Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human herpesvirus 8 (HHV-8) is considered the causative agent of Kaposi sarcoma, a highly vascularized neoplasm characterized by spindle-shaped cells of endothelial origin and inflammatory cell infiltration. The cell transforming ability of HHV-8 has been associated with the activation of NF-kappaB, a nuclear factor playing a pivotal role in promoting inflammation and cell proliferation; however, little is known about NF-kappaB activation during acute HHV-8 infection. In the present study, we used a recently established in vitro model of HHV-8 acute productive infection in endothelial cells to investigate the effect of HHV-8 on NF-kappaB activity and function. HHV-8 rapidly and potently induced NF-kappaB activity in endothelial cells via stimulation of the IkappaB kinase (IKK). Following IKK activation, HHV-8 selectively triggered the production of high levels of monocyte chemoattractant protein 1 (MCP-1), whereas it did not affect the expression of other NF-kappaB-dependent proinflammatory proteins, including TNF-alpha, IL-8, and RANTES. Deletion of NF-kappaB-binding sites in the MCP-1 enhancer resulted in significant inhibition of HHV-8-induced transcription. Furthermore, MCP-1 production was accompanied by virus-induced capillary-like structure formation at early stages of infection. The results suggest that HHV-8-induced MCP-1 may play an important role in promoting inflammation and pathogenic angiogenesis typical of HHV-8-associated lesions.
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PMID:Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-kappaB pathway. 1713 27

Cystic fibrosis (CF) is characterized by prolonged and excessive inflammatory responses in the lung and increased activation of NF-kappaB. Parthenolide is a sesquiterpene lactone derived from the plant feverfew, which has been used in folk medicine for anti-inflammatory activity. Several studies suggest that this compound inhibits the NF-kappaB pathway, but the exact site is controversial. We hypothesized that parthenolide might ameliorate the excessive inflammatory response in CF models by inhibiting activation of NF-kappaB. This was tested in vitro, using two pairs of cell lines with defective versus normal CF transmembrane conductance regulator (CFTR) (antisense/sense transfected 16 HBE and IB-3/S9), and in vivo, using CFTR-knockout (KO) mice. All cell lines were pretreated with parthenolide and then stimulated with IL-1beta and/or TNF. Parthenolide significantly inhibited IL-8 secretion induced by these cytokines and prevented NF-kappaB activation, IkappaBalpha degradation, and IkappaB Kinase complex activity. CFTR-KO and wild-type mice were pretreated with parthenolide or vehicle alone then challenged intratracheally with LPS. Bronchoalveolar lavage was performed 3, 6, and 8 h later. Parthenolide pretreatment inhibited PMN influx as well as cytokine and chemokine production. This was also associated with inhibition of IkappaBalpha degradation and NF-kappaB activation. We thus conclude that parthenolide inhibits IkappaB kinase, resulting in stabilization of cytoplasmic IkappaBalpha, which in turn leads to inhibition of NF-kappaB translocation and attenuation of subsequent inflammatory responses. IkappaB kinase may be a good target, and parthenolide and/or feverfew might be promising treatments for the excessive inflammation in CF.
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PMID:Parthenolide inhibits IkappaB kinase, NF-kappaB activation, and inflammatory response in cystic fibrosis cells and mice. 1727 24

Many of the healthcare consequences of cigarette smoking could be due to its ability to compromise the immune system, and in respiratory diseases like chronic obstructive pulmonary disease (COPD), a constant low level of infection could be responsible for some of the symptoms/pathology. The aim was to assess the impact of cigarette smoke (CS) on the release of innate effector cytokines in THP-1 cells and human lung macrophages, and to determine the molecular mechanism behind the altered response. Cells were exposed to CS with and without endotoxin stimulus, cytokines, glutathione, mitogen-activated protein kinase (MAPK) phosphorylation, IkappaB kinase-2 (IKK-2) activity, nuclear factor kappa B (NF-kappaB), and activator protein-1 (AP-1) pathway activation was measured. Attempts were made to mimic or block the effect of CS by using nicotine, nitric oxide donors/inhibitors, prostanoid inhibitors, and anti-oxidants. Results showed that CS initially delayed the production of "innate" cytokines (e.g., IL-1beta and IL-6) and reduced glutathione levels. This was associated with a reduction in NF-kappaB pathway activation, which suggested a causative link. CS also increased the phosphorylation of MAPK's and the production of IL-8 but interestingly only in stimulated cells. Exogenous glutathione treatment reversed both these effects of CS, which suggests that this molecule may play a central role. In conclusion, this data provides a novel mechanistic explanation for why smokers have increased prevalence/severity of respiratory infections. In addition, the suppression of the innate response is accompanied by an increase in the neutrophil chemoattractant, IL-8, which may suggest a link to the pathogenesis of smoking-related inflammatory disease.
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PMID:Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages. 1754 58

Activation of nuclear factor (NF)-kappaB is mediated by signal-induced phosphorylation of IkappaBalpha, subsequent IkappaBalpha degradation, and then translocation of unbound NF-kappaB to the nucleus. Termination of gene expression occurs when IkappaBalpha binds NF-kappaB subunits (Rel A) in the nucleus. Leptomycin B specifically inhibits export of IkappaBalpha and the inactive IkappaBalpha/Rel A complex via the nuclear export protein exportin 1. We hypothesized that inhibition of IkappaBalpha nuclear export would increase nuclear IkappaBalpha and attenuate NF-kappaB inflammatory gene expression in pulmonary microvascular endothelial cells. We found that inhibition of exportin 1 causes nuclear accumulation of both endogenous NF-kappaB (Rel A) and IkappaBalpha. IL-1beta causes nuclear accumulation of NF-kappaB (Rel A) but does not increase nuclear IkappaBalpha. Inhibition of exportin 1 before IL-1beta prevented an increase in the nuclear ratio of NF-kappaB (Rel A) to IkappaBalpha and decreases NF-kappaB DNA binding. Furthermore, inhibition of exportin 1 attenuates IL-1beta-induced phosphorylation of IkappaBalpha without affecting IkappaB kinase phosphorylation. Lastly, inhibition of exportin 1 attenuates monocyte chemoattractant protein, IL-8, and intercellular adhesion molecule expression in response to IL-1beta stimulation. We suggest that the decrease in cell activation due to exportin 1 inhibition is a result of termination of NF-kappaB DNA binding due to increased concentration of IkappaBalpha in the nucleus.
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PMID:Exportin 1 inhibition attenuates nuclear factor-kappaB-dependent gene expression. 1769 24

We have already demonstrated that human head and neck cancer cells have significantly enhanced levels of transcription factor nuclear factor (NF)-kappaB activity compared to their normal counterparts, suggesting that NF-kappaB plays an important role in the development of head and neck cancer. However, it has been reported that chemotherapeutic agents and radiation activate NF-kappaB activity in cancer cells, thus making the cells radioresistant and chemoresistant. In addition, we have shown that the suppression of NF-kappaB activity enhanced apoptosis in oral squamous cell carcinoma cells. In this study, we examined whether cepharanthin-induced inhibition of NF-kappaB activity enhances radiosensitivity in human oral carcinoma cells. Cepharanthin is a biscoclaurine alkaloid extracted from the roots of Stephania cepharantha hayata, and is widely used in Japan for the treatment of patients with leucopenia, nasal allergy, and venomous snakebites. gamma-irradiation (IR) induces NF-kappaB activity in oral carcinoma cells through the activation of upstream molecules, including Akt and IkappaB kinase. However, a luciferase assay revealed that cepharanthin suppresses IR-induced NF-kappaB activity in oral squamous cell carcinoma cells, thereby enhancing the radio-sensitivity. Western blot analysis showed an enhanced cleavage of poly-(ADP-ribose) polymerase protein in carcinoma cells by both cepharanthin treatment and IR exposure compared to IR or cepharanthin alone. In an in vivo study, B88 cells were s.c. inoculated into the backs of nude mice. Tumor-bearing nude mice received either cepharanthin, IR alone, or a combination of cepharanthin and IR. The combined treatment suppressed tumor growth significantly more than either cepharanthin or IR alone. Cepharanthin inhibited the production of IR-induced IL-6 and IL-8, which are downstream targets of NF-kappaB. In quantitative real-time RT-PCR, IR also induced the expression of anti-apoptotic proteins [cellular inhibitor of apoptosis protein (cIAP)-1 and -2] in carcinoma cells. Treatment of cancer cells with cepharanthin combined with exposure to IR decreased cIAP-1 and -2 mRNA expression. These findings suggested that the combination of radiotherapy and cepharanthin could enhance radiosensitivity in the treatment of human oral cancer.
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PMID:Cepharanthin-enhanced radiosensitivity through the inhibition of radiation-induced nuclear factor-kappaB activity in human oral squamous cell carcinoma cells. 1778 6

Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analog that is currently in phase II clinical trials as an anticancer agent. We show in this study that R-Roscovitine can downregulate nuclear factor-kappa B (NF-kappaB) activation in response to tumor necrosis factor (TNF)alpha and interleukin 1. Activation of p53-dependent transcription is not compromised when R-Roscovitine is combined with TNFalpha. We characterize the molecular mechanism governing NF-kappaB repression and show that R-Roscovitine inhibits the IkappaB kinase (IKK) kinase activity, which leads to defective IkappaBalpha phosphorylation, degradation and hence nuclear function of NF-kappaB. We further show that the downregulation of the NF-kappaB pathway is also at the level of p65 modification and that the phosphorylation of p65 at Ser 536 is repressed by R-Roscovitine. Consistent with repression of canonical IKK signaling pathway, the induction of NF-kappaB target genes monocyte chemoattractant protein, intercellular adhesion molecule-1, cyclooxygenase-2 and IL-8 is also inhibited by R-Roscovitine. We further show that treatment of cells with TNFalpha and R-Roscovitine causes potentiation of cell death. Based on these results, we suggest the potential use of R-Roscovitine as a bitargeted anticancer drug that functions by simultaneously causing p53 activation and NF-kappaB suppression. This study also provides mechanistic insight into the molecular mechanism of action of R-Roscovitine, thereby possibly explaining its anti-inflammatory properties.
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PMID:R-Roscovitine simultaneously targets both the p53 and NF-kappaB pathways and causes potentiation of apoptosis: implications in cancer therapy. 1797 52

LPS stimulates monocytes/macrophages through the activation of signaling events that modulate the production of inflammatory cytokines. Apigenin, a flavonoid abundantly found in fruits and vegetables, exhibits anti-proliferative and anti-inflammatory activities through poorly defined mechanisms. In this study, we demonstrate that apigenin inhibits the production of proinflammatory cytokines IL-1beta, IL-8, and TNF in LPS-stimulated human monocytes and mouse macrophages. The inhibitory effect on proinflammatory cytokine production persists even when apigenin is administered after LPS stimulation. Transient transfection experiments using NF-kappaB reporter constructs indicated that apigenin inhibits the transcriptional activity of NF-kappaB in LPS-stimulated mouse macrophages. The classical proteasome-dependent degradation of the NF-kappaB inhibitor IkappaBalpha was observed in apigenin LPS-stimulated human monocytes. Using EMSA, we found that apigenin does not alter NF-kappaB-DNA binding activity in human monocytes. Instead we show that apigenin, as part of a non-canonical pathway, regulates NF-kappaB activity through hypophosphorylation of Ser536 in the p65 subunit and the inactivation of the IKK complex stimulated by LPS. The decreased phosphorylation on Ser536 observed in LPS-stimulated mouse macrophages treated with apigenin was overcome by the over-expression of IKKbeta. In addition, our studies indicate that apigenin inhibits in vivo LPS-induced TNF and the mortality induced by lethal doses of LPS. Collectively, these findings suggest a molecular mechanism by which apigenin suppresses inflammation and modulates the immune response in vivo.
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PMID:Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-kappaB through the suppression of p65 phosphorylation. 1798 4

Heat-shock protein 27 (Hsp27) is a member of the small Hsp family that functions as molecular chaperones and protects cells against environmental stress. Hsp27 is expressed in the upper epidermal layers of normal human skin and has been reported to play a role in keratinocyte differentiation and apoptosis. In this investigation, we show an additional role of Hsp27 in the regulation of inflammatory pathways in keratinocytes. Downregulation of Hsp27 using Hsp27-specific small interfering RNA increased prostaglandin E(2) (PGE(2)) production in both unstimulated and tumor necrosis factor-alpha (TNF-alpha)-stimulated keratinocytes. Moreover, downregulation of Hsp27 increased the release of the pro-inflammatory cytokine IL-8 from TNF-alpha-stimulated and UV-irradiated keratinocytes, and this increase was inhibited by pretreatment with the NF-kappaB inhibitor BAY11-7082. Further studies showed that downregulation of Hsp27 resulted in induction of NF-kappaB reporter activity in keratinocytes. This correlated with enhanced degradation of IkappaB-alpha protein and accumulation of phosphorylated IkappaB-alpha in Hsp27 knockdown cells. Moreover, Hsp27 associated with the IkappaB kinase (IKK) complex. As synthesis of the pro-inflammatory cytokine IL-8 and the prostanoid PGE(2) are regulated by NF-kappaB, this could be a probable mechanism by which Hsp27 modulates the production of these inflammatory cytokines. Thus, Hsp27 plays a protective role in regulating inflammatory responses in skin.
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PMID:Hsp27 regulates pro-inflammatory mediator release in keratinocytes by modulating NF-kappaB signaling. 1800 87

Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-kappaB pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-kappaB activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IkappaB kinase-2/NF-kappaB activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.
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PMID:Candida albicans triggers activation of distinct signaling pathways to establish a proinflammatory gene expression program in primary human endothelial cells. 1805 90

The chronic inflammation of arterial walls is associated with the development of atherosclerosis. Earlier we reported that avenanthramide (Avn)s-enriched extract of oats (AvnsO) significantly suppressed interleukin (IL)-1beta-stimulated secretion of proinflammatory cytokines, such as IL-6, IL-8, and MCP-1, by human aortic endothelial cells (HAEC). The main objective of the current study was to determine if the mechanism of inhibitory effect of these polyphenols from oats on the expression of proinflammatory cytokines is mediated through modulation of nuclear factor kappaB (NF-kappaB)-dependent transcription. Confluent HAEC monolayers were treated for 24 h with AvnsO, and synthetically prepared Avn-c suppressed IL-beta-stimulated activation of NF-kappaB in a concentration-dependent manner. CH3-Avn-c, a synthetically prepared methyl ester derivative of Avn-c with a high biological potency, significantly and dose dependently decreased mRNA expression and secretion of IL-6, IL-8, and MCP-1 by HAEC as determined by real-time RT-PCR and ELISA, and it inhibited IL-1beta- and TNFalpha-stimulated NF-kappaB activation as determined by a NF-kappaB DNA binding assay and a NF-kappaB luciferase reporter assay. AvnsO and Avn-c as well as CH3-Avn-c also inhibited the NF-kappaB-dependent reporter gene expression activated by TNFR-associated factor 2 and 6 (TRAF2, TRAF6) and NFkappaB-inducing kinase (NIK). CH3-Avn-c also significantly and dose dependently decreased the phosphorylation level of IkappaB kinase (IKK) and IkappaB, and prevented IkappaB degradation as measured by Western blotting. In addition, CH3-Avn-c markedly increased the overall levels of high mass ubiquitin-conjugated protein levels while it mildly inhibited proteasome activity. These observations suggest that Avns, unique polyphenols from oats, decrease the expression of endothelial proinflammatory cytokines at least in part through inhibition of NF-kappaB activation by inhibiting the phosphorylation of IKK and IkappaB, and by suppressing proteasome activity.
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PMID:Avenanthramides, polyphenols from oats, inhibit IL-1beta-induced NF-kappaB activation in endothelial cells. 1806 32


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