Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.10 (IKK)
4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we examined the regulation of NF-kappaB activation and IL-8/CXCL8 expression by thrombin in human lung epithelial cells (EC). Thrombin caused a concentration-dependent increase in IL-8/CXCL8 release in a human lung EC line (A549) and primary normal human bronchial EC. In A549 cells, thrombin, SFLLRN-NH2 (a protease-activated receptor 1 (PAR1) agonist peptide), and GYPGQV-NH2 (a PAR4 agonist peptide), but not TFRGAP-NH2 (a PAR3 agonist peptide), induced an increase in IL-8/CXCL8-luciferase (Luc) activity. The thrombin-induced IL-8/CXCL8 release was attenuated by D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (a thrombin inhibitor), U73122 (a phosphoinositide-phospholipase C inhibitor), Ro-32-0432 (a protein kinsase C alpha (PKC alpha) inhibitor), an NF-kappaB inhibitor peptide, and Bay 117082 (an IkappaB phosphorylation inhibitor). Thrombin-induced increase in IL-8/CXCL8-Luc activity was inhibited by the dominant-negative mutant of c-Src and the cells transfected with the kappaB site mutation of the IL-8/CXCL8 construct. Thrombin caused time-dependent increases in phosphorylation of c-Src at tyrosine 416 and c-Src activity. Thrombin-elicited c-Src activity was inhibited by Ro-32-0432. Stimulation of cells with thrombin activated IkappaB kinase alphabeta (IKK alphabeta), IkappaB alpha phosphorylation, IkappaB alpha degradation, p50 and p65 translocation from the cytosol to the nucleus, NF-kappaB-specific DNA-protein complex formation, and kappaB-Luc activity. Pretreatment of A549 cells with Ro-32-4032 and the dominant-negative mutant of c-Src DN inhibited thrombin-induced IKK alphabeta activity, kappaB-Luc activity, and NF-kappaB-specific DNA-protein complex formation. Further studies revealed that thrombin induced PKC alpha, c-Src, and IKK alphabeta complex formation. These results show for the first time that thrombin, acting through PAR1 and PAR4, activates the phosphoinositide-phospholipase C/PKC alpha/c-Src/IKK alphabeta signaling pathway to induce NF-kappaB activation, which in turn induces IL-8/CXCL8 expression and release in human lung EC.
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PMID:c-Src mediates thrombin-induced NF-kappaB activation and IL-8/CXCL8 expression in lung epithelial cells. 1692 Sep 85

We examined the ability of the flavonoids quercetin and kaempferol to modulate inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and reactive C-protein (CRP) expression, and to induce changes in the nuclear factor kappa B (NF-kappaB) pathway in the human hepatocyte-derived cell line Chang Liver. Cells were incubated with a cytokine mixture supplemented with quercetin or kaempferol (5 to 200 micromol/l). Kaempferol produced a significant concentration-dependent decrease of iNOS, COX-2 and CRP protein level at all concentrations, but the percentage of inhibition induced by quercetin was reduced at high concentrations. Both flavonoids significantly inhibited mRNA level of iNOS, COX-2, and CRP. Inhibitory effects by quercetin and kaempferol were also observed on NF-kappaB activation and on protein concentration of the phosphorylated form of the inhibitor IkappaB alpha and of IKK (IkappaB kinase)alpha. The present study suggests that the modulation of iNOS, COX-2 and CRP by quercetin or kaempferol may contribute to the anti-inflammatory effects of these two structurally similar flavonoids in Chang Liver cells, via mechanisms likely to involve blockade of NF-kappaB activation and the resultant up-regulation of the pro-inflammatory genes. Our data also indicate that the minor structural differences between both compounds determine differences in their inhibitory capacity.
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PMID:The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. 1718 68

The neuropeptides calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), and vasoactive intestinal peptide (VIP) suppress Langerhans cell (LC) antigen presentation and modulate cytokine production. We have tested the hypothesis that these neuropeptides (NP) inhibit LC function by modulating activation of NF-kappaB. Lipopolysaccharide (LPS) activates NF-kappaB in both a LC-like cell line (XS52) and epidermal LC enriched to approximately 95% and this effect is inhibited by each of the NP. Furthermore, CGRP, PACAP, and VIP suppress phosphorylation of IkappaB kinase beta (P-IKKbeta), prevent degradation of the IkappaB alpha, and inhibit activation of NF-kappaB. Thus, these NP modulate LC function by reducing NF-kappaB activation. Bay 11-7085, an inhibitor of IKK, reduced tumor necrosis factor-alpha (TNFalpha) production from LPS-stimulated XS52 cells and inhibited the ability of LC to present antigen to a T-cell clone in vitro. Each NP also inhibited LPS-induced secretion of TNFalpha by XS52 cells and LC enriched to approximately 95% homogeneity. We suggest that the inhibitory activities of CGRP, PACAP, and VIP on LC function are mediated, at least in part, by inhibition of P-IKKbeta, which prevents IkappaB alpha degradation and activation of NF-kappaB. Modulation of this signaling pathway may be useful for therapeutic modulation of immunity in the skin.
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PMID:CGRP, PACAP, and VIP modulate Langerhans cell function by inhibiting NF-kappaB activation. 1749 62

Boswellia resin is a major anti-inflammatory agent in herbal medical tradition, as well as a common food supplement. Its anti-inflammatory activity has been attributed to boswellic acid and its derivatives. Here, we re-examined the anti-inflammatory effect of the resin, using inhibitor of nuclear factor-kappaB alpha (IkappaB alpha) degradation in tumor necrosis factor (TNF) alpha-stimulated HeLa cells for a bioassay-guided fractionation. We thus isolated two novel nuclear factor-kappaB (NF-kappaB) inhibitors from the resin, their structures elucidated as incensole acetate (IA) and its nonacetylated form, incensole (IN). IA inhibited TAK/TAB-mediated IkappaB kinase (IKK) activation loop phosphorylation, resulting in the inhibition of cytokine and lipopolysaccharide-mediated NF-kappaB activation. It had no effect on IKK activity in vitro, and it did not suppress IkappaB alpha phosphorylation in costimulated T-cells, indicating that the kinase inhibition is neither direct nor does it affect all NF-kappaB activation pathways. The inhibitory effect seems specific; IA did not interfere with TNFalpha-induced activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. IA treatment had a robust anti-inflammatory effect in a mouse inflamed paw model. Cembrenoid diterpenoids, specifically IA and its derivatives, may thus constitute a potential novel group of NF-kappaB inhibitors, originating from an ancient anti-inflammatory herbal remedy.
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PMID:Incensole acetate, a novel anti-inflammatory compound isolated from Boswellia resin, inhibits nuclear factor-kappa B activation. 1789 8

The role of the proteasome in neurodegenerative diseases is controversial. On the one hand, there is evidence that a dysfunction of proteasome activity can lead to neurodegeneration but there is also data showing that proteasome inhibition can protect nerve cells from a variety of insults. In an attempt to clarify this issue, we studied the effects of four different proteasome inhibitors in a well characterized model of oxidative stress-induced nerve cell death. Consistent with the hypothesis that proteasome inhibition can be neuroprotective, we found that low concentrations of proteasome inhibitors were able to protect nerve cells from oxidative stress-induced death. Surprisingly, the neuroprotective effects of the proteasome inhibitors appeared to be at least partially mediated by the induction of NF-kappaB since protection was significantly reduced in cells expressing a specific NF-kappaB repressor. The activation of NF-kB by proteasome inhibitors was mediated by IkappaB alpha and IKK and was blocked by antioxidants and inhibitors of mitochondrial reactive oxygen species production. These data suggest that low concentrations of proteasome inhibitors induce a moderate level of mitochondrial oxidative stress which results in the activation of neuroprotective pathways.
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PMID:Proteasome inhibitors prevent oxidative stress-induced nerve cell death by a novel mechanism. 1835 6

Although there has been considerable interest in the regulation of NFkappaB activation by glutathionylation, the possibility of IkappaB as a target for glutathionylation has not been investigated. We now report that Cys(189) of IkappaB alpha is a target for S-glutathionylation. This modification is reversed by thiols such as dithiothreitol and GSH. The glutathionylated IkappaB alpha appears to be significantly less susceptible than is native protein to phosphorylation by IkappaB kinase and casein kinase II, as well as to in vitro ubiquitination. This finding suggests that glutathionylation plays a regulatory role, presumably through structural alterations. HeLa cells treated with oxidant inducing GSH oxidation such as diamide showed the accumulation of glutathionylated IkappaB alpha. This mechanism suggests an alternative modification to the redox regulation of cysteine in IkappaB alpha and a possible mechanism in the regulation of NFkappaB activation.
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PMID:Glutathionylation regulates IkappaB. 1855 96

Pterostilbene, an active constituent of blueberries, is known to possess anti-inflammatory activity and also to induce apoptosis in various types of cancer cells. Here, we investigated the inhibitory effects of pterostilbene on the induction of NO synthase (NOS) and cyclooxygenase-2 (COX-2) in murine RAW 264.7 cells activated with lipopolysaccharide (LPS). Western blotting and real-time polymerase chain reaction (PCR) analyses demonstrated that pterostilbene significantly blocked the protein and mRNA expression of iNOS and COX-2 in LPS-induced macrophages. Treatment with pterostilbene resulted in the reduction of LPS-induced nuclear translocation of the nuclear factor-kappaB (NFkappaB) subunit and the dependent transcriptional activity of NFkappaB by blocking phosphorylation of inhibitor kappaB (IkappaB)alpha and p65 and subsequent degradation of IkappaB alpha. Transient transfection experiments using NFkappaB reporter constructs indicated that pterostilbene inhibits the transcriptional activity of NFkappaB in LPS-stimulated mouse macrophages. We found that pterostilbene also inhibited LPS-induced activation of PI3K/Akt, extracellular signal-regulated kinase 1/2 and p38 MAPK. Taken together, these results show that pterostilbene down regulates inflammatory iNOS and COX-2 gene expression in macrophages by inhibiting the activation of NFkappaB by interfering with the activation of PI3K/Akt/IKK and MAPK. These results have an important implication for using pterostilbene toward the development of an effective anti-inflammatory agent.
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PMID:Pterostilbene suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. 1865 26

NF-kappaB activation in response to pro-inflammatory stimuli relies upon phosphorylation of IkappaB alpha at serines 32 and 36 by the beta subunit of the IkappaB kinase complex (IKK). In this study, we build upon the observation that highly purified human IKKbeta subunit preparations retain this specificity in vitro. We show that IKKbeta constructs that lack their carboxy-terminus beginning at the leucine zipper motif fail to phosphorylate IkappaB alpha at Ser-32 and Ser-36. Rather, these constructs, which contain the entire IKKbeta subunit kinase domain, phosphorylate serine and threonine residues contained within the IkappaB alpha carboxy-terminal PEST region. Furthermore, removal of the leucine zipper and helix-loop-helix regions converts IKKbeta to monomer. We propose that the helix-loop-helix of the human IKKbeta subunit is necessary for restricting substrate specificity toward Ser-32 and Ser-36 in IkappaB alpha and that in the absence of its carboxy-terminal protein structural motifs the human IKKbeta subunit kinase domain exhibits a CK2-like phosphorylation specificity.
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PMID:The human IKKbeta subunit kinase domain displays CK2-like phosphorylation specificity. 1865 15

On the basis of the observations that chalcone 7 (MX781) and some related adamantyl arotinoids (AdArs) inhibit IkappaB alpha kinase beta (IKKbeta) activity, inhibit cell growth, and induce apoptosis in cancer cells, a new series of AdArs structurally related to 7 have been designed and synthesized. Modifications were intended to reduce or eliminate RAR activity, and we evaluated the effect of the novel analogues of 7 on IKKbeta activity and proliferation of a variety of cancer cell lines (leukemia, Jurkat; prostate, PC-3; breast carcinomas, T47D, MDA-MB-468). Consistent with the design principles, the biological activities of these AdArs do not appear to be RAR-mediated, since most analogues are unable to activate RAR-mediated transactivation and exhibit significantly diminished antagonist activity. All compounds are capable of inducing apoptosis in Jurkat cells, as demonstrated by elevated DEVDase activity and externalization of phosphatidylserine. Several of the analogues elicit stronger growth inhibitory activity against prostate (PC-3) and breast (MDA-MB-468) carcinoma cells, which contain elevated basal IKK activity; this antiproliferative activity correlates with increased inhibition of recombinant IKKbeta in vitro, suggesting that the anticancer activities of these AdArs might be related to the inhibition of IKK/NFkappaB signaling.
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PMID:Inhibition of IkappaB kinase-beta and anticancer activities of novel chalcone adamantyl arotinoids. 1870 57

Many cancer chemopreventive agents have been associated with lower cancer risk by suppressing nuclear factor-kappaB (NF-kappaB) signaling pathways, which subsequently leads to attenuated pro-inflammatory mediators and activities. Of the natural compounds, the isothiocyanates (ITCs) found in cruciferous vegetables have received particular attention because of their potential anti-cancer effects. However, limited studies regarding the influence of ITCs structure on NF-kappaB transactivation and anti-inflammatory action are reported. In the present study, the anti-inflammatory potential of ten structurally divergent synthetic ITCs were evaluated in HT-29-N9 human colon cancer cells and RAW 264.7 murine macrophages. The effect of ITCs on the basal transcriptional activation of NF-kappaB and the inflammatory response to bacterial lipopolysaccharide (LPS) were assessed. The synthetic ITC analogs suppressed NF-kappaB-mediated pro-inflammatory gene transcription. Among the ITC analogs, tetrahydrofurfuryl isothiocyanate, methyl-3-isothiocyanatopropionate, 3-morpholinopropyl isothiocyanate and 3,4-methyelendioxybenzyl isothiocyanate showed stronger NF-kappaB inhibition as compared to the parent compound, phenylethyl isothiocyanate (PEITC). Molecular analysis revealed that several of the pro-inflammatory mediators and cytokines (iNOS, COX-2, IL-1beta, IL-6 and TNF-alpha) were reduced by ITCs, and correlated with the downregulation of NF-kappaB signaling pathways. Immunoblotting showed that ITCs suppressed LPS-induced phosphorylation and degradation of IkappaB alpha and decreased nuclear translocation of p65. In parallel, ITCs suppressed the phosphorylation of IkappaB kinase alpha/beta (IKKalpha/beta). Taken together, our findings provide the possibility that synthetic ITC analogs might have promising cancer chemopreventive potential, based on their stronger anti-NF-kappaB and anti-inflammatory activities, than the natural ITCs.
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PMID:Anti-NF-kappaB and anti-inflammatory activities of synthetic isothiocyanates: effect of chemical structures and cellular signaling. 1915 19


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