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)

Tyrphostins are well-established selective inhibitors of protein tyrosine kinase activity of EGF receptor and other growth factor receptors. Unexpectedly, we found that, in U-937 monocytic cells, tyrphostin AG-126 augments the sensitivity of the corresponding genes to NO, in contrast to other protein tyrosine kinase inhibitors like genistein, PD 168393, PP2, and SU 11652. Moreover, by itself AG-126 appeared to be a potent activator of the expression of heme oxygenase 1 (HO-1), H-ferritin, activating transcription factor 3 (ATF3), interleukin 8 (IL-8), and several other NO- and redox-regulated genes. The most sensitive to AG-126 was the HO-1 gene, with a fold-change of expression reaching 300. Besides, we showed that AG-126 stimulated key elements of upstream signaling systems as p38 MAP kinase and AP-1 and Nrf2 transcription factors. Together with AG-126, structurally related benzylidenemalononitrile tyrphostins AG-9, AG-10, AG-18, and AG-1288 were able to up-regulate the expression of HO-1 and several other genes, although with relatively less efficacy. Conversely, tyrphostins AG-30 and AG-490 were ineffective regulators of gene expression. Comparison of the chemical structures of these compounds indicates that most important for transcriptional activation of target genes is the presence of either the 4-nitro or 4-methoxy group in the benzene ring and two CN-groups of the malononitrile residue. Several lines of evidence indicate that the gene induction capacity of AG-126-like tyrphostins is not related to the inhibition of protein tyrosine kinases.
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PMID:Stimulatory effect of benzylidenemalononitrile tyrphostins on expression of NO-dependent genes in U-937 monocytic cells. 1937 63

Dendritic cell (DC) maturation in response to contact sensitizers is a crucial step in the induction of sensitization reactions; however the underlying mechanism of activation remains unknown. To test whether the extent of protein haptenation is a determinant in DC maturation, we tested the effect of five dinitrophenyl (DNP) analogues of different reactivity, on maturation markers in the cell line, THP-1. The potencies of the test compounds in upregulating CD54 levels, inducing IL-8 release and triggering p38 MAPK phosphorylation did not correlate with their ability to deplete intracellular glutathione (GSH) levels or cause cell toxicity. However, the compounds' potency at inducing p38 phosphorylation was significantly associated with the amount of intracellular protein adducts formed (p<0.05). Inhibition experiments show that, at least for DNFB, p38 MAP kinase signalling controls compound-specific changes in CD54 expression and IL-8 release. 2D-PAGE analysis revealed that all the DNP analogues appeared to bind similar proteins. The analogues failed to activate NFkB, however, they activated Nrf2, which was used as a marker of oxidative stress. Neither GSH depletion, by use of buthionine sulfoximine, nor treatment with the strongly lysine-reactive hapten penicillin elicited maturation. We conclude that protein haptenation, probably through reactive cysteine residues may be a trigger for maturation events in this in vitro model and that p38 activation may be a discriminatory marker for the classification of potency of chemical sensitizers.
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PMID:Role of protein haptenation in triggering maturation events in the dendritic cell surrogate cell line THP-1. 1942 79

The etiology of acne is a complex process, and acne is one of the most common skin disorders affecting millions of people. The pathogenesis of acne is closely associated with the bacterium, Propionibacterium acnes which was previously known as Corynebacterium parvum. Both viable and non-viable P. acnes/C. parvum have been shown to induce an immunostimulatory effect in vivo, suggesting that even dead bacteria continue to activate an inflammatory response. Acne treatments with lasers or devices, induce a bactericidal effect through heat generation which may not address the immunogenic activity of P. acnes and the resulting acne inflammation. Therefore, we sought to determine whether killed P. acnes is capable of inducing an inflammatory response and therefore could be a contributing factor in acne. Direct heat treatment of P. acnes cultures with temperatures ranging from 50 degrees C to 80 degrees C reduced P. acnes viability. Both viable and heat-killed P. acnes activated the p38 MAP kinase and its downstream substrate Hsp27. Stimulating keratinocytes with normal and heat-inactivated P. acnes resulted in an induction of proinflammatory nitric oxide and IL-8 production. Thus killed P. acnes is capable of inducing inflammation in skin suggesting that therapies that have both bactericidal and anti-inflammatory effects may result in a more effective treatment of patients with acne than treatments that are bactericidal alone.
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PMID:Heat-killed Propionibacterium acnes is capable of inducing inflammatory responses in skin. 1962 31

p38MAP kinase plays a crucial role in intracellular signal transduction of inflammation. The inhibitor of p38 MAP kinase, FR167653, has been proven to be effective to suppress proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in various animal models. The aim of our study was to investigate p38MAP kinase inhibition by FR167653 on the inflammatory profile of cells involved in vascular injury. HUVEC incubated with FR167653 in concentrations of 0.1 to 20 mumol for 24 hours were stimulated with TNF-alpha (20 ng/mL). Human monocytes were incubated with equal concentrations of FR167653 and stimulated with lipopolysaccharides (LPS; 10 microg/mL). In monocytes, p38 MAP kinase could be inhibited by FR167653 (Western blot). The cytokines IL-6 and IL-8 were dose dependently downregulated by FR167653 (enzyme-linked immunosorbent assay) [ELISA]. These results were confirmed at a transcriptional level by real-time polymerase chain reaction (PCR). Gene expression of IL-6 and IL-8 was dose dependently downregulated. The expression pattern of ICAM-1 and VCAM-1 was not altered by FR167653 (ELISA). In HUVEC, the cytokines IL-6 and IL-8 were dose dependently downregulated by FR167653 (ELISA). These results were confirmed on a transcriptional level by real-time PCR. Gene expression of IL-6 and IL-8 were also dose dependently suppressed by FR167653. In addition FR167653 downregulated the expression of the adhesion molecules ICAM-1 and VCAM-1 (ELISA). FR167653 suppressed the development of a proinflamatory profile of HUVEC and human monocytes after stimulation with TNF-alpha or LPS, respectively. These results indicated anti-inflammatory properties of FR167653 on endothelial and inflammatory cells, which may be therapeutically useful to ameliorate vascular injury.
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PMID:FR167653 Ameliorates expression of proinflammatory mediators in human umbilical venous endothelial cells and human monocytes. 1971 86

Mitogen-activated protein kinase phosphatase (MKP)-1 is a protein phosphatase that regulates the activity of p38 mitogen-activated protein (MAP) kinase and c-Jun NH2-terminal kinase (JNK) and, to lesser extent, p42/44 extracellular signal-regulated kinase. Studies with MKP-1(-/-) mice show that MKP-1 is a regulating factor suppressing excessive cytokine production and inflammatory response. The data on the role of MKP-1 in the regulation of inflammatory gene expression in human cells are much more limited. In the present study, we investigated the effect of MKP-1 on the expression of interleukin (IL)-6, IL-8 and cyclooxygenase (COX)-2 in response to stimulation with cytokines (tumor necrosis factor, IL-1beta, and interferon-gamma; 10 ng/ml each) in A549 human lung epithelial cells. Cytokines enhanced p38 and JNK phosphorylation and MKP-1 expression. p38 MAP kinase inhibitors 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] phenol (SB202190) and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB 796) inhibited cytokine-induced phosphorylation of p38 substrate MAP kinase-activated protein kinase 2 and expression of IL-6, IL-8, and COX-2. An aminopyridine-based JNK inhibitor, N-(4-amino-5-cyano-6-ethoxypyridin-2-yl)-2-(2,5-dimethoxyphenyl)acetamide (JNK inhibitor VIII), inhibited phosphorylation of a JNK substrate c-Jun but did not have any effect on IL-6, IL-8, or COX-2 expression. Down-regulation of MKP-1 with small interfering RNA enhanced p38 and JNK phosphorylation and increased IL-6, IL-8, and COX-2 expression in A549 cells. In conclusion, cytokine-induced MKP-1 expression was found to negatively regulate p38 phosphorylation and the expression of IL-6, IL-8, and COX-2 in human pulmonary epithelial cells. Our results suggest that MKP-1 is an important negative regulator of inflammatory gene expression in human pulmonary epithelial cells, and compounds that enhance MKP-1 may have anti-inflammatory effects and control inflammatory response in the human lung.
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PMID:Mitogen-activated protein kinase phosphatase-1 negatively regulates the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in A549 human lung epithelial cells. 2008 8

Irsogladine maleate (IM) counters Aggregatibacter actinomycetemcomitans-induced reduction of the gap junction intercellular communication and the expression of zonula occludens-1, which is a major tight junction structured protein, in cultured human gingival epithelial cells (HGEC). In addition, IM obviates the A. actinomycetemcomitans-induced increase in interleukin (IL)-8 levels in HGEC. Thus, by regulating the intercellular junctional complex and chemokine secretion in HGEC, IM may be useful to prevent periodontal disease. To clarify the effects and regulatory mechanism of IM in vivo and in vitro, we examined the expression of E-cadherin and neutrophil chemotaxis induced by A. actinomycetemcomitans under IM pretreatment. Immunohistochemical studies revealed that A. actinomycetemcomitans application to the gingival sulcus decreased the number of cells positive for E-cadherin and increased those positive for cytokine-induced neutrophil chemoattractant-2alpha (CINC-2alpha) in rat gingival epithelium. However, in IM-pretreated rats, A. actinomycetemcomitans application had little effect on CINC-2alpha and E-cadherin in gingival epithelium. In cultured HGEC, real-time PCR and Western blotting showed that IM and the ERK inhibitor PD98059 abolished the A. actinomycetemcomitans-induced increase in CXCL-1 and IL-8 in HGEC. On the other hand, IM, PD98059, and the p38 MAP kinase inhibitor SB203580 recovered the decrease in E-cadherin expression. In addition, conditioned medium from A. actinomycetemcomitans-stimulated HGEC enhanced human neutrophil chemotaxis, compared to that from un-stimulated HGEC or that from A. actinomycetemcomitans-stimulated HGEC under IM pretreatment. Furthermore, IM down-regulated the p38 MAP kinase and ERK phosphorylations induced by A. actinomycetemcomitans. In conclusion, IM may control A. actinomycetemcomitans-induced gingival inflammation by regulating neutrophil migration and E-cadherin expression in gingival epithelium.
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PMID:Irsogladine maleate regulates neutrophil migration and E-cadherin expression in gingival epithelium stimulated by Aggregatibacter actinomycetemcomitans. 2009 65

Pneumococcal surface protein A (PspA) plays a key role in the pathogenesis of invasive pneumococcal infection. PspA might modulate specific immune responses in human population. Circulating monocytes are essential for the innate responses and subsequent acquired immune responses to Streptococcus pneumoniae. In this study, we investigated the effects of PspA on cytokine and chemokine secretion from human peripheral blood monocytes and the underlying intracellular signaling mechanisms. Stimulation of monocytes with purified PspA protein induced the significant release of inflammatory cytokine IL-6 and chemokines including CXCL8, CCL2, CCL4 and CCL5. Products from PspA-deficient mutant pneumococcus that did not express PspA induced significantly less secretion of these mediators than those from wild type pneumococcus. Further investigations showed that PspA activated the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen activated protein kinase (MAPK) and nuclear factor (NF)-kappaB signaling pathways in human monocytes. Moreover, inhibition of these pathways using selective inhibitors could significantly reduce the cytokine and chemokine secretion induced by PspA. Taken together, our findings provide insight for PspA-mediated activation of human monocytes via NF-kappaB and MAPKs signaling cascades in the pathogenesis of invasive pneumococcal infection.
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PMID:Molecular mechanisms of the secretion of cytokines and chemokines from human monocytes activated by pneumococcal surface protein A (PspA): Roles of mitogen-activated protein kinases and NF-kappaB. 2022 79

Intestinal epithelial cells act as innate immune sentinels, as the first cells that encounter diarrheal pathogens. They use pattern recognition molecules such as the Toll-like receptors (TLRs) to identify molecular signals found on microbes but not host cells or food components. TLRs cannot generally distinguish the molecular signals on pathogenic bacteria from those found in commensals, yet under healthy conditions epithelial immune responses are kept in check. We hypothesized that, in the setting of tissue damage or stress, intestinal epithelial cells would upregulate their responses to TLR ligands to reflect the greater need for immediate protection against pathogens. We treated Caco-2 cells with the TLR5 agonist flagellin in the presence or absence of H(2)O(2) and measured chemokine production and intracellular signaling pathways. H(2)O(2) increased flagellin-induced IL-8 (CXCL8) production in a dose-dependent manner. This was associated with synergistic phosphorylation of p38 MAP kinase and with prolonged I-kappaB degradation and NF-kappaB activation. The H(2)O(2)-mediated potentiation of IL-8 production required the activity of p38, tyrosine kinases, phospholipase Cgamma, and intracellular calcium, but not protein kinase C or protein kinase D. H(2)O(2) prolonged and augmented NF-kappaB activation by flagellin. In contrast to IL-8, CCL20 (MIP3alpha) production by flagellin was reduced by H(2)O(2), and this effect was not calcium dependent. Oxidative stress biases intestinal epithelial responses to flagellin, leading to increased production of IL-8 and decreased production of CCL20. This suggests that epithelial cells are capable of sensing the extracellular environment and adjusting their antimicrobial responses accordingly.
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PMID:Oxidative stress enhances IL-8 and inhibits CCL20 production from intestinal epithelial cells in response to bacterial flagellin. 2059 17

L-selectin is a key molecule that participates in neutrophil tethering and subsequent rolling. It is cleaved from the surface of neutrophils activated in the presence of lipopolysaccharides, N-formyl-methionine-leucine-phenylalanine (fMLP), or Interleukin-8 (IL-8). We previously showed that L-selectin is also shed from the neutrophil surface during rolling on sialyl Lewis-x coated surfaces in a force-, ADAM-17 sheddase-, and p38 MAP kinase-dependent manner under flow. c-Abl tyrosine kinase is phosphorylated when L-selectin on the surface of neutrophils is cross-linked with anti-L-selectin antibodies. Here, we study the effect of c-Abl inhibition on L-selectin shedding from primary human neutrophils in static conditions following exposure to fMLP, IL-8, and hypotonic buffer and under flow through sialyl Lewis-x coated microtubes. Results indicate that c-Abl inhibition by STI571 significantly affects neutrophil adhesion via L-selectin, by decreasing the average rolling velocity and increasing the flux of rolling cells. The change in surface receptor expression was verified by flow cytometry. Interestingly, other forms of L-selectin shedding induced by fMLP, IL-8 or osmotic swelling were unaffected by STI571 treatment. These findings implicate the c-Abl signaling molecule in regulating L-selectin mechanical shedding in response to shear stress, setting this type of signaling apart from those triggered by the presence of a hypotonic environment, fMLP, or IL-8. This study sheds light on the role of c-Abl in neutrophil adhesion not previously reported in the literature.
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PMID:Role of c-Abl in L-selectin shedding from the neutrophil surface. 2127 37

Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we hypothesized that GrK induces pro-inflammatory cytokine release through the activation of protease-activated receptors. The direct effect of extracellular GrK on PAR activation, intracellular signaling and cytokine was assessed using cultured human lung fibroblasts. Extracellular GrK induced secretion of IL-6, IL-8 and MCP-1 in a dose- and time-dependent manner in lung fibroblasts. Heat-inactivated GrK did not induce cytokine release indicating that protease activity is required. Furthermore, GrK induced activation of both the ERK1/2 and p38 MAP kinase signaling pathways, and significantly increased fibroblast proliferation. Inhibition of ERK1/2 abrogated the GrK-mediated cytokine release. Through the use of PAR-1 and PAR-2 neutralizing antibodies, it was determined that PAR-1 is essential for GrK-induced IL-6, IL-8 and MCP-1 release. In summary, extracellular GrK is capable of activating PAR-1 and inducing fibroblast cytokine secretion and proliferation.
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PMID:Granzyme K activates protease-activated receptor-1. 2176 Aug 80

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