activity was affected in both a time- and titanium particle concentration-dependent fashion. Titanium particles led to increased ERK, JNK, and p38 activation in MG-63 osteoblast cells, and IL-8 protein release was suppressed by specific inhibitors of the ERK and p38 MAPK pathways. Together, our results suggest that wear debris particles induce chemokine expression in osteoblasts via NF-kappaB-mediated transcriptional activation, which is controlled by the MAPK signal transduction pathway.
 ...
PMID:Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-kappaB. 1595 Apr 27

Understanding how cells withstand a depletion of intracellular water is relevant to the study of longevity, aging, and quiescence because one consequence of air-drying is metabolic arrest. After removal of medium, HEK293 spheroids with intracellular water content of approximately 65% survived partial vacuum, with antistatic control, for weeks in the dark at 25 degrees C. In contrast, only a limited exposure of monolayers to air was lethal; the mitochondrion being a target of this stress. The pathways activated during the long-term arrest and recovery of spheroids depended on both NF-kappaB signaling and sustained JNK activation. A cyclical cascade, presumably originating from an intercellular stress signal, led to endogenous cytokine production (TNF-alpha, IL-1b, and IL-8) and propagation of the cellular stress signal through the co-activation of NF-kappaB and JNK. Increased levels of downstream pathway signaling members, specifically Gadd45beta, c-jun, and ATF3 were observed, as was activation of c-jun (phosphorylation). Activation of these pathways permit cells to survive long-term storage and recovery because chemical inhibition of both NF-kappaB nuclear translocation and JNK phosphorylation led to cell death. The capacity of an immortalized cell to enter, and then exit, a state of long-term quiescence, without genetic or chemical intervention, has implications for the study of cell transformation. In addition, the ability to monitor the relevant signaling pathways at endogenous levels, from effector to transcriptional regulator, emphasizes the utility of multicellular aggregate models in delineating stress response pathways.
 ...
PMID:Long term metabolic arrest and recovery of HEK293 spheroids involves NF-kappaB signaling and sustained JNK activation. 1615 29

Polymorphonuclear cell (PMN) infiltration is a hallmark of ricin-induced mucosal inflammation, yet the cellular processes involved in initiating this reaction remain undefined. In this study we report that ricin stimulates the human monocyte/macrophages cell line 28SC to secrete IL-8, a potent PMN chemoattractant. IL-8 release in response to ricin was both dose- and time-dependent. 28SC cells did not secrete IL-8 when exposed to formaldehyde-inactivated holotoxin or ricin B subunit. Furthermore, IL-8 induction could be blocked by brefeldin A, which inhibits ricin translocation into the cytosol. As predicted from the literature, we observed elevated levels of p38 mitogen activated protein kinase (MAPK), a post-transcriptional regulator of IL-8, in 28SC cells as early as 3h after ricin exposure. Treatment of 28SC cells with the pyridylimidizole analogue SB203580, a known inhibitor of p38 MAPK, suppressed ricin-mediated IL-8 release. We conclude that ricin stimulates human monocyte/macrophages to produce IL-8 by activation of the p38 MAPK pathway, raising the possibility that p38 MAPK inhibitors may potentially serve as therapeutic agents to suppress mucosal inflammation associated with ricin intoxication.
 ...
PMID:Ricin induces IL-8 secretion from human monocyte/macrophages by activating the p38 MAP kinase pathway. 1643 99

Human airway smooth muscle (ASM) plays an immunomodulatory role in asthma. Recently, IL-17A has become of increasing interest in asthma, being found at elevated levels in asthmatic airways and emerging as playing an important role in airway neutrophilia. IL-17A predominantly exerts its neutrophil orchestrating role indirectly via the induction of cytokines by resident airway structural cells. Here, we perform an in vitro study to show that although IL-17A did not induce secretion of the CXC chemokine IL-8 from ASM cells, IL-17A significantly potentiates TNF-alpha-induced IL-8 protein secretion and gene expression in a concentration- and time-dependent manner (P < 0.05). Levels of IL-8 protein produced after 24 h of incubation with TNF-alpha were enhanced 2.7-fold in the presence of IL-17A, and conditioned media significantly enhanced neutrophil chemotaxis in vitro. As IL-17A had no effect on the activity of NF-kappaB, a key transcriptional regulator of IL-8 gene expression, we then examined whether IL-17A acts at the posttranscriptional level. We found that IL-17A significantly augmented TNF-alpha-induced IL-8 mRNA stability. Interestingly, this enhanced stability occurred via a p38 MAPK-dependent pathway. The decay of IL-8 mRNA transcripts proceeded at a significantly faster rate when cells were pretreated with the p38 MAPK inhibitor SB-203580 (-0.05763 +/- 0.01964, t(1/2) = 12.0 h), compared with vehicle (-0.01030 +/- 0.007963, t(1/2) = 67.3 h) [results are expressed as decay constant (means +/- SE) and half-life (t(1/2) in h): P < 0.05]. Collectively, these results demonstrate that IL-17A amplifies the synthetic function of ASM cells, acting via a p38 MAPK-dependent posttranscriptional pathway to augment TNF-alpha-induced secretion of the potent neutrophil chemoattractant IL-8 from ASM cells.
 ...
PMID:IL-17A acts via p38 MAPK to increase stability of TNF-alpha-induced IL-8 mRNA in human ASM. 1668 53


1 2 3 Next >>